Nano Drug Delivery Strategies for the Treatment of Cancers [1 ed.] 0128197935, 9780128197936

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NANO DRUG DELIVERY STRATEGIES FOR THE TREATMENT OF CANCERS

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NANO DRUG DELIVERY STRATEGIES FOR THE TREATMENT OF CANCERS Edited by

AWESH K. YADAV Bhagyoday Tirth Pharmacy College, Sagar, India

UMESH GUPTA Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, India

RAJEEV SHARMA Formulation Scientist, Pharmaceutical Company, Chandigarh, Punjab, India

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-819793-6 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Senior Acquisitions Editor: Rafael E. Teixeira Senior Editorial Project Manager: Pat Gonzalez Production Project Manager: Niranjan Bhaskaran Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India

Dedication I would like to dedicate this book to my father (Mr. Shiv Narayan Yadav) and my mother (Mrs. Maya Yadav), my brother Anand and my sisters Rashmi and Reeta who always motivated me to do better. This book is also dedicated to my wife Archana and my adorable daughters Doorva and Son Darsh. Without their valuable support this book could not have been completed within a year. —Dr. Awesh K. Yadav I would like to dedicate this book to my parents (Lt. Mr. Dayaram and Mrs. Malti Devi Gupta), my brother Rakesh and my sisters Kusum, Rekha, Shashi, Meena, and Seema who always motivated me to do better. This book is also dedicated to my loving wife Namrata (Mini) and my adorable daughters Manu and Peehu, without whose love and sacrifice this was not possible. —Dr. Umesh Gupta I would like to dedicate this book to my beloved family who encouraged and supported me to complete this book. I am indebted to my wife Upasna and daughter Aanya for their immeasurable support and patience, and without whose love and sacrifice this would not have been possible. I also wish to place on record the encouragement I received from friends, seniors (especially Awesh Snr. and Umesh Snr.), juniors, and many well-wishers who have helped in our attempt to produce this book. —Dr. Rajeev Sharma

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Contents 2.4.2 Passive targeting 40 2.4.3 Active targeting 41 2.5 Mechanistic pathways employed by nanoparticles to cross the blood
brain barrier 41 2.5.1 Carrier-mediated transport 41 2.5.2 Receptor-mediated transport 42 2.5.3 Adsorptive-mediated transport 43 2.6 Nanomedicine for the treatment and diagnosis of gliomas 43 2.7 Nanomedicine for the diagnosis of brain cancers 43 2.7.1 Magnetic resonance imaging 44 2.7.2 Raman scattering and computed tomography imaging 45 2.7.3 Nanoparticles as carriers of fluorescent dyes for imaging tumors 45 2.7.4 Nanoparticles as fluorescent agents for tumor imaging 48 2.8 Nanomedicine for the treatment of brain cancer 51 2.8.1 Metal nanoparticles 51 2.8.2 Liposomes 56 2.8.3 Polymeric nanoparticles 58 2.8.4 Dendrimers 60 2.9 Nanomedicines for brain cancer using a combinatorial approach 60 2.9.1 Combination of magnetic resonance imaging and therapy 61 2.9.2 Combination of optical imaging and therapy 63 2.9.3 Combination of multimodal imaging and therapy 63 2.10 Future perspectives and challenges 64 2.11 Conclusion 65 Acknowledgment 66 Abbreviations 66 References 67

List of contributors xiii Preface xv 1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment 1 Laxmikant Gautam, Anamika Jain, Priya Shrivastava, Sonal Vyas and Suresh P. Vyas

1.1 Introduction 1 1.2 Conventional therapies for the treatment of cancer 2 1.2.1 Role of surgery for cancer treatment 2 1.2.2 Role of radiotherapy for cancer treatment 5 1.2.3 Role of chemotherapy in cancer treatment 6 1.3 Novel approaches for the treatment of cancer 8 1.3.1 Lipid-based nanomedicines 8 1.3.2 Polymer-based nanomedicines 20 1.3.3 Miscellaneous nanocarriers 25 1.4 Conclusion 27 Acknowledgment 27 References 27

2. Nanomedicine: future therapy for brain cancers 37 Shagufta Haque, Caroline Celine Norbert and Chitta Ranjan Patra

2.1 Introduction 37 2.2 Global statistics of brain cancers 38 2.3 Major drawbacks and circumstances in brain tumors 39 2.4 General strategy of nanoparticles for the treatment of brain cancers 40 2.4.1 Physical properties 40

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3. Nano drug delivery strategies for the treatment and diagnosis of oral and throat cancers 75 Sandra J. Perdomo, Angela Fonseca-Benı´tez, Andre´s CardonaMendoza, Consuelo Romero-Sa´nchez and Jenny Pa´rraga

3.1 Oral and throat cancers 75 3.1.1 Conventional therapies for the management of oral cancers 75 3.1.2 Cisplatin 76 3.1.3 5-Fluorouracil 76 3.1.4 Paclitaxel/docetaxel 76 3.2 Transport barriers to drug delivery in head and neck tumors 77 3.3 Nanotechnology in head and neck cancer detection and diagnosis 78 3.3.1 Nano-based molecular imaging 79 3.3.2 Nanotechnology-based drug delivery systems for the treatment of head and neck cancer 88 3.4 Conclusion 97 References 97

4. Nanoparticles and lung cancer

107

Sudha Vengurlekar and Subhash Chandra Chaturvedi

4.1 Introduction 107 4.1.1 Cause, molecular target 108 4.1.2 Traditional therapies for treatment 108 4.1.3 Shortcomings with existing treatments 109 4.2 Nanotechnology and lung cancer 110 4.2.1 Organic nanoparticles for lung cancer 111 4.2.2 Inorganic nanoparticles for lung cancer 112 4.2.3 Natural or biomaterials as nanoparticles 113 4.2.4 Other novel nanoparticles systems for lung cancer 114 4.3 Conclusion 115 References 116

5. Nanoparticles and liver cancer Mohammad Bayat and Davood Ghaidari

5.1 Introduction

119

119

5.2 Drug delivery to the liver with nanoparticles 120 5.3 Cellular uptake in vitro 124 5.4 Antitumor efficacy in vivo 126 5.5 Doxorubicin and lovastatin co-delivery liposomes 128 5.5.1 Anticancer activity 129 5.5.2 Histological analysis 130 5.6 Gold nanoparticles 130 5.6.1 Gold nanoparticle thermal therapy 132 5.6.2 Mechanism 134 5.6.3 Antitumor effect in vivo 138 5.7 Toxicity 139 5.8 Conclusion 140 References 140

6. Nanoparticles and pancreas cancer 145 Akanksha Malaiya, Dolly Jain and Awesh K. Yadav

6.1 Introduction 145 6.2 Physiology of pancreatic cancer 145 6.3 Current scenario and epidemiology of pancreatic cancer 146 6.4 Treatment of pancreatic cancer 147 6.5 Mechanism of nanoparticle uptake in pancreatic cancer 148 6.6 Receptor for targeting pancreatic cancer 149 6.6.1 Epidermal growth factor receptor 149 6.6.2 CD44 receptor 149 6.6.3 Folate receptor 150 6.6.4 Transferrin receptor 150 6.6.5 Vascular endothelial growth factor 150 6.7 Characterization techniques 151 6.8 Nanocarrier systems in the treatment of pancreatic cancer 151 6.8.1 Nanoparticles 151 6.8.2 Liposomes 155 6.8.3 Carbon nanotubes 157 6.8.4 Dendrimer 157 6.8.5 Micelles 158 6.8.6 Nanogel 158 6.8.7 Quantum dots 159 6.9 Conclusion 159 References 160

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7. The role of nanoparticles in the treatment of gastric cancer 165 Kuldeep Rajpoot and Sunil K. Jain

7.1 Introduction 165 7.2 Nanoparticles in the imaging of gastric cancer 166 7.2.1 Nanoparticles in systemic imaging 167 7.2.2 Other ways of imaging 170 7.3 Nanoparticles in the detection of tumors 172 7.3.1 Nanoparticles in the early detection of gastric cancer via endoscopy 172 7.3.2 Nanoparticles in the detection of gastric cancer using biomarkers 173 7.3.3 Nanoparticles in the detection of circulating tumor cells in gastric cancer 173 7.4 Nanoparticle-based therapy of gastric cancer 174 7.4.1 Chitosan nanoparticles 174 7.4.2 Polymeric nanoparticles 175 7.4.3 Silver nanoparticles 177 7.4.4 Gold nanoparticles 178 7.4.5 Magnetic nanoparticles 178 7.4.6 Carbon nanotubes 178 7.4.7 Photodynamic therapy 179 7.4.8 Miscellaneous 179 7.5 Conclusion 179 Disclosure statement 180 Abbreviations 180 References 181

8. Nanoparticles and colon cancer

191

Priya Shrivastava, Rajeev Sharma, Laxmikant Gautam, Sonal Vyas and Suresh P. Vyas

8.1 Introduction 191 8.2 Molecular biology of colon cancer 193 8.2.1 Adenoma
carcinoma sequence 193 8.2.2 Genetic mutations 194 8.2.3 Biomarkers 194 8.3 Conventional treatment options for colon cancer and their limitations 203 8.3.1 Surgical resection 203 8.3.2 Radiation therapy 204 8.3.3 Chemotherapy 204 8.3.4 Targeted therapy 204 8.3.5 Immunotherapy 206

8.4 Nanoparticles: the modern trends in the treatment of colon cancer 206 8.4.1 pH-responsive nanoparticles 207 8.4.2 Liposomes 208 8.4.3 Polymeric nanoparticles 209 8.4.4 Solid lipid nanoparticles 213 8.4.5 Metallic nanoparticles 213 8.4.6 Magnetic nanoparticles 214 8.4.7 Viral nanoparticles 215 8.4.8 Polymeric micelles 216 8.4.9 Hydrogel 216 8.4.10 Polymerosomes 217 8.4.11 Carbon nanotubes 217 8.5 Conclusion 218 Acknowledgment 218 Conflict of interest 219 References 219

9. Treating blood cancer with nanotechnology: A paradigm shift 225 Chinmay Thakur, Pallavi Nayak, Vijay Mishra, Mayank Sharma and Gaurav K. Saraogi

9.1 9.2 9.3 9.4 9.5 9.6

Introduction 225 Cancer statistics 226 Blood cancer 226 Types of blood cancer 228 Pathophysiology of blood cancer 228 Therapies for blood cancer 229 9.6.1 Gene therapy 229 9.6.2 Chemotherapy 229 9.6.3 Immunotherapy 230 9.6.4 Radiation therapy 230 9.6.5 Advancements in blood cancer treatment 231 9.7 Nanotechnology in treatment of cancer 231 9.7.1 Nanoparticles 233 9.7.2 Drug
protein conjugation 234 9.7.3 Liposomes 234 9.7.4 Polymeric nanoparticles 234 9.7.5 Dendrimeric nanoparticles 235 9.7.6 Quantum dots 235 9.7.7 Carbon nanotubes 235 9.7.8 Metal nanoparticles 235 9.7.9 Silver nanoparticles 236 9.7.10 Gold nanoparticles 236 9.7.11 Mesoporous silica nanoparticles 236 9.7.12 Properties of nanocarriers 236

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9.8 Challenges and remedies in the treatment of leukemia 237 9.8.1 Challenges 237 9.8.2 Biological barriers 237 9.8.3 Reticuloendothelial system 237 9.8.4 Renal system 238 9.8.5 Remedies 238 9.9 Diagnosis of blood cancer 239 9.9.1 Current theranostic approach 239 9.9.2 Recent and ongoing clinical trials 240 9.10 Regulation aspects of nanotechnology-based tools 241 References 241

10. Nanoparticles and skin cancer

245

Vishal Gour, Poornima Agrawal, Vikas Pandey, Indu Lata Kanwar, Tanweer Haider, Rahul Tiwari and Vandana Soni

10.1 Introduction 245 10.2 Classification of skin cancer 247 10.2.1 Nonmelanoma skin cancer 248 10.2.2 Malignant melanoma 248 10.3 Pathogenesis of skin cancer 248 10.3.1 Ultraviolet radiation 248 10.3.2 Immunosuppression and organ transplant recipients 249 10.3.3 Human papillomavirus 250 10.4 Detection of skin cancer 250 10.5 Skin cancer treatment modalities 251 10.5.1 Curettage and electrodesiccation 251 10.5.2 Cryotherapy 251 10.5.3 Photodynamic therapy (PDT) 253 10.5.4 Radiation therapy 253 10.5.5 Hedgehog pathway inhibitors 253 10.5.6 Nonbiologics 254 10.5.7 Synthetic chemotherapeutic agents 254 10.5.8 Natural-origin bioactives 256 10.5.9 Photosensitizers 258 10.5.10 Miscellaneous products 259 10.5.11 Biologics 259 10.6 Nanocarriers as a potential tool for effective treatment of skin cancer 259 10.6.1 Nanoparticles 259 10.7 Conclusion 264 References 264

11. Nanoparticles and prostate cancer 275 Ashish Garg, Sweta Garg and Nitin Kumar Swarnakar

11.1 Introduction 275 11.1.1 Cancer 275 11.1.2 Prostate gland and prostate cancer 275 11.2 Nanotechnology 278 11.3 Drug delivery 279 11.3.1 Drug targeting toward tumor cells 280 11.3.2 Active and passive targeting 280 11.4 Routes of drug delivery to the prostate 281 11.4.1 Systemic route 281 11.4.2 Locoregional route 283 11.5 Classification of nanoparticle systems for prostate targeting 285 11.5.1 Liposomal nanoparticles in prostate cancer 285 11.5.2 Albumin-bound system 286 11.5.3 Polymeric nanoparticle systems for cancer treatment 287 11.5.4 Carbon-based system 289 11.5.5 Dendrimeric platform 289 11.5.6 Quantum dot device 290 11.5.7 Gold nanoparticulate system 290 11.5.8 Metallic nanoparticle platform 292 11.5.9 Nanocolloidal 295 11.6 Treatment for prostate cancer: nanotechnology and prostate cancer 295 11.6.1 Nanochemoprevention of prostate cancer 297 11.6.2 Treatment of prostate cancer via gene delivery with nanomaterials 298 11.6.3 Treatment of prostate cancer via cancer immunotherapy with nanomaterials 300 11.7 Nanotechnology approach and prostate cancer diagnosis 301 11.7.1 Nanotechnologies for fluorescence diagnosis of prostate cancer 302 11.7.2 Targeted prostate-specific antigen nanoprobe for imaging prostate cancer 303 11.7.3 Targeted prostate-specific membrane antigen nanoprobes for imaging prostate cancer 303

Contents

11.8 Conclusion References 304

303

12. Nanomedicine-based multidrug resistance reversal strategies in cancer therapy 319 Rishi Paliwal, Shivani Rai Paliwal and Rameshroo Kenwat

12.1 Introduction 319 12.2 Multidrug resistance in cancer therapy: a brief account 320 12.3 Mechanisms of multidrug resistance in cancer cells 320 12.3.1 Overexpression of P-glycoprotein efflux proteins 320 12.3.2 Xenobiotics 321 12.3.3 Tumor suppressor genes 321 12.3.4 Hypoxia 322 12.3.5 Autophagy 322 12.4 Novel strategies to combat multidrug resistance in cancer therapy 322 12.5 Nanomedicine-based multidrug resistance reversal strategies 322

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12.6 Multidrug resistance in cancer therapy: the case of doxorubicin 323 12.7 Multidrug resistance reversal of doxorubicinloaded nanomedicines 325 12.7.1 Nanomedicine coloaded with small interfering RNA and doxorubicin 325 12.7.2 Nanomedicine coloaded with P-gp efflux inhibitors and doxorubicin 329 12.7.3 Nanomedicine coloaded with Dα-tocopherol polyethylene glycol 1000 succinate and doxorubicin 331 12.7.4 Miscellaneous approaches 333 12.8 Conclusion 335 12.8.1 Grant support 335 Abbreviations 336 References 336

Index 341

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List of contributors Poornima Agrawal Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India

Scientific and Innovative Research (AcSIR), Ghaziabad, India

Mohammad Bayat Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran

Anamika Jain Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India

Andre´s Cardona-Mendoza Cellular and Molecular Immunology Research Group (INMUBO), Universidad El Bosque, Bogota´, Colombia

Dolly Jain Drug Delivery and Nanotechnology Laboratories, Department of Pharmaceutics, Bhagyoday Tirth Pharmacy College, Sagar, India

Subhash Chandra Chaturvedi Sri Aurobindo Institute of Pharmacy, Indore, MP, India

Sunil K. Jain Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India

Angela Fonseca-Benı´tez Cellular and Molecular Immunology Research Group (INMUBO), Universidad El Bosque, Bogota´, Colombia Ashish Garg Department of P.G. Studies and Research in Chemistry and Pharmacy, Rani Durgavati University, Jabalpur, India Sweta Garg Department of P.G. Studies and Research in Chemistry and Pharmacy, Rani Durgavati University, Jabalpur, India Laxmikant Gautam Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India Davood Ghaidari Department of Chemistry, Faculty of Science, University of Guilan, Rasht, Iran Vishal Gour Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India Tanweer Haider Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India Shagufta Haque Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; Academy of

Indu Lata Kanwar Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India Rameshroo Kenwat Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India Akanksha Malaiya Drug Delivery and Nanotechnology Laboratories, Department of Pharmaceutics, Bhagyoday Tirth Pharmacy College, Sagar, India Vijay Mishra School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India Pallavi Nayak School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India Caroline Celine Norbert Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India Suresh P. Vyas Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India

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List of contributors

Rishi Paliwal Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India

Gaurav K. Saraogi NMIMS, School of Pharmacy and Technology Management, Shirpur, India

Shivani Rai Paliwal SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur, India

Rajeev Sharma Formulation Scientist, Pharmaceutical Company, Chandigarh, Punjab, India

Vikas Pandey Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India

Priya Shrivastava Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India

Jenny Pa´rraga Biomaterials and Tissue Engineering group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

Mayank Sharma NMIMS, School of Pharmacy and Technology Management, Shirpur, India

Vandana Soni Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India

Chitta Ranjan Patra Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

Nitin Kumar Swarnakar Scientist III at BASF, Tarrytown, NY, United States

Sandra J. Perdomo Cellular and Molecular Immunology Research Group (INMUBO), Universidad El Bosque, Bogota´, Colombia

Rahul Tiwari Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India

Kuldeep Rajpoot Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India

Sudha Vengurlekar Sri Aurobindo Institute of Pharmacy, Indore, MP, India

Consuelo Romero-Sa´nchez Cellular and Molecular Immunology Research Group (INMUBO), Universidad El Bosque, Bogota´, Colombia

Chinmay Thakur NMIMS, Pharmacy and Technology Shirpur, India

School of Management,

Sonal Vyas Bundelkhand Medical College & Hospital, Sagar, India Awesh K. Yadav Drug Delivery and Nanotechnology Laboratories, Department of Pharmaceutics, Bhagyoday Tirth Pharmacy College, Sagar, India

Preface Cancers, Nanoparticles and Brain Cancers, Nanoparticles and Mouth and Throat Cancer, Lactoferrin Based Nanocarriers for Cancer Therapy and Imaging, Nanoparticles and Lung Cancer, Nanoparticles and Liver Cancer, Nanoparticles and Pancreatic Cancer, Nanoparticles and Stomach Cancer, Nanoparticles and Colon Cancer, Nanoparticles and Blood Cancer, Nanoparticles and Skin Cancer, An Update in Drug Targeting Nanostrategies to Improve Cancer Treatment, Molecular Targets for Nanomedicine Based MDR Reversal Strategies in Cancer Therapy. Each chapter discusses an introduction of cancer, development, current status of nano drug delivery system containing anticancer drug, and future prospects of the concerned nano drug delivery system with a particular cancer type. We hope the book shall be a useful compilation for undergraduate, postgraduate, doctoral students, and researchers working in drug delivery research, research and development, and national research institutes. We hope to receive feedback, suggestions, and inputs from teachers, researchers and students that will help improve the next edition of the book.

Nano drug delivery system(s) refer to strategies and the development of such delivery vehicles that can be safely administered within body as needed for optimum therapeutic benefits while ensuring minimum to nil toxic effects. Various methods have been used to construct nanocarriers to deliver the encapsulated drug to cancer cells directly. The development of such carriers modifies the anticancer drug accumulation and distribution thus producing the best possible therapeutic effects to the cancerous cells. Nano drug delivery by various drug delivery systems has emerged as a commanding technology for the treatment of various cancers. However, most of the techniques lack differentiation between cancerous and normal cells with associated loss of life. Anticancer drugs have a lot of limitations and reaches to cancerous cells in a limited concentration. To conquer such limitations researchers have prepared various target-specific nanoparticles to treat cancers. The book contains 13 chapters including, Introduction: An Overview of the Anatomy and Physiology of Different Cancers, Novel Treatment Approaches and Conventional Therapies for Effective Treatment to

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C H A P T E R

1 Emergence of novel targeting systems and conventional therapies for effective cancer treatment Laxmikant Gautam1, Anamika Jain1, Priya Shrivastava1, Sonal Vyas2 and Suresh P. Vyas1 1

Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India 2Bundelkhand Medical College, Sagar, India

1.1 Introduction The World Health Organization clearly state in its report of 2018 that cancer is the second leading cause of death in the world, and it is assumed that it would increase exponentially to reach 12 million deaths per year by 2030 (Siegel, Miller, & Jemal, 2019). In developing and developed countries, a major cause of death is cancer due to bad habits (smoking tobacco, etc.) (Saadat et al., 2015). For the treatment of cancer, the therapeutic approaches used include chemotherapy, radiation, and surgery. Most of the time, combination therapy is applied to get the desired outcome and avoid resistance during cancer therapy. In cancer treatment, extensive heterogeneity in terms of response to drugs and drug resistance of melanomas are major impediments. The overexpression of antiapoptotic proteins and the emanation of anticancer drugs from cancer cells result in chemoresistance (Dry, Yang, & Saez-Rodriguez, 2016; Gandhi, Tekade, & Chougule, 2014; Xu et al., 2016). Although significant attempts have been made by researchers in the development of effective cancer therapies such as radiation, chemotherapy, surgery, immunotherapy, novel targeted approaches, or combinations of these approaches (Jain et al., 2018), the survival rate still remains quite low because the causes of cancer are still unknown. The survival rate and prognosis of cancer patients can be improved by early diagnosis at the early stages of cancer so that timely and effective treatment can be extended (Gautam & Anamikajain, 2019). Hence there is an urgent need for the development of improved alternative diagnostics and therapeutic strategies and interventions. The aim of these analyses of causes is to

Nano Drug Delivery Strategies for the Treatment of Cancers DOI: https://doi.org/10.1016/B978-0-12-819793-6.00002-3

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© 2021 Elsevier Inc. All rights reserved.

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

explore effective therapeutic opportunities to improve and increase the normal life span of cancer patients. Some of the conventional treatment procedures are described here for the treatment of cancer: • Primary treatment: By using this treatment cancer cells are removed from the body or destroyed completely. In every type of cancer, overgrowth surgical removal is the most accepted method used in primary treatment. If patients are sensitive to the other types of treatments such as radiation therapy or chemotherapy then surgery remains a good option. • Neoadjuvant or adjuvant treatment: The aim of this therapy is to kill those cancer cells that remain after the primary treatment, which can grow as a skipped lesson. Lai et al. worked on cancer in which miRNA was used as an adjuvant to increase the efficacy of small molecular inhibitor oncogenes (Lai, Eberhardt, Schmitz, & Vera, 2019). In clinical practice, in order to make primary treatment accessible, neoadjuvant therapy is given; for example, Lynn et al. report that in HER2-positive early breast cancer, an adjuvant treatment is given, which consisted of pertuzumab in combination with trastuzumab and chemotherapy (Howie et al., 2019). • Palliative treatment: Palliative treatments may be given at any stage of cancer treatment, which may help to control or reduce the side effects of cancer treatments, including pain, shortness of breath, and toxicity (de Man et al., 2019). The critical analysis of these methods suggests that treatment strategies are largely dependent on the stage and type of cancer. The analysis further suggests that some patients need single treatment, while in most cases, a combination of treatments is beneficial in the later stages of cancer as reported in patent no. US10301290B2 (Keilhack, Knutson, & Kuntz, 2019). Thus surgery, chemotherapy, radiation therapy, immunotherapy, hormone therapy, targeted drug therapy, etc., or a combination of any of these may be used for the treatment of cancer. In the present scenario, novel drug delivery approaches are being invented, targeted at different molecular targets such as the nucleus, mitochondria, cytoplasm, or endoplasmic reticulum for the effective treatment of cancer (Haider, Tiwari, Vyas, & Soni, 2019).

1.2 Conventional therapies for the treatment of cancer 1.2.1 Role of surgery for cancer treatment Surgery is a medical branch that constitutes one of the treatment methods of cancer and that surgically removes cancer with the help of instruments. Surgery can involve cutting, abrading, suturing, or the management of acute illnesses and injuries as extricated from slowly progressing and chronic diseases. 1.2.1.1 Types of surgery There are different types of surgery as shown in Fig. 1.1 and described here: • Curative surgery: The removal of a tumor from the body is known as curative surgery; radiation may be used before and/or after this surgery. This type of treatment is often

Nano Drug Delivery Strategies for the Treatment of Cancers

1.2 Conventional therapies for the treatment of cancer

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FIGURE 1.1 Various types of surgery.

considered as a primary form of treatment. Parker et al. reported that through the use of curative surgery in rural Kenya, the survival rate of colorectal cancer patients increased (Parker et al., 2020). In another research work, Liu et al. showed the clinical significance of curative surgery in skin lymph node metastasis in pN1 gastric cancer patients, which resulted in increased survival times (Liu, Deng, et al., 2019). • Preventive surgery: Preventive surgery is used to remove tissue that does not contain cancer cells, but may subsequently develop into a malignant tumor. For example, ipsilateral and contralateral breast cancer BRCA1 mutation, which is an age-specific risk is reduced by preventive surgery (Lubinski et al., 2019). Another preclinical study showed the preventive effect of surgical intervention in the recurrence of colon cancer (Majumdar, 2019). • Diagnostic surgery: Diagnostic surgery is used to determine whether cells are cancerous; diagnostic surgery is extremely helpful. In this surgery, samples can be studied by different testing methods; for example, MRI (esophageal cancer) (Vollenbrock et al., 2019)

Nano Drug Delivery Strategies for the Treatment of Cancers

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

or CT and MRI (gallbladder cancer) (de Savornin Lohman et al., 2019). The analysis will confirm which stage or type of cancer is present in a given sample. Staging surgery: In this surgery, the extent of the disease or cancer in the body is uncovered. For example, endometrial cancer (Watson et al., 2019), esophageal cancer (Patel et al., 2019), prostate cancer (Nandurkar et al., 2019), or gastric cancer by 18F-FDG PET-CT (Findlay et al., 2019), etc. Debulking surgery: This type of surgery is used to remove a portion of a cancerous tumor. It is used in certain situations when removing an entire tumor may cause damage to an organ or the body. As per the research, this method of surgery is mostly used in ovarian carcinoma (Ceppi et al., 2019; Heitz et al., 2019; Manning-Geist et al., 2019; Song & Gao, 2019), etc. Palliative with supportive surgery: Palliative surgery is used to treat cancer at advanced stages. It does not cure cancer, but is used to relieve discomfort or to correct other problems related to cancer. Also, another type of surgery helps with palliative surgery, which is a supportive surgery by nature. An example of supportive surgery is the insertion of a catheter to help with chemotherapy. Restorative surgery: Restorative surgery is sometimes used as a followup to curative or other surgeries to change or restore a person’s appearance or the function of an impaired body part. For example, women with breast cancer sometimes need breast reconstruction (plastic) surgery to restore the physical shape of the affected breast(s). Curative surgery for oral cancer can cause a change in the shape and appearance of a patient’s mouth. Restorative surgery may be applied to address these visible deformations.

There are several specialized surgeries that are used for cancer treatment. A list of some of these surgical treatments is provided here: Cryosurgery: This surgery technique essentially involves the use of low temperatures to kill cancer cells. It is mainly used for skin cancer (Collins, Savas, & Doerfler, 2019), breast cancer (Pusceddu, Paliogiannis, Nigri, & Fancellu, 2019), pancreatic cancer (Zemskov et al., 2019), lung cancer (Kumar, Upadhyay, & Rai, 2019), and prostate cancer (Marra et al., 2019), etc. Laser surgery: This technique uses beams of light energy instead of instruments to remove extremely small cancerous growths without destroying surrounding healthy tissue or to activate drugs to kill, shrink, or destroy tumors. Examples include thyroid cancer (Jiang, Solbiati, Zhan, & Mauri, 2020), glottic cancer (Rodrigo et al., 2019), prostate cancer (Greenwood et al., 2019), cervical cancer (Zhu, Wang, Pang, & Zhang, 2019), penile cancer (Shkolyar et al., 2019), gynecological cancer (Athanasiou et al., 2020), etc. Electrosurgery: In this type of surgery, an electric current (radio frequency) is applied to increase focused and localized heat that kills cancer cells. This surgery is used to treat skin cancer (Collins et al., 2019), lung cancer (Zhang, Zheng, et al., 2019), ovarian cancer (Nieuwenhuyzen-de Boer et al., 2019), etc. Microscopically controlled surgery: This surgery is useful when cancer affects parts of the body that are delicate and located deep in the body such as the eye. Skin layers are removed and analyzed. An example is basal cell carcinomas (Peters, Schubert, Geppert, & Moehrle, 2019; Peters, Schubert, Metzler, Geppert, & Moehrle, 2019), etc.

Nano Drug Delivery Strategies for the Treatment of Cancers

1.2 Conventional therapies for the treatment of cancer

5

1.2.1.2 Risk and side effects of surgery in cancer treatment Every procedure of cancer treatments suffers some risk. In the case of cancer treatment, it is important to learn about the types and stages of the cancer in question. Though science and medical technology have made surgery a safe and reliable treatment option, there is always a risk of potential problems and side effects. In many cases, however, the positive effects of surgery outweigh the risks. There may be some problems during surgery, including blood loss, damage to vital organs of the body, and adverse reactions. Some problems may occur after the surgery, including discomfort or pain, infections, and other illnesses such as blood loss or circulatory clot formation. The procedure of surgery in the treatment of cancer is risky. The application of surgery in the treatment of cancer provides a safe and reliable treatment option.

1.2.2 Role of radiotherapy for cancer treatment Intense energy is generated by radioactive substances such as platinum, osmium, cobalt, or by functionalized equipment such as an atomic particle (linear) accelerator. Radiation conversely destroys cells that split rapidly and that encounter difficulty in repairing their DNA. Shi et al. studied that combining targeted therapies with radiation is beneficial for patients with lung cancer (Shi, Shao, Jiang, & Huang, 2016). Stereotactic body radiation therapy (SBRT) applied in pancreatic cancer showed late toxicity (Moningi et al., 2015). 1.2.2.1 Principles of radiation therapy In this therapy, the cancer cells have been destroyed by using the source of energy. The radiation used is called ionizing radiation because it forms electrically charged particles or rays (γ, X-rays, UV rays, etc.,), and this energy can enter into and kill cancer cells or cause genetic changes, finally killing the bombarded cells (Fig. 1.2). 1.2.2.2 Some types of radiation therapy For the treatment of cancer, different types of radiation therapies are used in different types of cancers, which include stereotactic ablative body radiotherapy for lung cancer (Phillips, Sandhu, Lu¨chtenborg, & Harden, 2019), volumetric modulated arc therapy for neck and head cancer (Leung, Wu, Liu, & Cheng, 2019), 3D conformal radiotherapy for rectal cancer (Luna & de Torres Olombrada, 2019), external beam radiation therapy (EBRT) for osteosarcoma (Tolomeo et al., 2019), image-guided radiotherapy (Shah, Agarwal, et al., 2020) for prostate cancer (Jereczek-Fossa et al., 2019), intensity-modulated radiation therapy for cervical cancer, etc. (Lin et al., 2019). EBRT is most commonly used (Tajaldeen, Ramachandran, Alghamdi, & Geso, 2019). In this process, a beam of electromagnetic radiation energy, that is, gamma rays or X-rays are generated by a linear accelerator and targeted (focused) at the cancer site. Christopher et al. indicated the use of EBRT by which prostate-specific antigen after neoadjuvant androgen suppression in prostate cancer patients, receiving short-term androgen suppression (Hallemeier et al., 2019). McDonnell et al. reported that long-term use of EBRT on patients suffering from tracheobronchial amyloidosis is well tolerated and many patients exhibited significant symptomatic improvement (McDonnell, Funk, Foote, Kalra, & Neben-Wittich, 2019).

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

FIGURE 1.2 Role of radiation in targeting carriers for the treatment of cancer.

1.2.3 Role of chemotherapy in cancer treatment Cell autonomous genetic disease further converts into cancer as a consequence of alterations in tumor suppressor genes, genome stability genes, and oncogenes. Different treatments for cancer are used alone or in combination (Zitvogel, Apetoh, Ghiringhelli, & Kroemer, 2008). Chemotherapy is one of the three most conventional methods for oncological treatment, together with radiotherapy and surgery. Other treatments such as hormone therapy and immunotherapy can also be used in the case of certain types of cancer (Baskar, Lee, Yeo, & Yeoh, 2012). The use of chemotherapy for cancer treatment started in the 20th century with attempts to narrow the multitude of chemicals that might affect the disease by developing methods to screen chemicals using transplantable tumors in rodents (DeVita & Chu, 2008). It was, however, for World War II-related programs, and the effects of the drugs that evolved from them provided the impetus to establish, in 1955, the national drug development effort known as the Cancer Chemotherapy National Service Center (Bud, 1978). 1.2.3.1 Principles of cancer treatment by chemotherapy Chemotherapy uses chemicals to kill or inhibit malignant cells without much affecting the host cells (Alam et al., 2018). All cytotoxic chemotherapeutic agents exert their effects by disrupting the cell cycle by one or more mechanisms (Diakos, Charles, McMillan, & Clarke, 2014). Drugs that inhibit pathways involved in cell growth have been developed.

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Cancer cells differ from normal cells by their ability to grow and survive (Brown & Attardi, 2005). Acquired mutations to protooncogenes and tumor suppressor genes promote cell division because the normal cell cycle checkpoints are lost. The cells become insensitive to growth-inhibitory signals and evade programmed cell death (Harrington, 2011). Drugs used in chemotherapy cause cell death by apoptosis, either by directly interfering with DNA or by targeting the key proteins required for cell division. Unfortunately, they can also be “cytotoxic” to normal dividing cells, particularly those with a high turnover such as the bone marrow and mucous membranes (Dickens & Ahmed, 2018). Chemotherapeutics are classified in one of two ways, that is, by their cell cycle effects or by their biochemical properties. Classifying them by their cell cycle specificity is useful because it influences how drugs are scheduled and combined for maximal effect (Fernando & Jones, 2015). 1.2.3.2 Indications for chemotherapy • Palliative: Palliative chemotherapy can often significantly improve symptoms and overall quality of life. Palliative chemotherapy improves survival in some cancer types. Clinical trials of palliative chemotherapy are focused on overall survival and improving response rates without significantly increasing toxicity (Glimelius et al., 1995; Karavasilis et al., 2008). • Curative: A number of cancers are extremely sensitive to cytotoxic chemotherapy. Testicular tumors, lymphomas, acute leukemias, and many pediatric malignancies respond so well that chemotherapy may be curative even in extensive disease. If chemotherapy is given with a curative intent, short-term toxicity is considered more acceptable and, therefore, many of these treatments are extremely toxic (e.g., high-dose chemotherapy) (Frei, 1985). • Adjuvant: Many patients may be cured of their disease after surgery or primary radiotherapy, but many others relapse and die due to micrometastatic disease that is undetected at the diagnosis level. Chemotherapy may be an adjunct to primary therapy to kill micrometastases. Adjuvant chemotherapy is used routinely in the treatment of breast cancer (Rampurwala, Rocque, & Burkard, 2014; Saurel, Patel, & Perez, 2010). • Neoadjuvant: The aim of neoadjuvant therapy is to treat micrometastases not visible with conventional imaging. It may also reduce the size of tumors, permitting surgery or allowing for a less radical procedure to be done. Examples include neoadjuvant therapy in breast cancer, enabling women to undergo a wide local excision rather than a mastectomy; it is also used routinely in the management of esophageal cancers and osteosarcomas (Abdel-Bary, El-Kased, & Aiad, 2009). Resistance to chemotherapy is one of the main reasons for treatment failure, and in any given tumor type, there are usually a combination of different mechanisms that contribute to drug resistance; examples include reduced delivery of cytotoxic agents to the cell, decreased drug uptake, decreased drug activation, increased drug efflux, alteration in target protein, increased DNA repair, increased drug metabolism, and detoxification (Johnstone, Ruefli, & Lowe, 2002; Luqmani, 2005). Although there are strategies under development to reverse drug resistance, currently, the only realistic choice for clinicians is

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

to switch to an alternative cytotoxic drug or a combination. The absence of a valid alternative normally results in the cessation of chemotherapy and switching to symptomatic control (Caley & Jones, 2012).

1.3 Novel approaches for the treatment of cancer 1.3.1 Lipid-based nanomedicines 1.3.1.1 Liposomes Liposomes are bilayer structures made up of phospholipids that have the capacity to deliver both hydrophilic and hydrophobic drugs as payloads. Liposomes are lipid-based nanocarriers that were introduced by Bangham et al. in 1965. It has also been reported that univalent cations and anions spontaneously diffuse out from the liquid crystal of lecithin, similarly to how small ions cross the cell membrane in a biological system (Alavi, Karimi, & Safaei, 2017). Liposomes emerge as potential drug carriers for the delivery of therapeutics to their target sites, which is particularly important in cancer therapy due to their ability to decrease the side effects of anticancer drugs and improve the efficacy. A major drawback associated with anticancer drugs is their toxicity to both normal and cancer cells; however, this can be minimized by designing active and passive targeting. Anticancer efficacy can be enhanced by increasing the accumulation of liposomes at the target site (Yingchoncharoen, Kalinowski, & Richardson, 2016). Advantages of the use of liposomes as drug carriers are (Jain et al., 2018): • Liposomes are biocompatible in nature. • Due to the amphiphilic properties of phospholipids, liposomes can encapsulate hydrophilic drugs in their core and lipophilic drugs in their lipid layer and are considered to be versatile drug carriers. • Surface modification with PEG enhances the circulation time in the bloodstream. • Targeting ligands associated with liposomes may specifically target tumor sites. Ikemoto et al. reported the use of Bauhinia purprea agglutinin (BPA)-PEG-modified liposomes encapsulating doxorubicin for the treatment of prostate cancer. BPA is a lectin, which recognizes galactosyl glycoproteins and glycolipids on cancer specimens. After i.v. injection into DU145 solid cancer
bearing mice, it was observed that BPA-PEG-LP accumulated preferentially at cancer tissue and efficiently attached to prostate cancer tissue. BPA-PEG-LP-DOX considerably decreased DU145 cancer cell growth, while at the same dose, PEG-LP-DOX was less effective. Thus it could be an effective drug carrier for the treatment of prostate cancer (Ikemoto et al., 2016). Petrilli et al. used cetuximab, an antiepidermal growth factor receptor (EGFR) antibody with 5-fluorouracil (5-FU) for the treatment of squamous cell carcinoma (SCC). The coadministration of an antibody (cetuximab) with an anticancer drug (5-FU) allows for the selective delivery of therapeutics to cancer cells. In vitro cell uptake studies revealed that the cellular uptake of cetuximab
immunoliposomes by EGFR-positive cells was 3
5 times greater than that of plain liposomes. In vivo studies suggested that this formulation decreased the tumor volume by more than 60% as compared to the negative control and

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9

by 50% when the 5-FU solution and plain liposome treatments were used. Additionally, iontophoresis increased the reduction of the tumor volume by twice as compared to the subcutaneous delivery of the 5-FU solution and plain liposomes. Histopathological studies reveal that subcutaneous administration iontophoresis of formulation is efficacious than for decreasing cell proliferation. Thus topical delivery of cetuximab
immunoliposomes incorporating 5-FU via iontophoresis is an effective strategy for the treatment of SCC (Petrilli et al., 2018). Liposomal nanodrugs exhibit excellent results in preclinical and clinical experiments in cancer patients; various liposomal nanodrugs have been exploited as nanomedicine for cancer. Feng et al. conjugated the anticancer drug cisplatin with phospholipid along with other lipids. By doping with lipophilic dye (1,10 -dioctadecyl-3,3,30 ,30 -tetramethyl indotricarbo cyanine iodide; DiR) with near IR absorbance and fluorescence, the resulting DiR
cisplatin liposomes have been established as effective probes for bimodal imaging. DiR
cisplatin liposomes exhibit an increased therapeutic efficacy when combined with photothermal chemotherapy. Liposomal carriers, thus, have emerged as efficient carriers for proteins as well as small hydrophilic molecules. The prodrug-based approach with tunable drug compositions, passive uptake, and simultaneous loading of different types of diagnostic and imaging agents makes this strategy attractive (Feng et al., 2016). Some liposomal formulations for cancer treatment are listed in Table 1.1. 1.3.1.2 Niosomes Niosomes have a bilayer structure similar to that of liposomes that additionally contains nonionic surfactants in an aqueous phase. They are biodegradable, nonimmunogenic, biocompatible, show greater stability, have a long shelf life, and can deliver a therapeutic to its target site in a sustained manner. Different types of nonionic surfactants are utilized for the formation of niosomes such as alkyl ether, alkyl esters, alkyl amide, fatty alcohols, etc. (Ag Seleci, Seleci, Walter, Stahl, & Scheper, 2016). Niosomal drug delivery systems offer various advantages over conventional systems such as allowing for a reduction of dose due to their targeting mechanism, thereby decreasing the exposure of therapeutics to normal cells. Water-based vehicles are used in the preparation of niosomes, which exhibit better patient compliance as compared to oilbased systems. The oral bioavailability of a given drug is also enhanced by delaying systemic clearance and providing protection to the drug upon oral absorption from the biological environment. Niosomes are osmotically active and enhance the stability of drugs. Controlled release can be obtained using niosomes due to their vesicles, which act as a depot preparation, and thus, release the drug in a sustained manner; also niosomes are biocompatible, nonimmunogenic, biodegradable, and do not require any special storage conditions (Khan & Irchhaiya, 2016). Kulkarni et al. developed tamoxifen- and doxorubicin-loaded self-assembled niosomes for breast cancer treatment. The entrapment efficiencies of tamoxifen and doxorubicin were found to be 74.3% and 72.7% respectively. Drug release studies revealed that the drugs were released in a sustained manner for up to 3 years. Cytotoxicity studies on an MCF-7 cell line revealed a 15 times improvement (0.01 mg/mL) and a greater synergistic effect of the formulation as compared to the plain drug combination (0.15 mg/mL).

Nano Drug Delivery Strategies for the Treatment of Cancers

TABLE 1.1 Various liposomal formulations and their targets. S. No.

Drug

Formulation

Type/targeting organ

Receptor

Comments

References

1.

Doxorubicin

pH-responsive polymeric liposomes

Cancer immune therapy

Matrix PD-L1 inhibitor metalloproteinases

Optimal tumor suppression efficiency and enhanced antitumor effect.

Liu, Chen, Yang, Qiao, and Wang (2019)

2.

Doxorubicin

Dual pH-sensitive liposomes

Breast cancer

Glucosedependent insulin-tropic polypeptide receptor

MDA-MB-435S cells taken for ex vivo studies.

Zhai (2019)

3.

Paclitaxel

Liposome

Ligand

Polypeptide DVar7

Increased encapsulation efficiency and good in vitro stability.

Pancreatic cancer gp60 Albumin Albumin receptor/caveolin1 pathway

Subcutaneously inoculated with AsPC1 cell and administered intravenously.

Okamoto et al. (2019)

High accumulation on tumor site. 4.

siRNA and Paclitaxel

Polyethyleneiminemodified liposomes

Ovarian cancer

Sulfated proteoglycans

Polyethyleneimine
HeLa, SKOV3-TR and A2780phospholipid AD xenograft model. The protein adsorption of the system acts as a shield against macrophage uptake, facilitates cellular biocompatibility, and prevents multidrug resistance.

5.

Doxorubicin and erlotinib

Dual functionalized liposome

Brain tumor

Transferrin receptor

Transferrin and penetrating

U87, bEnd.3, and glial xenograft model. Excellent bioavailability and significant increase in survival rate.

6.

Daunorubicin and dioscin

Liposome

Nonsmall cell lung cancer

Matrix PFVYLI (PFV) cellmetalloproteinase- penetrating peptide 2, vascular endothelial cadherin

A549 xenograft model. Cellular uptake significantly increased due to PFV. Negligible systematic toxicity.

Mendes, Sarisozen, Luther, Pan, and Torchilin (2019)

Lakkadwala, dos Santos Rodrigues, Sun, and Singh (2019) Wang, Fu, et al. (2019)

7.

5-Fluoro uracil and doxorubicin

Vesosome-containing liposome

Cervical cancer







HeLa cell line was used. Increased antitumor therapeutic effect by encouraging the massive necrosis of tumor cells.

Zhang, Zong, et al. (2019)

Synergistic effect observed. 8.

RNAi

Liposome

Breast cancer







MDA-MB-231, MFC-10A, MCF-7 cell lines.

Rocha et al. (2019)

Provides high stability and permanence of RNAi in circulation. 9.

Daunorubicin plus honokiol

Cationic liposome

Breast cancer

CD44 receptor

Hyaluronic acid

MCF-7 and MDA-MB-435S cell lines.

Ju et al. (2018)

Electrostatic adsorption and destroyed vasculogenic mimicry channels by the incorporation of honokiol. 10.

11.

12.

Doxorubicin

Paclitaxel

Bevacizumab monoclonal antibody

Dual-functional liposomes

Multifunctional liposomes

Ovarian cancer

Transferrin receptor (transmembrane single-chain glycoprotein)

Cancer stem cells CD34, CD133 in malignant glioma

Nano Pancreatic cancer VGFR photoactivatable liposome

Transferrin and octa-arginine

A2780, NIH-3T3, CCD 27 SK cell lines. Dual-functional targeting; passive targeting by octaarginine and active targeting by transferrin.

Cysteine-modified octa-arginine

Benzoporphyrin derivative

C6 stem cells. High targetability and exhibited an efficient inhibition effect on vasculogenic mimicry. AsPC1 cells. Enhanced the extra- and intracellular delivery of bevacizumab. Enhanced tumor reduction.

Deshpande, Jhaveri, Pattni, Biswas, and Torchilin (2018) Liu et al. (2015)

Tangutoori et al. (2016)

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

Thus niosomes appear to have potential in the treatment of breast cancer (Kulkarni & Rawtani, 2019). Pawar et al. prepared an N-lauryl glucosamine
anchored doxorubicin niosomal formulation in which a glucose transporter was used as a targeting ligand. The N-lauryl glucosamine was synthesized and incorporated into doxorubicin-loaded niosomes using cholesterol as a membrane stabilizer, Span 60 as a surfactant, and diacetyl phosphate as a stabilizer. The formulation exhibits a 110 6 5 nm particle size, a 230 6 5 mV zeta-potential, and a 95% entrapment efficiency. The niosomal formulation was more cytotoxic with an IC50 value of 0.830 ppm as compared to the nontargeted formulation with an IC50 value of 1.369 ppm in B6F10 melanoma cell lines. In vitro studies suggested that the targeted niosomal formulation was selectivity internalized and showed a greater retention time as compared to the nontargeted niosomal formulation and free doxorubicin. Hence the NLG-anchored niosomal formulation of doxorubicin was more cytotoxic with a receptor binding potential and internalization, thus, seeming to be a promising strategy for cancer therapy (Pawar & Vavia, 2016). Other examples of niosomal formulations used for cancer treatment are listed in Table 1.2. 1.3.1.3 Ethosome There are various drawbacks associated with oral drug delivery such as the degradation of therapeutics by gastrointestinal tract enzymes, first-pass metabolism, and irritation in gastric mucosa, while the pain associated with parental drug delivery systems limit their uses. Hence transdermal drug delivery systems are preferred by patients. Ethosomes are interesting, preferred, innovative drug delivery systems. Drugs with poor penetration ability through the skin can be delivered using ethosomes. Basically ethosomes are ethanolic liposomes that are composed of lipid vesicles having phospholipids; the alcohol used may be ethanol or isopropyl alcohol in high concentrations. The unique structure of ethosome is due to the high concentration of ethanol with an alcohol concentration of 20%
30%. Phosphatidyl choline, phosphatic acid, alcohol, water, phosphatidyl inositol, and hydrogenated phosphatidyl choline are some phospholipids that are used in the preparation of ethosome (Jaiswal, Kesharwani, Kesharwani, & Patel, 2016). 1.3.1.3.1 Ethosomal drug delivery systems showed various benefits

As compared to transdermal and dermal drug delivery systems, ethosomal drug delivery systems possess various advantages such as (Chauhan, Pandey, Joshi, Dubey, & Jain, 2018): • Large molecules such as peptides and proteins can be delivered via this route. • Penetration and permeation of drugs are enhanced when delivered through the skin. • Patient compliance is enhanced due to it being administered either in a gel or cream form. • Different physicochemical characteristics are shown by drugs entrapped within ethosomes. • Ethosomes are composed of nontoxic raw materials. Jain et al. prepared ethosomes loaded with a carbopol hydrogel formulation for transdermal delivery. They screened various carbopols (C71, C934, C974, C941, and C971), out of which, C934, C974, and C971 grades were selected and used further for their flow and

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1.3 Novel approaches for the treatment of cancer

TABLE 1.2 Various niosomal formulations for cancer treatment.

S. No.

Drug

Formulation

1.

Lawsone and Hinna extract

Niosome

Type/ targeting organ Breast cancer

Comments

References

MCF-7 cell line

Barani, Mirzaei, TorkzadehMahani, and Nematollahi (2018)

Increased drug solubility Sustained release and cytotoxicity significantly increased Good carrier for phytoconstituents

2.

3.

siRNA and Octadecylamine thymoquinone conjugated multilamellar gold niosome

Breast cancer

Curcumin

Cervical cancer

Folic acid conjugated

Akt overexpressed the MCF-7 cell line Enhanced apoptosis by inducing p53 and inhibiting MDM2 expression HeLa229 cell line Effective targeting toward the site

4.

Doxorubicin, Cationic niosome quercetin, and siRNA

Gastric, AGS, PC3, MCF-7, HFF cell lines prostate, Synergistic antitumor effect breast cancer cells

5.

Artemether

Breast cancer

6.

7.

8.

Nanoniosomes

Tamoxifen and doxorubicin

Niosome

Tamoxifen

Niosome

Silibinin

Nanoniosome

Rajput et al. (2015)

Breast cancer

Breast cancer Breast cancer

4T1 cell line The slow rate of angiogenesis and proliferation of tumor cells cut down the tumor volume and increased the tumor necrosis MCF-7 cell line Localized action increased due to the synergistic effect of the drug MCF-7 cell line Increased the percent of apoptosis T47D cell line Fall off in miR-21, miR-15a, and miR-141, although showed an increase in miR-200c expression levels

You, Liu, Fang, Xu, and Zhang (2019) Hemati et al. (2019)

Mirzaei-Parsa et al. (2019)

Kulkarni and Rawtani (2019)

Shah, Khalid, et al. (2019) Yazdi Rouholamini et al. (2018)

viscoelastic properties. The ethosomal formulation loaded with the C974 hydrogel in concentrations of 0.50% and 0.75% w/w respectively exhibited considerable plastic flow with different yield stress and relatively frequency independent elastic (G0 ) and viscous (Gv). In vitro, skin permeation studies revealed that the ethosome loaded with the C974

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

TABLE 1.3 Various ethosomal formulations for cancer treatment. Type/targeting organ

Comments

References

Sodium cholate and polyethylenimine modified ethosome

Melanoma

B16 cell line

Ma et al. (2019)

Binary ethosomes

Skin cancer

S. No.

Drug

Formulation

1.

Doxorubicin and curcumin

Fisetin

2.

Transdermal delivery, effective to overcome MDR

Rat skin Better penetration, significant downfall of the level of inflammatory cytokines TNF-α and IL-1α

3.

Moolakkadath et al. (2019)

Nasr et al. (2019)

Ferrous Ethosome and chlorophyllin nanocarriers

Squamous cell carcinoma

A-431 cell line

4.

Curcumin and paclitaxel

Ethosome

Melanoma skin cancer

High release profile, effective targetability

Kollipara, Tallapaneni, Sanapalli, Kumar, and Karri (2019)

5.

Paclitaxel

Pegylated ethosome

Melanoma

SK-MEL-3 cell line

Eskolaky, Ardjmand, and Akbarzadeh (2015)

Photodynamic therapy used for iron detection at local site

4.5-Fold increases cytotoxicity

hydrogel with a 0.5% w/w concentration of polymer showed a comparable permeability through the skin. Thus C974 allows for a high permeation of diclofenac and acts as a potential vehicle system for ethosomal vesicles (Jain, Patel, Madan, & Lin, 2016). In another study by Jin et al., eugenol-entrapped ethosome nanoparticles (ELG-NPs) were prepared. ELG-NPs were optimized with 0.5% eugenol, 2% lecithin, and 30% ethanol. The nanoparticles were 44.21 nm in size with an 82% entrapment efficiency. This formulation showed antibacterial activity ( . 93%) against fruit pathogens, which was higher than the free eugenol. Permeability studies revealed that eugenol delivered transdermally with ethosome nanoparticles was 6 times greater than free eugenol. Slow-release and prolonged antibacterial action were achieved through the use of ELG-NPs. Thus this seems to be a potential strategy with wide applications such as in cosmetic, agricultural, food, and medical areas (Jin, Yao, Qin, Chen, & Du, 2019). Some ethosomal formulations and their results are shown in Table 1.3. 1.3.2.4 Transferosome Transferosomes are used for transdermal drug delivery systems; they are a special variation of liposomes that contain phosphatidyl choline and an edge activator. They penetrate the stratum corneum transcellularly or via an intracellular route through the generation of

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an osmotic gradient. Transferosomes possess various benefits such as being biocompatible, having a wide range of solubilities, greater penetration, and being biodegradable, etc. The transferosomes are applied in the transportation of large molecular weights compounds, transdermal immunization, controlled release and targeted delivery to the peripheral subcutaneous tissue, etc.(Solanki, Kushwah, Motiwale, & Chouhan, 2016). 1.3.2.4.1 Characteristics of transferosomes

The ideal transferosomes should possess certain characteristics, including (Chaurasia, Singh, Arora, & Saxena, 2019): • The ability to be modified by tapered squeeze without caliper loss. • They have their own bases, which are expressed by the deliquescent and aquaphobic tribes. • The superior twisted afford to allow to administer the whole cyst. • The vermicular cyst has the assured greater magnitude adaptable as compared to liposomes. Hadidi et al. prepared bovine lactoferrin
loaded transferosomal vesicles for the transdermal delivery of the treatment for genital warts. Lactoferrin is a member of the transferrin family, which shows antiviral activity against human papillomavirus. The transferosomes were prepared by two methods, that is, reverse-phase evaporation and thin-film hydration methods using cholesterol, lecithin, DOTAP, SDS, Tween 80. These exhibited a 100 nm size with a 91% entrapment efficiency. In vitro studies revealed that the IC50 value of transferosomal lactoferrin was low as compared to the free lactoferrin (Hadidi, Saffari, & Faizi, 2018). Kumar et al. prepared acyclovir-loaded transferosome to increase the penetration through the skin. The acyclovir transferosomes were optimized and a carbopol 934 gel base was used to carry the transferosomes. The gel was evaluation for viscosity, pH, in vitro penetration, and spreadability. The prepared formulation showed a greater entrapment efficiency ranging from 65% to 81% with smaller particle sizes, that is, from 181.9 to 401.8 nm. An in vitro release study revealed that there is an inverse relationship between entrapment efficiency and in vitro release. The release profile follows the Korsmeyer
Peppas model. Thus acyclovir incorporated in transferosomes can penetrate deeper into the skin (Kumar, Nayak, & Ghatuary, 2019). Some transferosomal formulations and their results are shown in Table 1.4. 1.3.2.5 Nanoemulsion A nanoemulsion is a biphasic dispersion of two immiscible liquids, either oil in water (o/w) or water in oil (w/o), that is stabilized by a surfactant. It forms an ultrafine dispersion having unique characteristics such as differential drug loading, visual properties, and viscoelastic properties. The mean droplet diameter of nanoemulsions is generally less than 500 nm. A clear or hazy appearance is obtained with a small droplet size, while a milky white appearance occurs with a coarse emulsion. A nanoemulsion can be sometimes interchanged with a mini or submicron emulsion, but it should not be mixed with a microemulsion. Nanoemulsions are classified based on their constituents and the relative

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1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

TABLE 1.4 Various transferosome formulations for cancer treatment. Type/targeting organ Comments

S. No.

Drug

Formulation

1.

5-Fluorouracil

Carbopolbased transferosome gel

Skin cancer

Transferosome gel

Skin cancer

2.

Embelin

Effective permeability of gel in skin layers

References Khan et al. (2015)

Less hyperkeratosis and mild acanthosis compared to marketed formulation Herbal formulation showed good result

Jain and Jain (2017)

High drug entrapment efficiency 3.

Carvedilol

Transferosome

Skin cancer

SKH-1 hairless mice were used for the activity

Chen (2019)

Photoprotection by UV light 4.

Indocyanine green

Transferosome

Basal cell carcinoma

Fadel, Samy, High penetration potential (drug reached the dermal layer) Nasr, and Alyoussef (2017) Effective in topical delivery over conventional therapy

5.

Apigenin

Transferosome

Skin cancer

Optimization was done by Box
Behnken design The skin of hairless mice (Swiss albino mice)

6.

Thiophenyl sulfonated zinc phthalocyanine

Transferosome

Hepatocellular carcinoma

HepG2 cell line Effective as compared to liposome

Jangdey, Gupta, Saraf, and Saraf (2017)

Fadeel et al. (2018)

distribution of the internal dispersed phase. They can be termed as biphasic (o/w or w/o) or multiple nanoemulsions (w/o/w) (Singh et al., 2017). Shanmugapriya et al. formulated a nanoemulsion of astaxanthin and α-tocopherol with Sodium caseinate using spontaneous emulsification and ultrasonication for the production analysis of intracellular reactive oxygen species (ROS) in apoptosis. Both astaxanthin and α-tocopherol have the potential to induce ROS synthesis in the cytosol, ER, and mitochondria. Nanoemulsions exhibit high stabilities with small sizes and zeta-potential of spherical droplets with faster cell penetration and lesser toxicity. This type of formulation exhibits considerably high therapeutic effects against cancer. Thus it may be a potential way to eradicate cancerous cells and seems to a promising strategy (Shanmugapriya, Kim, & Kang, 2019). In another study by Fei et al., a doxorubicin-containing nanoemulsion was prepared for the treatment of pancreatic cancer. Three pancreatic cancer cell lines, namely PANC-1, MIA PACA-2, and BxPC-3 were used, and cells were treated with free doxorubicin and

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1.3 Novel approaches for the treatment of cancer

17

doxorubicin-loaded nanoemulsions. The uptake studies of the different formulations were evaluated by fluorescence microscope and flow cytometer. Sulforhodamine B (SRB) assay was used to evaluate the cytotoxicity of the formulations. The uptake studies were further evaluated by the pretreatment of cells with inhibitors such as chlorpromazine (inhibits clathrin-mediated endocytosis), nystatin (depletes cholesterol and affects rafts), cytochalasin D (inhibits caveolin-mediated endocytosis), and amiloride (inhibits micropinocytosis). The uptake of the doxorubicin in the nanoemulsions was 1.4-fold, 1.2-fold, and 1.2-fold greater in the PANC-1, BxPC-3, and MIA PACA-2 cell lines respectively. The IC50 value of the free doxorubicin is 1.3 μM. The IC50 value in the case of doxorubicin in the targeted nanoemulsion was 0.3 μM, while in the nontargeted nanoemulsion it was 0.6 μM. Inhibitors did not cause a significant effect on the doxorubicin uptake in the nontargeted and targeted nanoemulsions. Thus it seems to be a good strategy for the treatment of pancreatic cancer (Fei, O’Barr, & Lambros, 2018). Some nanoemulsion formulations and their results are shown in Table 1.5. 1.3.2.6 Solid lipid nanoparticles Various limitations are associated with traditional formulations such as biocompatibility, safety, and toxicity, and to overcome these limitations, lipid-based drug delivery systems have been introduced. As compared to liposomes, SLNs are advantageous in terms of the prevention of the chemical degradation of drugs and their flexibility in altering the release of drugs. SLNs have unique properties such as high drug loading, drug protection from the surrounding environment, enhanced bioavailability, and increased surface area. SLNs have great potential for site-specific drug delivery, controlled drug delivery as well as gene delivery (Dolatabadi, Valizadeh, & Hamishehkar, 2015). Solid lipid nanoparticles consist of triglycerides, in which polar heads are arranged to form a polar crown toward the aqueous phase; this arrangement is quite similar to chylomicron. Thus this self-assembled system provides help for lymphatic transport and the absorption of therapeutics via the GIT tract. SLNs have been reported to increase the oral bioavailability of many drugs (Gautam & Anamikajain, 2019). Liu et al. formulated the paclitaxel (PTX) and α-tocopherol succinate-cisplatin prodrug (TOS-CDDP)-loaded SLNs of the trans-activating transcriptional activator (TAT) for the treatment of cervical cancer. The formulations were synthesized by the solvent evaporation and emulsification methods. In vitro studies suggested that the formulation was successfully internalized by HeLa cells and provided synergistic action for the suppression of cancer cell growth. The formulation showed superior antitumor efficiency, lower toxicity in vivo, and greater tumor tissue accumulation. Thus it can be a potential strategy for the codelivery of therapeutics for the treatment of cervical cancer (Liu et al., 2017). Erlotinib-loaded SLNs were prepared by Bakhtiary et al. for the treatment of nonsmall cell lung cancer (NSCLC). Erlotinib is available in oral dosage form; thus, the local delivery of tyrosine kinase inhibitors to lung cells enhances its therapeutic potential. The researchers prepared an SLN formulation for dry powder inhalation using compritol or poloxamer 407. The SLNs were of a spherical shape with a size of 100 nm and a 78.21% entrapment efficiency. MTT assay and 40 ,6-diamidino-2-phenylindole (DAPI) staining studies showed that the SLNs increased the cytotoxicity of the drug in human alveolar adenocarcinoma epithelial A549 cells as a model for NSCLC. This formulation exhibited

Nano Drug Delivery Strategies for the Treatment of Cancers

TABLE 1.5 Various nanoemulsion formulations for cancer targeting. S. No.

Drug

Formulation

1.

Perfluorocarbon and siRNA

Nanoemulsion

Type/targeting organ Lung metastatic osteosarcoma

Receptor

Comments

References

Chemokine receptors (C-X-C receptor type)

Tumor proliferation and angiogenesis by CXCR4 antagonism and STAT3 silencing.

Li, Shen, et al. (2019)

Good siRNA delivery. This overcomes the immunosuppressive tumor microenvironment as suggested by the decrease of MDSCs and Tregs.

2.

3.

Decitabine (DAC) and Panobinostat

Lipid Breast cancer nanoemulsions

Astaxanthin and α-tocopherol with sodium caseinate

Nanoemulsions Cancer cells via mitochondrialmediated apoptosis

Lysophosphatidic acid receptor 1 (LPAR1)




CDH1 2 /FOXM1 1 triple negative cell line. DAC/PAN-LNEs were efficient in downregulating the growth of mesenchymal breast cancer cells by rehabilitating CDH1/E-cadherin and suppressing forkhead box M1 (FOXM1) expression. Epithelial breast cancer cells expressing low FOXM1 and high CDH1 were unaffected by DAC/PAN-LNEs. HT-29 and AGS cell lines. Effective thermodynamic stability and nontoxic at low concentrations.

Kim, Pena, and Auguste (2019)

Shanmugapriya et al. (2019)

Significant intracellular ROS generation and apoptosis induction in cancer cells. 4.

Perfluoro-hexane

Nanoemulsion

Breast cancer

5.

Docetaxel

Theranostic nanoemulsion

Ovarian cancers

MCF-7 cell line. Fourfold greater targeting by ultrasound bubble. Folate receptor

Theranostic property by gadolinium.

Fernandes and Kolios (2019) Patel et al. (2018)

NCI-60-, KB-WT-, and paclitaxel-sensitive and KBPR-10- and paclitaxel-resistant cells were used. Functional targeting of folic acid was evaluated against FR-α KB cells and results showed significant improvement in cell guild.

6.

Chlorine6

Magneto lowdensity nanoemulsion

Breast cancer

Overexpressed low-density lipoprotein receptors

MCF-7 and NHI-3T3 cell lines and citrate-coated iron oxide nanoparticle were used.

Pellosi, Macaroff, Morais, and Tedesco (2018)

7.

Quercetin

Plam-based aerosol nanoemulsion

Lung cancer

Epidermal growth factor receptor

Good viscosity, conductivity, osmolality, and pH values.

Arbain, Basri, Salim, Wui, and Rahman (2018)

1.3 Novel approaches for the treatment of cancer

19

better flowability and aerodynamic properties. Other measurements such as next-generation impactor, Carr’s index, and the Hausner ratio indicated the deep inhalation pattern of the SLNs. Thus these findings suggest that ETB-SLN DAPI could be a promising strategy for the treatment of NSCLC (Bakhtiary et al., 2017). 1.3.1.7 Nanostructured lipid carriers Nanostructured lipid carriers (NLCs) are second-generation lipid carriers, which were developed to overcome the drawbacks of SLNs. NLCs have superior characteristics as compared to other lipid formulations. NLCs are crystallized lipid particles that have sizes below 100 nm that are dispersed into the aqueous phase, which contains an emulsifier. The use of NLCs as a delivery system offers various advantages as compared to other colloidal carriers. NLCs have a high drug loading of hydrophobic as well as hydrophilic drugs, high encapsulation efficiency, and improved stability (Salvi & Pawar, 2019). NLCs offer various advantages including (Jaiswal, Gidwani, & Vyas, 2016): • Improved physical stability and enhanced dispersibility in aqueous media. • Encapsulation of both hydrophilic and hydrophobic drugs is possible with a high entrapment efficiency. • Particle size can be controlled, hence, NLCs are considered to be suitable for pulmonary delivery. • Skin occlusion can be increased by the use of NLCs. • Extended-release of drugs can be obtained by NLCs. • NLCs can penetrate the stratum corneum due to the small size of lipid particles. • NLCs are suitable for drugs that are applied via the topical route due to having lipid components that are used commercially in pharmaceutical preparations or topical cosmetics. Hajipour et al. developed arginyl-glycyl-aspartic acid (RGD)-containing NLCs for the treatment of breast cancer. They prepared RGD-containing epigallocatechin gallate (EGCG)-loaded NLCs using the hot homogenization method. The particle size of the NLCs was 85 nm with a zeta-potential of 221 mV and an 83% entrapment efficiency. Apoptosis and cytotoxicity studies revealed that the EGCG-loaded NLC-RGD exhibited greater apoptotic activity and this formulation arrested the cell cycle more effectively than EGCG. Hence the loading of the EGCG onto the NLC-RGD increases the targeting as well as the accumulation of the formulation in cancer cells. Thus the strategy can improve the therapeutic outcome of EGCG (Hajipour et al., 2018). Li et al. prepared pH-sensitive ApoB-100/oleic acid-DOX/NLC (AODN) nanoparticles based on NLCs for the treatment of cancer. The composition of these NLCs was similar to low-density lipoprotein (LDL), which can enhance the targeting efficiency of nanoparticles. Simultaneously, the doxorubicin prodrug was used to enhance the drug loading and to modulate the release. In vitro studies reported that these nanoparticles were more phagocytosed by LDL receptor-mediated endocytosis and, therefore exhibited greater cytotoxicity in 4T1 cells. In vivo studies demonstrated that the NLCs accumulated at tumor sites, decreasing the systemic toxicity. Thus the findings suggested that by combining the bionics and prodrug strategies better results can be obtained (Li, Fu, et al., 2019).

Nano Drug Delivery Strategies for the Treatment of Cancers

20

1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

1.3.1.7.1 Nanosuspension Some nanosuspension formulations and their results are shown in Table 1.6.

1.3.2 Polymer-based nanomedicines 1.3.2.1 Carbon nanotubes Carbon nanotubes (CNTs) are generally barrel-shaped (cylindrical) molecules consisting of a single layer of rolledup sheets of carbon atoms (graphene) in a smooth cylinder that can be open-ended or capped, having a high aspect ratio with a diameter as small as 1 nm and a length of several micrometers. They can be used as nanocarriers. They can be singlewalled with a diameter of less than 1 nm, while several concentrically interlinked nanotubes constitute multiwalled nanotubes with diameters reaching more than 100 nm. Their length may exceed several micrometers or even millimeters (Yu, Tan, Zheng, Tan, & Zheng, 2016). Since Iijima’s discovery in 1991, there has been great interest in these carbon allotropes because of their distinctive physicochemical characteristics. CNTs are chemically bonded with sp2, a linkage which is considered to be a highly strong form of molecular interaction. These features provide an opportunity to design ultrahigh strength, low molecular weight materials possessing highly electrical and thermal properties. These potential applications in a broad spectrum of areas, ranging from sensors and electronic devices to nanocomposite materials of low weight and high strength, opened the way for bio-applications of CNTs. Drug delivery systems based on CNTs are promising strategies in the treatment of cancer. Harsha et al. (2019) designed and developed a pegylated system based on CNTs that is an explorative nanomedicine for the treatment of brain cancer cells. In this study, the authors synthesized a polyethylene glycol linked conjugate of CNTs with mangiferin. A cytotoxicity assay and cell uptake studies were conducted on U87 cell lines. In vitro studies revealed that at the cancer cell pH, a spatiotemporal pattern of release of mangiferin was observed. From the cytotoxicity study, it was noted that there was a 1.28-fold reduction in the IC50 value, suggesting an effective anticancer activity, while the hemolysis profile established safety. Cell uptake studies showed that the nanoconjugate had effective apoptosis induction with minimum necrosis. The pharmacokinetic data revealed a 4 times increase in the area under curve (AUC). Hence it can be concluded that these surface-modified nanocarrier systems are capable of safe and effective delivery of phytochemicals to brain cancer cells (Harsha et al., 2019). Prajapati, Jain, Shrivastava, and Jain (2019) reported an multiwalled carbon nanotubes (MWCNTs) ligand conjugate for targeting colon cancer. The author developed hyaluronic acid (HA)-conjugated MWCNTs loaded with gemcitabine (GEM). HA was conjugated on the surface of aminated or pegylated MWCNTs. A drug release study demonstrated that under acidic conditions (pH 7.3), the release rate of GEM was more rapid than under the physiological conditions (PBS, pH 7.4), and it showed a sustained release pattern. The prepared formulations showed considerably less hemolytic toxicity (7.73% 6 0.4%) compared to the plain drug (18.71% 6 0.44%). The formulations demonstrated greater cytotoxicity against HT29 cells (colon cancer cell line). An antitumor activity assay revealed that the developed formulation significantly regressed the tumor volume compared to plain GEM, and as a

Nano Drug Delivery Strategies for the Treatment of Cancers

21

1.3 Novel approaches for the treatment of cancer

TABLE 1.6 Various nanosuspension formulations for cancer treatment. S. No.

Drug

1.

19-tertNanosuspension Butyldiphenylsilyl8,17-epoxy andrographolide

2.

Formulation

Naringenin (NAR)

D-α-Tocopheryl

Type/targeting organ

Colorectal cancer HCT116 cancer cell line Chitosan acted as a stabilizer, influence the cell growth inhibition Breast cancer

polyethylene glycol succinate 1000 (TPGS) polymeric nanosuspension (NARNS)

3.

Genistein BIO 300

4.

5.

Synthetic genistein nanosuspension

Comments

MCF-7 cell line was used. Reverse drug resistance of P-gpoverexpression was observed

References Kansom et al. (2019)

Rajamani, Radhakrishnan, Sengodan, and Thangavelu (2018)

Colorimetric assay explained higher cytotoxic efficacy of NARNS, also showed dose-dependent in vitro cancer activity Prostate cancer

PC3 or LNCaP PCa cells Jackson et al. (2019) The role of BIO 300 in blocking RiED and inhibiting tumor growth was observed

Paclitaxel-betulinic Hybrid acid nanosuspensions

Breast cancer

MCF-7 cell line was used. Paclitaxel promoted the polymerization of tubulin and betulinic acid inhibited the viability and migration of cancer cells

Wang, Yang, et al. (2019)

Curcumindocetaxel

Breast cancer

MCF-7 cell line

Sahu et al. (2016)

Nanosuspension

High tumor inhibition rate of up to 70% in MCF-7 treated mice Reduced level of angiogenesis

result, enhanced the survival rate. In vivo studies revealed an improvement in the pharmacokinetic parameters such as AUC, area under the moment curve (AUMC), and mean survival time in tumor carrying rats treated with drug-loaded HA conjugated MWCNTs as compared to plain GEM (P , .0001). From these results, it can be concluded that MWCNTs are a safe and efficacious nanomedicine for targeting colon cancer (Prajapati et al., 2019).

Nano Drug Delivery Strategies for the Treatment of Cancers

22

1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

1.3.2.2 Dendrimers Dendrimers are synthetic, highly branched, three-dimensional, polymeric macromolecules arranged in a well-organized framework of nanometric size. These nanocarriers are highly complex molecules with a core, branches, and end groups. They are characterized by three components, namely an outer surface with functional surface groups, an interior dendritic structure (the branches), and a central core. The linked surface functional groups influence the solubility and chelation ability and also promote the attachment of targeting moieties and other bio-recognizable motifs, which increase therapeutic effectiveness. While, the varied cores confer capture release features, absorption capacity, and unique properties to the cavity size. Dendrimers represent a significant part of the polymers used in the delivery of bioactives and nanomedicines. These distinctive polymers have many chemical branches that are extended outwardly to facilitate the attachment of bioactive payloads. The void space between the dendritic branches could be utilized to entrap bioactives. The distinctive dendritic properties make it possible for reactive reagents to be presented on the surface, making them available for biological interactions. They can be built from molecular level to nanoscale size (1
10 nm) (Yang, 2016). Some dendrimer formulations and their results are shown in Table 1.7. Several applications of dendrimers having nanoscale size reported in the literature include the delivery of bioactive having, energy harvesting, gene transfection, size determination, and technology transfer. 1.3.2.3 Polymeric nanoparticles Polymeric nanoparticles are classified as colloidal particulate dispersions of solid particles with a diameter of 10
1000 nm. These drug delivery systems offer a physical approach to alter and improve the pharmacokinetic and pharmacokinetic characteristics of bioactive molecules. Polymeric nanoparticles have gained considerable interest over the past few years due to their nanosize and varied behavior. They have a matrix structure consisting of biocompatible and biodegradable polymers of synthetic or natural origin; in which a bioactive can be encapsulated or entrapped in the nanocarrier system, chemically attached to the surface, or physically adsorbed on the surface of the carrier. The most commonly used synthetic polymers are polyacrylates, polycaprolactones, polylactide, and polylactide
polyglycolide copolymers. The copolymer, that is, lactide
glycolide, has been extensively explored. Alginate, albumin, and chitosan are the most widely explored among the various natural polymers. Morphologically polymeric nanoparticles are mainly of two types depending on the preparation method, that is, nanosphere or nanocapsule. Nanospheres are made up of a matrix structure in which the bioactive is uniformly distributed, whereas in nanocapsules, the bioactive is embedded in a cavity and the cavity is surrounded by a polymeric membrane. The preparation methods of polymeric nanoparticles include nanoprecipitation, emulsification, solvent evaporation, dialysis, salting out and supercritical fluid, controlled radical polymerization and interfacial polymerization, coacervation of hydrophilic polymers, and ionic gelation. Polymeric nanoparticles are recognized by their attractive properties such as water solubility, stability during storage, small size, biodegradability, and long shelf life. Such features make them potential and promising candidates for the delivery of therapeutics, proteins, DNA, or genes to targeted tissues or organs. These drug delivery systems are, therefore, used in cancer

Nano Drug Delivery Strategies for the Treatment of Cancers

TABLE 1.7 Various dendrimer-based formulations for cancer treatment. S. No.

Drug

Formulations

1.

Paclitaxel and TR3 siRNA

Plectin-1 targeted peptide
modified dendrimer

2.

siRNA

Dendrimer

Targeting organ

Receptor

Comments

References

Pancreatic cancer

Orphan nuclear receptor TR3/Nur77

Panc-1 cells and HeLa cells were used. siTR3 Li et al. (2017) resolved exchange of TR3 while decreasing the expression of antiapoptotic proteins, including Bcl2, and surviving in pancreatic cancer cells.

Triple negative breast cancer

Polo-like kinase (PLK1)

MDA-MB-231 and MCF-7 cells.

Jain et al. (2019)

Cell arrest in sub-G1 phase increased. Structural difference found unchanged by siPLK1.

3.

4.

5.

Epirubicin

Aptamers (Apts) dendrimer

10Multifunctional Hydroxycamptothecin cholesterol
modified dendrimers of generation 5

Ova

Polyamidoamine dendrimer modified with guanidino benzoic acid

Breast cancer

Cervical cancer

Tumor size in tumor-bearing mice after treatment reduced by 6.2-fold.

Bulbake, Kommineni, Ionov, Bryszewska, and Khan (2019)

HeLa-HFAR and HeLa-LFAR cells.

Fu et al. (2019)

MCF-7 and C26 cells.

Folate receptor

Complexes reserved the anticancer therapeutic efficacy and can target HFAR & LFAR-expressing cancer cells with a preferential inhibition effect to the cancer cells.

Melanoma

B16-OVA melanoma cells.

Immunotherapy

Nanovaccine was shown to be effective to treat established B16-OVA melanoma when used in combination with the programmed cell death protein 1 (PD-1).

MDR, Multidrug resistance; VGFR, Vascular endothelial growth factor.

Xu et al. (2019)

24

1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

therapy, gene therapy, and vaccines as well as in the diagnosis of diseases (Choudhury, Gorain, Pandey, Kaur, & Kesharwani, 2019). Boondireke, Le´onard, Durand, and Wongsatayanon (2019) developed monomyristinloaded polymeric nanoparticles for the treatment of cervical cancer. Monomyristin was loaded into dextran-covered polylactide (PLA) nanoparticles. The nanoparticles consisted of a PLA core in which monomyristin was encapsulated. The cytotoxicity of the monomyristin was examined on HeLa cells (cervical cancer cells). A thin layer of dextran-loops conjugated with protein (transferrin), which is being over-expressed on the surface of tumor cells. The lower doses of myromyristin in myromyristin-loaded nanoparticles showed higher cytotoxicity against the HeLa cells than the free myromyristin. Moreover, the existence of conjugated transferrin further increased the cytotoxicity of myromyristin as compared to nonconjugated nanoparticles against cervical cancer cells (Boondireke et al., 2019). Abriata et al. (2019) designed and developed paclitaxel-loaded polymeric nanoparticles. The nanocarrier system was successfully prepared by the nanoprecipitation method with a particle size distribution of B140 nm, a PDI smaller than 0.1, and a high percentage of paclitaxel entrapment. A cytotoxicity assay was performed on a SKOV-3 cell line; the results obtained showed that the developed nanocarrier system was able to release paclitaxel in the tumor microenvironment and reduce the cancer cell viability. The results of the flow cytometry assay suggested that the developed nanostructured system demonstrated a time-dependent cellular uptake, revealing the internalization of the polymeric nanoparticles. The obtained results are satisfactory, showing improved passive targeting in the tumor microenvironment when administered intravenously (Abriata et al., 2019). Jadon et al. prepared lipid polymer hybrid nanoparticles loaded with docetaxel for breast cancer. The nanocarrier system was prepared by a self-assembled nanoprecipitation technique. A cytotoxicity assay was performed on MDA-MB-231 breast cancer cells. The developed formulation showed a greater cytotoxic effect with an IC50 value of 5
8 μg/mL as compared to the free docetaxel against MDA-MB-231 breast cancer cells. A reduction in the percentage of cancer cell viability was recorded and the P-value was found to be statistically significant (P , .001), showing antitumor properties against MDA-MB-231 breast cancer cells at much lower concentrations as compared to free docetaxel. A fluorescence-activated cell sorting (FACS) analysis demonstrated an enhanced cellular uptake efficiency of the developed nanocarrier formulation (45%
48%) as compared to free docetaxel (37%
39%). In vivo study findings showed an extended half-life (T1/2) and prolonged residence time for the docetaxel lipid polymer hybrid nanoparticle
based formulation in comparison to the free docetaxel formulation, indicating the potential of the developed carrier for breast cancer targeting (Jadon & Sharma, 2019). 1.3.2.4 Polymeric micelles Polymeric micelles are nanoscopic molecules with a core
shell structure that are constituted by the spontaneous arrangement or self-assembly of amphiphilic block copolymers in aqueous solutions. Such nanoparticles possess a hydrophobic core
hydrophilic shell structure that facilitates the loading of lipophilic bioactives into the core while the hydrophilic part stabilizes the hydrophobic core in aqueous media and increases the aqueous solubility of polymers. These nanocarrier systems are used in the delivery of bioactives due to their attractive features like their core
shell arrangement, high stability, nanosize,

Nano Drug Delivery Strategies for the Treatment of Cancers

1.3 Novel approaches for the treatment of cancer

25

micellar association, morphology, biocompatibility, and low systemic toxicity. Polymeric micelles usually consist of several hundred molecules. The corresponding diameter typically varies between 10 and 100 nm. There are several interesting clinical applications offered by polymeric micelles such as protection of encapsulated bioactives and the solubilization of poorly soluble bioactives. These drug delivery systems are fabricated by three methods, namely solvent casting, dialysis, and direct dissolution. These nanocarrier systems are promising for their use in the therapy of various ailments such as in estrogen, cancer, antiinfluenza, and antiviral therapies (Zhang & Mi, 2019). Yang et al. (2019) developed polymeric prodrug micelles conjugated with glycyrrhetinic acid codelivered with doxorubicin for the treatment of liver cancer. The polymer prodrug micelles based on polyethylene glycol
derivatized glycyrrhetinic acid were developed for the dual delivery of doxorubicin and glycyrrhetinic acid. A cytotoxicity assay was performed on HepG2 cancer cells. The IC50 value of the doxorubicin-loaded polymer prodrug micelles was found to be 0.11 μg/mL, which was significantly lower than that of free doxorubicin, with an IC50 value of 0.36 μg/mL against HepG2 cancer cells. The results of a cell apoptosis analysis showed that the apoptosis-inducing effect was maximum in the developed nanocarrier formulation with 47.2% apoptosis as compared to free doxorubicin, which showed 27.2% apoptosis against HepG2 cancer cells. Moreover, the doxorubicinloaded polymer prodrug micelles demonstrated a prolonged blood circulation time, a greater bioactive concentration area under the curve, and decreased the volume of distribution and clearance as compared to the free doxorubicin. Biodistribution studies revealed that at the tumor site, the developed micellar formulations were preferentially accumulated. In vivo therapeutic efficacy results revealed that the tumor growth inhibition effect of the developed micellar formulation was higher after coloading with doxorubicin compared with the free doxorubicin. Therefore polymer prodrug micellar systems are promising dual bioactive delivery systems to achieve a synergistic anticancer effect (Yang et al., 2019). Valenzuela-Oses et al. (2017) developed polymeric micelles loaded with miltefosine for cancer treatment. The hydrodynamic diameter and polydispersity index of micelles were 29 nm and 0.105 respectively. The results of a thermal analysis study revealed that miltefosine was dispersed within the polymeric micelles. The polymeric micelles loaded with miltefosine of the copolymer Pluronic F-127 showed a sharp decline in the hemolytic effect (80%, P , .05) as compared to free miltefosine. A cytotoxicity assay was performed on HeLa (human epithelioid cervix carcinoma) cells. The cytotoxicity assay results demonstrated that after 24, 48, and 72 h of incubation and at the same drug concentration, the miltefosine-loaded polymeric micelles and free miltefosine showed similar cytotoxicities in HeLa cells, suggesting the potential of the developed nanocarrier system to treat HeLa carcinoma cells (Valenzuela-Oses et al., 2017).

1.3.3 Miscellaneous nanocarriers 1.3.3.1 Quantum dots Quantum dots (QDs) are artificial, small-sized, semiconductor-based nanostructures ranging typically between 1 and 10 nm with distinctive optical properties, high brightness, and antiphoto bleach characteristics. QDs allow scientists to investigate cellular processes at the level of a

Nano Drug Delivery Strategies for the Treatment of Cancers

26

1. Emergence of novel targeting systems and conventional therapies for effective cancer treatment

single molecule, and can considerably improve the diagnosis and therapy of diseases like cancer. QDs are used as effective sensor components in high-resolution cellular imaging, where the fluorescence properties of QDs are modified when they react with an analyte. They are also used in passive label probes, where selective receptor molecules such as antibodies are linked to the surface of QDs. QDs might revolutionize medicine. They can be easily modified with targeting moieties. QDs can easily be incorporated in amphiphilic polymers in order to improve solubility, size, specificity, and visualization properties (Riyaz, Sudhakar, & Mishra, 2019). QDs have been shown to be a promising candidate since they can be coupled to antibodies and other proteins. These nanocarrier systems can also be fabricated with distinct core
shell structures or with different compositions that can be useful for multiplexed sensing. The most widely used QDs consist of a CdS or CdSe core (Fig. 1.3). The outer shells provide functional groups for bioreceptor immobilization with inert and biocompatible coatings (Gautam & Anamikajain, 2019). In contrast to laborious enzymatic methodologies, the use of QDs eliminates the need for substrate addition, which can help to reduce the analytical time by applying a simple process consisting of QD dissolution to release metal ions, electrochemical deposition of the released ions, and potential scanning to detect the deposited metal. The electrochemical signal thus obtained can then quantitatively be related to the analyte concentration. Du, Wang, Wen, Li, and Li (2016) fabricated graphene QD nanocomposites by linking Ce6 onto graphene QDs via disulfide bonds. Pluronic F-127 was also coated on the graphene

FIGURE 1.3 Schematic representation of quantum dots and their uptake mechanism.

Nano Drug Delivery Strategies for the Treatment of Cancers

References

27

QD nanocomposites as a stabilizer. When the nanocarrier formulation entered the local tumor tissue, glutathione in the tumor cells promoted disulfide cleavage. This could release the Ce6 from the graphene QD nanocomposites and its phototoxicity was restored. In vitro and in vivo studies showed that the developed redox responsive graphene QD nanostructures showed an effective suppression of HeLa cell growth (Du et al., 2016). Havanur et al. (2019) developed poly(N,N-diethyl acrylamide)-functionalized graphene QD hydrogels loaded with doxorubicin for the treatment of metastatic lung cancer. The nanocarrier system was prepared by inverse emulsion polymerization. The size of the nanohydrogel was in the range of 57
59.5 nm. The size of the graphene QD
incorporated nanohydrogels was observed to be in the range of 68.1
87.5 nm. The prepared nanohydrogel had an IC50 value of 1000 μg/mL against B16F10 melanoma cancer cell lines. The results demonstrated that the developed nanocarrier system was found to be more cytotoxic against B16F10 melanoma cancer cell lines as compared to free doxorubicin. Histopathological and viable tumor cell count studies demonstrated that complete recovery of the lungs from melanoma was not shown in nanohydrogel formulations. This indicates its potential application as a drug carrier (Havanur et al., 2019).

1.4 Conclusion The methods used for the treatment of cancer are surgery, radiation, and chemotherapy. These methods are used separately or in combination but complete treatment is not yet possible. The reason behind this is the late diagnosis, high treatment cost, and loss of organs in case of surgery, etc. But even after that, all the medical facilities only extends the life span of patients, not a complete cure. For achieving this goal, scientists are still working on nanomedicine-based technologies for the effective treatment of cancer. They are still trying to develop a novel delivery system that can effectively target cancer cells without affecting normal cells.

Acknowledgment This work was supported by the Indian Council of Medical Research (ICMR, New Delhi), India (Grant Number: For Laxmikant Gautam 45/16/2018-Nan/BMS, dated 11/05/2018, and Anamika Jain 45/38/2018-PHA/BMS, dated 24/07/2018).

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355. Ag Seleci, D., Seleci, M., Walter, J.-G., Stahl, F., & Scheper, T. (2016). Niosomes as nanoparticular drug carriers: Fundamentals and recent applications. Journal of Nanomaterials, 2016. Alam, A., Farooq, U., Singh, R., Dubey, V. P., Kumar, S., Kumari, R., . . . Dhar, K. L. (2018). Chemotherapy treatment and strategy schemes: A review. Journal of Toxicology, 2(7). Alavi, M., Karimi, N., & Safaei, M. (2017). Application of various types of liposomes in drug delivery systems. Advanced Pharmaceutical Bulletin, 7(1), 3.

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C H A P T E R

2 Nanomedicine: future therapy for brain cancers Shagufta Haque1,2, Caroline Celine Norbert1 and Chitta Ranjan Patra1,2 1

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India 2Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

2.1 Introduction Brain cancers are considered to be the most fatal and aggressive forms of cancer. They result in large mortality and morbidity worldwide (Patel et al., 2019). Brain tumors are considered to be heterogeneous collections of primary and metastatic neoplasms located in the central nervous system. The unmet challenges of this disease to date include moderate prognosis and a poor survivability rate of patients (Arvanitis, Ferraro, & Jain, 2019). In accordance with the malignancies of brain cancers, the World Health Organization (WHO) has categorized them from grade I (identified by lesions that have a low tendency to proliferation) to grade IV (malignant and have great tendency to proliferation, often regarded as active neoplasms) (Louis et al., 2016). Primary gliomas are those that originate from the glia known as malignant gliomas and are the cause of 70% of new primary brain cancers (Davis, 2016). Among these, glioblastoma multiforme (GBM) is the most aggressive form of cancer, which falls under the category of grade IV astrocytoma as classified by the WHO (Wen & Kesari, 2008). The central nervous system has another class of tumors known as brain metastases that originate from the cancers of the lung, skin, and breasts (Chamberlain, Baik, Gadi, Bhatia, & Chow, 2017). The main obstacle that is encountered while treating brain cancers is the inability of drugs to cross the brain barriers and their entry into the brain since it is highly protected and sensitive to the entry of foreign molecules (Warren, 2018). Furthermore, commercially available drugs are sometimes incapable of crossing the blood
brain barrier (BBB) and surgery, radiation therapy, and chemotherapy have high costs coupled with many side effects (Blakeley, 2008). Hence to overcome the crucial need of proper diagnosis and

Nano Drug Delivery Strategies for the Treatment of Cancers DOI: https://doi.org/10.1016/B978-0-12-819793-6.00003-5

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treatment, new technology is urgently required to combat these deadly diseases. The field of nanotechnology is slowly and steadily developing toward the treatment and diagnosis of cancers, especially for brain tumors (Ramos, Cruz, Tovani, & Ciancaglini, 2017). Therefore it is anticipated that it will change the overall treatment and diagnosis strategies of brain cancers (Mendes, Sousa, Pais, & Vitorino, 2018; Meyers, Doane, Burda, & Basilion, 2013). Nanotechnology is a potential emerging candidate in the field of cancer to be used for therapeutic treatments. The utilization of nanoparticles in the area of brain cancer has the potential to treat it since nanoparticles are able to cross the BBB (Zhou, Peng, Seven, & Leblanc, 2017). Nanoparticles also help drugs and other targeting moieties to cross the BBB and reach the target location by increasing their selectivity as well as specificity to enhance their therapeutic efficacy (Caruso et al., 2013). Therefore this chapter focuses on the overall topic of brain cancers, their global value, problems regarding their treatment, and it also highlights the utilization of nanoparticles in treating brain cancers. The chapter concludes with the future prospective and challenges regarding nanoparticles and ways to overcome these challenges to become as a potential candidate for theranostic utilization in brain cancers.

2.2 Global statistics of brain cancers Brain cancers form heterogeneous groups of cancers and can be classified into 29 histologic groups according to the WHO Classification of Tumors of the CNS. The histology of brain cancers depends upon the incidence pattern of the demography, therapeutic regimens, and the scenario after diagnosis (Ostrom et al., 2016). According to 2016 reports of the Central Brain Tumor Registry of the United States (CBTRUS), 79,270 cases of nonmalignant, primary malignant, and other brain cancers were predicted to be diagnosed by 2017 in the United States (Report, January 2017). In another report by CBTRUS, the number of deaths occurring due to malignant brain cancer was 79,718 between 2012 and 2016. It was expected that 86,010 cases of all types of brain cancers would be diagnosed by 2019, of which 25,510 were expected to be malignant and 60,490 to be nonmalignant (Ostrom et al., 2019). The survival rate statistics are 35.8% for malignant cancers and 91.5% for nonmalignant cancers with glioblastoma having the lowest survival rate of 6.8% (Ostrom et al., 2019). The occurrence of brain cancer is mostly reported in the United States, Europe, Australia, and Canada. However, it is significantly less prevalent in India, Southeast Asia, and East Asia. The statistics are 5.74 age-adjusted incidence rates (AAIR) in the United States, 6.53 AAIR in Canada, and 6.59 AAIR in Northern Europe being the highest and 3.07 AAIR in East Asia, 2.85 AAIR in India, and 2.55 AAIR in Southeast Asia being the lowest. Astrocytic tumors are known to have the highest incidence of occurrence worldwide with medulloblastoma and other tumors being relatively less prevalent. The incidence of occurrence is different in European and Asian countries because of the variance in environmental as well as ancestral factors (Leece et al., 2017). The overall market value of brain tumors for diagnosis and therapy was USD354.9 million in 2015 with an 8.1% compound annual growth rate (CAGR) growth rate. North America holds a share of more than 45.0% in the brain cancers therapy and diagnosis market. A number of

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companies are highly involved in the brain cancers market worldwide, including Philips Healthcare, GE Healthcare, Shimadzu Corporation, Hitachi Ltd., etc. (Report, January 2017). Global statistics and the high market value of brain cancers encouraged scientists to find alternative and affordable approaches to combat this deadly disease. In this context, nanomedicine may solve these issues efficiently.

2.3 Major drawbacks and circumstances in brain tumors Besides being the most malignant and invasive form of cancer, brain cancer is stated to have diverse forms. Depending upon its heterogeneity and abnormalities in molecular mechanisms, brain tumors have been classified by the WHO as oligodendroglial tumors, ependymal tumors, diffuse astrocytomas, and other astrocytic tumors. The current trends in research focus mainly on glioblastoma cells, which fall under the category of astrocytomas (Wu et al., 2019). The major difficulties that lead to the problems faced in brain cancers include (1) the complex structure of the brain, (2) the metastatic and heterogeneous features of brain cancers, (3) problems in locating tumor boundaries, (4) the non-selectivity of tumor targeting agents and drugs to tumor sites, and (5) the development of resistance to chemotherapeutic drugs (Cheng, Morshed, Auffinger, Tobias, & Lesniak, 2014). As the brain is the most complicated system in terms of treating cancers, even after successful surgery and chemotherapy, tumors recur in the abscission margin (Davis, 2016; Sneed et al., 1994). The problems faced by the current conventional therapies are due the BBB, which inhibits most molecules from moving across it (Warren, 2018). The BBB functions in preventing the entry of harmful molecules from the blood (both endogenous and exogenous) into the brain, thus resulting in the inhibition of tumor therapy drugs into the brain. The BBB is made up of tight junctions within endothelial cells, a basement membrane, astrocytes, and pericytes (Cheng, Dai, et al., 2014; Cheng, Morshed, et al., 2014). Since cerebral endothelial cells have deficient pinocytotic vesicles, transcytosis and BBB selectivity are affected. The increased expression of ATP-binding cassette transporters on the BBB prevents the transportation of molecules (Miller, 2015). Other barriers include cerebrospinal fluid and interstitial fluid, which prevent drug molecules and other agents from reaching tumor sites. Choroid epithelial cells form the basis of the cerebrospinal fluid, which determines the entry of molecules into the brain parenchyma interstitial fluid (Ghersi-Egea et al., 2018). Also, the active transport systems present in the choroid plexus inhibit the therapeutic effects of the organic acids used for brain cancers by preventing their entry into the brain parenchyma interstitial fluid (Johanson, 2018). In addition to the mentioned troubles, the tight junctions of tumors hinder the penetration of drugs into it (Dong, 2018). This barrier is formed between the blood and the tumor. The interstitial fluid pressure of the blood and the lymph vessels surrounding the tumor obstruct the entry of drug molecules (Choi, Strauss, Richter, Yun, & Lieber, 2013). This prevents the open diffusion of therapeutics. As a result, drugs are distributed heterogeneously, which hampers the therapeutic effect of drugs (Tee et al., 2019). There is a wide range of diagnostic techniques used such as magnetic resonance imaging (MRI), computed tomography (CT) scanning, and different therapeutic methods available like radiation therapy, chemotherapy, etc. However, all these techniques have

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exhibited certain drawbacks in their accuracy while imaging or as a therapeutic agent (Thust, van den Bent, & Smits, 2018). Surgical therapy is a mode of treating brain cancers, but it may result in the incomplete clearance of the full tumor. Also, chemotherapy initiates the apoptosis of cancer cells and inhibits the cell cycle, but triggers systemic problems with insufficient tumor bioavailability (Dasari & Tchounwou, 2014). Hence there is a need to find novel therapeutic and diagnostic treatments for eliminating brain cancers. Since nanotechnology is a new area to explore regarding different types of diseases, including cancers, scientists are focusing on utilizing the potential properties of nanoparticles for eradicating gliomas (Zottel, Videtiˇc Paska, & Jovˇcevska, 2019).

2.4 General strategy of nanoparticles for the treatment of brain cancers Nanoparticles, in order to be selected as a brain cancer targeting agent, have to have certain characteristics, composition, abilities of passive targeting, and surface modification with active targeting (Palanisamy & Wang, 2019). Nanoparticles are composed of a range of materials and are classified accordingly such as polymers, liposomes, inorganic nanoparticles, composite nanoparticles, dendrimers, micelles, etc. (Chowdhury, Kunjiappan, Panneerselvam, Somasundaram, & Bhattacharjee, 2017; Patra et al., 2018). These are described here briefly.

2.4.1 Physical properties The main feature of nanoparticles that contributes to their increased loading functionality is their surface to volume ratio (Rizvi & Saleh, 2018). They help to enhance the solubility and circulation of drugs in the blood along with their controlled discharge within tumors. Certain drug molecules or targeting agents that find difficulty in reaching the desired site due to solubility issues can be loaded into nanoparticles to enhance the systemic circulation half-life (Din et al., 2017; Singh, Biswas, Shukla, & Maiti, 2019). Also, the drug release can be controlled since nanoparticles can react to a variety of environmental cues such as temperature and pH. Other than these features, some types of nanoparticles exhibit properties such as thermal, magnetic, and electrical properties, which can be exploited for diagnostic and therapeutic applications (Jeevanandam, Barhoum, Chan, Dufresne, & Danquah, 2018; Tang et al., 2019). There is a new system of nanotechnology being introduced that takes into account multiple nanoparticles with different features that are used as a single system. The applications of these multiple nanoparticle systems have been discussed in the following sections.

2.4.2 Passive targeting Passive targeting refers to the process through which nanoparticles are accumulated inside tumors due to the leaky, hyper vascularized lymphatic system of tumors and contact the intratumoral space (Meyers et al., 2013; Pristis, Kommineni, & Khan, 2017). This phenomenon is referred to as the enhanced permeability and retention (EPR) effect

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brain barrier

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(Golombek et al., 2018; Maeda, Wu, Sawa, Matsumura, & Hori, 2000). This situation is not observed in normal cells (Bazak, Houri, Achy, Hussein, & Refaat, 2014). In order for nanoparticles to be capable of passive targeting, their sizes should be less than 100 nm. Chemotherapeutic agents usually do not follow this pathway and, hence, they enter nonselectively into both cancer as well as normal cells. Thus with the EPR effect, a large number of nanoparticles can be used for therapeutics as well for the diagnosis of brain tumors. But in order for nanoparticles to have maximum efficacy, they should be hydrophilic with a size range of less than 100 nm and must possess a neutral charge (Wu et al., 2019; Yan et al., 2012).

2.4.3 Active targeting The process of active targeting of nanoparticles helps in reaching the desired target location. This is based on the receptor nature that the nanoparticle is targeting. The functionalization of nanoparticles with the targeting ligand is done to reach the tumor site (Villaverde & Baeza, 2019). The surface modification of nanomaterials helps to enhance their features such as hydrophobicity, surface charge, their localization inside the blood circulation, and also their half-life (Din et al., 2017). Nanoparticles are used in conjugation with various targeting agents and molecules in order to penetrate the cell to enhance the therapeutic efficacy of drugs. They undergo surface modification or surface functionalization with BBB targeting molecules or cell penetrating peptides (CPP) (Silva, Almeida, & Vale, 2019). For example, pegylation is one such modification that results in increasing the half-life of nanoparticles in circulation so that they can reach the brain tissues. In other cases, the tumor vasculature may not be leaky enough for nanoparticles to enter. Hence nanoparticles are often conjugated with targeting agents such as integrins or transferring receptors, which are expressed on the tumor endothelial cells or remain in the blood within the vicinity of the tumor (Rosenblum, Joshi, Tao, Karp, & Peer, 2018; Suk, Xu, Kim, Hanes, & Ensign, 2016). Therefore there are wide ranges of methods in which nanoparticles can target the brain tissues, either with surface modification or by conjugating them with certain receptors and ligands, etc.

2.5 Mechanistic pathways employed by nanoparticles to cross the blood
brain barrier The nanoparticles adopt different mechanisms to cross the BBB. Either they can cross the BBB by themselves or with the help of any targeting ligand or moiety they cross the BBB. Depending upon various methods the mechanisms employed by nanoparticles are divided into three categories which are briefly described as follows.

2.5.1 Carrier-mediated transport Carrier-mediated transport (CMT) is usually employed to transfer substances into the brain through the BBB without being effluxed back (Bellettato & Scarpa, 2018). It is also done to maintain homeostasis in a bidirectional manner. Active efflux transporters

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determine the transfer of substances across the BBB. Betzer et al. developed in vivo neuro imaging and tracking of exosomes by labeling them with glucose-coated gold nanoparticles. This results in the direct elimination of the need for labeling parent cells. They also found that the intranasal mode of administration has numerous advantages and is more effective than intravenous system (IVS) injection in various CNS diseases. Additionally, they found that the 5 nm gold nanoparticles (GNPs) showed admirable exosome labeling. Finally, it was demonstrated that the glucose transporter GLUT-1 helps in the uptake of glucosecoated GNPs into the mesenchymal stem cells (MSC-derived) exosomes. The MSC-derived, GNP-labeled exosome specifically homed to the brain regions enabled the imaging and tracking of exosomes in vivo and can be utilized for the treatment of brain cancers (Betzer et al., 2017). Another research group, Bhunia et al. designed and synthesized a liposomal drug carrier that is selective to large amino acid transporter-1 (LAT1) from a l-3,4-dihydroxyphenylalanine (L-DOPA)-functionalized amphiphile (Amphi-DOPA). The in vitro studies conducted with the help of Rh-PE labeled liposomes showed cellular uptake mediated by LAT1. Biodistribution assays of Amphi-DOPA liposomes labeled with near-infrared (NIR) dye showed the specific accumulation of NIR-dye in the brain tissues. The survivability of the orthotopical glioblastoma mice model (C57BL/6 J) increased by approximately 60% when treated with Amphi-DOPA liposomes loaded with WP1066 in comparison to the untreated group. The dendritic cell
targeted chemotherapy mediated by the designed liposomes conjugated with DNA vaccination using a survivin-encoded DNA vaccine increased the survivability of the tumor bearing mice by 300% (Bhunia et al., 2017).

2.5.2 Receptor-mediated transport The receptor-mediated transport (RMT) process regulates the transportation of molecules across the BBB through certain receptors present on its surface. These peptide receptors present help in the transcytosis of ligands from the blood toward the brain and from the brain back to the blood (Pulgar, 2019). The abundance of these receptors and their expression over the BBB determine the transport of substances into the brain through the BBB. Magnetic particle imaging (MPI) has been gaining a large amount of interest due to its submillimeter spatial resolution and admirable sensitivity. To this end, Arami et al. conjugated targeting glycoprotein to nanoparticles to increase the uptake of the nanoparticles by brain tumor xenografts with the help of a surface functionalization platform. Lactoferrin, which has been known to transverse the BBB easily, was conjugated to poly (maleic anhydride-alt-1-octadecene)-polyethylene glycol (PMAO
PEG) surface coating MPI contrast agents that improved the uptake by tumor cells. Two- and three-dimensional tomographic and positive contrast images of the cancers were obtained with multimodal MPI/CT/X-ray imaging. These MPI contrast agents were radiolabeled with Ga-NOTA, which proved that these nanoparticles had no observable renal clearance owing to their large hydrodynamic diameters. The flexible PMAO
PEG coating on the surface enabled the scope for different conjugation strategies for multimodal MPI/CT/NIRF/MRI/CT/ SPECT imaging (Arami et al., 2017). Again, nanoparticles that can transport drugs to tumor sites by overcoming the BBB are becoming increasingly important. In this context, Muntoni et al. synthesized solid-lipid nanoparticles (SLN) with the help of fatty acid

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coacervation and loaded them with the active lipophilic ester of the drug methotrexate. The nanoparticles were further functionalized with transferrin or insulin, which are receptors that are present abundantly in the BBB. Accordingly, a maleimide linker with reactivity to thiolated proteins was grafted on the surface of the nanoparticles to achieve functionalization. In vitro studies showed that the nanoparticles could successfully overcome the BBB, which was attributed to the improved ligand
receptor interactions and target tissue selectivity. In vivo studies with these functionalized nanoparticles showed that the targeted moieties attached to the nanoparticles assisted the transport of the SLNs toward the BBB (Muntoni et al., 2019).

2.5.3 Adsorptive-mediated transport In the adsorptive type of transcytosis, the process requires a ligand or molecule that interacts with the cell surface. This type of interaction usually occurs due to a difference in charge and finally occurs through the clathrin-mediated pathway. This method of crossing the BBB is unidirectional (Grabrucker et al., 2016). Using this concept, Ahlschwede et al. designed poly(lactic-co-glycolic acid) (PLGA) nanoparticles to which chitosan was conjugated to the surface and K16ApoE (cationic BBB targeting peptide) was physically adsorbed (Ahlschwede et al., 2019). This peptide could easily penetrate the BBB owing to the increased affinity of the nanoparticles to amyloid plaques. The K16ApoE-targeted nanoparticles were highly specific to the vasculotropic Dutch Aβ40 peptide, which commonly accumulates in the cerebral vasculature. The formed nanoparticles have the extra advantage that hydrophobic therapeutic and imaging agents could be added to them to enable early diagnosis with the help of MR imaging and treatment of the pathological changes that are caused due to amyloidosis (Ahlschwede et al., 2019).

2.6 Nanomedicine for the treatment and diagnosis of gliomas The most important characteristics of nanoparticles for treating brain cancers includes their composition, unique physicochemical properties, ability of passive and active targeting along with surface functionality, which can be tunable (Lombardo, Kiselev, & Caccamo, 2019; Palanisamy & Wang, 2019). All these features of nanoparticles help in the diagnosis and treatment of brain cancers and also in the delivery of therapeutic agents through the BBB.

2.7 Nanomedicine for the diagnosis of brain cancers Proper detection of glioblastomas for treatment and surgery is one of the prime concerns to eradicate the disease. Since brain cancers are extensively invasive, it is difficult to detect their location for surgery and post operational treatment (Lara-Velazquez et al., 2017). The most common conventional method for brain tumor imaging is by using contrast agents in weighted T1 MRI (Macdonald, Cascino, Schold, & Cairncross, 1990; Pope & Brandal, 2018).

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But the precision of MR imaging is gravely affected by pseudo-progression, vasal leakage, pseudo response, and all the antiangiogenic and radiation therapies (Zikou et al., 2018). Other therapies include positron emission tomography (PET) and positron emitting radionuclides that are used to detect tumors through the autoradiography of tissues (Chen & Chen, 2011). Similarly, these methods have various limitations, including sensitivity, specificity issues, contrast agents having a short half-life, and imaging that requires increased doses (Zhao et al., 2018). To overcome these drawbacks, nanoparticles are being used to enhance the sensitivity, specificity, and to decrease the doses for imaging.

2.7.1 Magnetic resonance imaging There are several reports of nanoparticles being used for MR imaging. Related to this, gadolinium chelates, which were amphiphilic, self-assembling nanoparticles, were used for an increased imaging effect. Mekuria et al. used gadolinium-incorporated PEG nanoparticles as T1 and T2 contrast agents for MR imaging. The designed nanoparticles exhibited good biocompatibility with RAW cell lines when injected into an in vivo tumor model, and it showed enhanced signals in all major organs (Mekuria, Debele, & Tsai, 2017). Exploiting this property of gadolinium, Li et al. used metallofullerene consisting of gadolinium in the form of a cage bearing positively charged amino groups on its surface. The metallofullerene was functionalized with a trimetallic nitride template and was characterized by dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and infrared spectroscopy (IR). The nanoparticles exhibited admirable 1H MR relativity. Since the nanoparticles were positively charged they could efficiently bind with the phospholipid bilayer surfaces of cells, which were negatively charged. Again, the metallofullerene was conjugated with interleukin-13 (IL-13) peptide since it targets GBM cells. Therefore the designed nanoparticles exhibited increased targeting to U251 GBM cell lines. The nanoparticles, when injected orthotopically in a GBM mouse model, were successfully delivered to the desired location (Li et al., 2015). Other than gadolinium, manganese and iron have also been explored as nanodiagnostic agents because of their magnetic features. Taking advantage of this character of iron, Jordan et al. designed iron oxide nanoparticles doped with tungsten that had many uncoupled magnetic moments along with a disordered crystal. The designed nanoparticles exhibited paramagnetic properties and a T1 weighted feature. The nanoparticles were injected into the brain of a rat model for observing their magnetic properties for MRI. They exhibited enhanced signal intensity and these nanoparticles can be used in the future for the diagnosis of brain cancers (Clavijo Jordan, Beeman, Baldelomar, & Bennett, 2014). There are several reports of increasing the superparamagnetic properties of iron oxide nanoparticles by functionalizing them with peptides and antibodies that target the brain, which includes cRGD peptides, antibodies like EGFRvIII, and chlorotoxin like targeted toxin (Hadjipanayis et al., 2010; Stephen et al., 2014). In this context, Richard et al. used cRGD peptides conjugated with iron oxide nanoparticles on their surface for MRI in brain tumors (Richard, Boucher, Lalatonne, Meriaux, & Motte, 2017). Taking into consideration the magnetic properties of manganese, Zhou et al. synthesized manganese nanoparticles that were used to chelate an albumin-binding molecule. The as synthesized nanoparticles exhibited admirable magnetic properties and

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worked as T1
T2 dual-modal contrast agents for MRI. The nanoparticles were tested in both orthotopic and subcutaneous models of brain cancer in mice. Fig. 2.1 exhibits the orthogonal computations of the orthotopic brain tumor model using T1 2 T2 dual-modal MRI. As depicted in Fig. 2.1A
G, the injected nanoparticles help in the clear detection of the lesion area in the images of postcontrast shown by yellow arrows. The hyperintense foci is seen in the postcontrast brain images displayed by the R1 map. The tumor tissues H&E staining also depicts the presence of one brain tumor and helped in the elimination of false signals coming from other loci. Finally, the PET images of the tumor showed increased tumor signals with greater uptake of nanoparticles. Such signals are absent in the normal areas since they have a well-formed BBB. Hence the overall experiment helped to abolish doubtful and false-positive results that usually arise during brain imaging in mouse models (Zhou et al., 2019).

2.7.2 Raman scattering and computed tomography imaging Other than MRI, scientists have developed other nanoparticles that combine surfaceenhanced resonance Raman scattering and MRI in order to perform direct surgery of brain tumors. As a result of injecting these nanoparticles, they were active even after 24 h of their treatment and helped in forming the tumor outline (Han et al., 2019). Li et al. developed gallium-BNOTA-PRGD2 (68Ga-PRGD2) nanoparticles that were used as a testing agent for PET and CT scans in diagnosing gliomas. The target (68Ga-PRGD2) accumulated more near the integrins αvβ3 and helped in the detection of those brain tumors expressing these integrins. In comparison to the existing PET/CT scan agents, the formed nanoparticles with the targeting agent showed increased sensitivity and specificity. This method is a noninvasive form of imaging integrins and helps in better imaging tumors (Li et al., 2014). In another study of a similar kind, Gao et al. designed a pegylated dimeric isoDGR peptide along with its analogue, which is an albumin binder. The formed nanoparticles were further fabricated with their equivalent radiotracers, which are 9mTc-3PisoDGR2 and 99mTc-AB-3PisoDGR2. The designed nanoparticles were studied for their tumor eliminating activities in both orthotopic and subcutaneous models of tumors. The researchers established through their experiments that the isoDGR peptide dimerization showed increased affinity to the tumors as compared to its monomeric form. NanoScan SPECT/CT imaging of the glioma tumors using the nanoparticles exhibited more accurate images with relatively low background. Fig. 2.2A
E shows the uptake of the designed nanoparticles by the gliomas, which can easily be detected. The H&E staining exhibits the tumor images with the nanoparticles. Hence the formed nanoparticles have the potential to be used as contrast agents for CT scanning (Gao et al., 2019).

2.7.3 Nanoparticles as carriers of fluorescent dyes for imaging tumors A wide number of nanoparticles have been reported to act as carriers for fluorescent dyes, which are used for imaging brain cancers (Ma et al., 2017). Liposomes have been reported to successfully transport fluorescent dyes to the tumor specific sites in the brain (Bruun & Hille, 2019). Since liposomes are biocompatible, they are able to survive and carry these dyes and drugs effectively (Deng et al., 2018). In this context, Li et al. designed self-assembled

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FIGURE 2.1 Orthogonal computations on T1 2 T2 dual-modal MRI of orthotopic brain tumor model. (A) Illustration of acquisition of pre- and postcontrast T1 2 T2 dual-modal MRI with the same in-plane slices through a prefixed catheter for intravenous injection of contrast agents. (B) Representative T1- and T2-weighted images of mouse brain at pre- and postcontrast points. Yellow arrows indicate hyperintense foci in the brain. (C) The R1 and R2 maps for the pre- (1 and 2) and postcontrast (10 and 20 ) points of the imaging slice shown in B. (D) The ΔR1 and ΔR2 maps were obtained from numerical subtraction of postcontrast R1 and R2 maps by precontrast R1 and R2 maps respectively. The ΔR1 and ΔR2 maps were then deduced by two logic filters (F1: ΔR1 ,0, ΔR2 ,0; F2: ΔR1 .ΔR2) to filter out falsepositive relaxation changes on the maps, which were then used for generating ΔR1 * ΔR2 map. Pink arrow shows suspicious relaxation change possibly from the CSF flow. Yellow arrow indicates the hyperintense foci. (E) H&E staining of mouse brain slice showing the presence of a brain tumor. (F) PET images of mouse with brain tumor (yellow arrow). Scale bar: 100 μm. (G) Quantification of CNR of the brain tumor for the T1- and T2-weighted images, ΔR1, ΔR2, and ΔR1 * ΔR2 maps. Values are presented as mean 6 SD. Source: Reprinted with permission from Zhou, Z., Bai, R., Wang, Z., Bryant, H., Lang, L., Merkle, H., . . . Chen, X. (2019). An albumin-binding T1
T2 dual-modal MRI contrast agents for improved sensitivity and accuracy in tumor imaging. Bioconjugate Chemistry, 30(6), 1821
1829, Copyright r 2019 American Chemical Society.

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FIGURE 2.2 Representative SPECT/CT images of 99mTc-3PisoDGR2 and 99mTc-AB-3PisoDGR2 in mice bearing orthotopic U87MG glioma. (A) Representative maximum intensity projection image of 99mTc-3PisoDGR2 at 1 h p.i. with a tumor size .50 mm3. (B) Representative sectional images of 99mTc-3PisoDGR2 at 1 h p.i. with a tumor size ,2 mm3. (C) Representative sectional images of 99mTc-AB-3PisoDGR2 at 1 h p.i. with a tumor size ,2 mm3. (White arrows and dotted circles indicate the tumors.) (D) Quantified tumor/brain ratios from the orthotopic imaging shown in B and C. (***means P , .005 by Student’s t test.) (E) H&E staining result of the orthotopic U87MG tumor obtained from B and C imaged tumor model. Source: Reprinted with permission from Gao, H., Luo, C., Yang, G., Du, S., Li, X., Zhao, H., . . . Wang, F. (2019). Improved in vivo targeting capability and pharmacokinetics of 99mtc-labeled isodgr by dimerization and albumin-binding for glioma imaging. Bioconjugate Chemistry, 30(7), 2038
2048, Copyright r 2019 American Chemical Society.

IR780-phospholipid micelles. IR780 has been reported to have admirable properties of targeting tumor tissues and their imaging, but it has hydrophobic problems. Hence when IR780 is attached to phospholipids, it is more stable and accumulates well inside tumors and the mitochondria. The activity of the nanoparticles along with the dye was done in ectopic tumors of U87MG, intracranial tumors, and also in orthotopic glioma models. The results depicted excellent NIRF imaging in tumor specific sites and, hence, pose as an efficient candidate for imaging and in the brain tumor surgery (Li, Johnson, Peck, & Xie, 2017). Several scientists have used many different polymeric nanoparticles such as poly(lactic-co-glycolic acid) (PLGA) to enhance the time of circulation of the nanoparticles (Tivnan et al., 2017). Han et al. designed an approach of enhancing the

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FIGURE 2.3 (A) Schematic representation of the autocatalytic delivery strategy of ABTT nanoparticles. (B) Fluorescence signals in mice and excised organs were registered at 24 h after the last nanoparticle treatment using an IVIS imaging system. Confocal imaging of ABTT nanoparticles in the brain, ABTT nanoparticles (magenta) effectively binding to small tumor sites (green) rather than binding outside the tumor. ABTT nanoparticles (magenta) passed through the vascular wall (cyan) and were endocytosed by tumor cells (green). Source: Reprinted with permission from Han, L., Kong, D. K., Zheng, M. Q., Murikinati, S., Ma, C., Yuan, P., . . . Zhou, J. (2016). Increased nanoparticle delivery to brain tumors by autocatalytic priming for improved treatment and imaging. ACS Nano, 10(4), 4209
4218, Copyright r 2016 American Chemical Society.

delivery of nanoparticles into the brain by an “autocatalytic” process (Han et al., 2016). They used polymeric nanoparticles that were surface modified with brain tumor targeting chlorotoxin (CTX). The formed nanoparticles entered into the brain through transcytosis and by the gaps in the BBB that had been damaged by the tumors. Once inside the BBB, the nanoparticles release modulators, which create a positive feedback loop for more nanoparticles to come inside. Fig. 2.3A
B shows a schematic diagram of the overall mechanism of the synthesized nanoparticles. The confocal images display that the fluorescence intensity of the nanoparticles at the site of the brain is much enhanced in comparison to other organs. The formed nanoparticles specifically bind to the tumor sites that are depicted in green and the crossing of the BBB is shown by the color cyan. The nanoparticles with CTX-mHph2 (cell penetration peptide)-III-62% were readily assimilated inside the tumors and the fluorescence intensity increased by 20-fold in comparison to liver and normal tissues of the brain (Han et al., 2016). In another report, Ray et al. synthesized clusters of silver nanoplates that were incorporated inside a nanomatrix polymer. The idea to immobilize the nanoplates inside the nanomatrix was aimed at increasing their stability along with their optical features inside the animals. The nanoparticles were also conjugated with a fluorescent dye along with F3 peptide, which is tumor targeting. The as synthesized nanoparticles, when injected in a rat glioma tumor model as photoacoustic contrast agents, exhibited a 90% enhancement with respect to the control. Therefore the functionalized nanoparticles can be used as excellent contrast agents for diagnostic purposes and they also possess the potential to be used for therapeutic purposes (Ray et al., 2014).

2.7.4 Nanoparticles as fluorescent agents for tumor imaging There are a wide variety of nanoparticles that themselves acts as fluorescent agents when excited by certain wavelengths of light and they simultaneously emit a different

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wavelength (Bao, Mitragotri, & Tong, 2013; Wolfbeis, 2015). Hence they act as contrast agents that can be used for targeting and imaging tumors. The most common nanomaterials are quantum dots, upconversion nanoparticles, and silver nanoclusters, which are used for imaging purpose (Deng & Goldys, 2014; Zhang, Goswami, Xie, Zhang, & He, 2017). Quantum dots are usually preferred for imaging since they have admirable solubility, a low fluorescence quenching rate, high fluorescence quantum yield, and stable chemical features (Das, Rajender, & Giri, 2018). Relevant to this, Liu et al. synthesized quantum dot nanoparticles that were conjugated with RGD and their emission characterization was done through confocal microscopy. Toxicity testing was done in a mouse fibroblast cell line (3T3), which is a normal cell line, and in a human glioma cell line (U251). The confocal results revealed that only the U251 cancer cell line showed the uptake of fluorescent quantum dots and fluorescence was absent in the normal 3T3 cell line. Hence these quantum dots conjugated with RGD can be used as an efficient agent for the imaging and therapy of gliomas (Liu, Zhong, Dou, Visocchi, & Gao, 2017). Similarly, Tang et al. designed quantum dots and conjugated aptamer 32 (A32) on their surface. This was done because A32 is a single stranded DNA that specifically binds to the surface of glioma cells through EGFRvIII (epidermal growth factor receptor variant III). The biocompatibility of the formed nanoparticles revealed their nontoxic nature. The activity of the nanoparticles was checked in human brain glioma tissues along with glioma cell lines. The results revealed that both the glioma tissues and glioma cells showed uptake of the nanoparticles in vitro. Also, when the fluorescence imaging of the quantum dots was checked in an orthotopic glioma model of mice having U87
EGFRvIII, it was observed that the nanoparticles could easily cross the BBB. As a result, there was a greater accumulation of the nanoparticles in the tumors expressing EGFRvIII and they expressed admirable fluorescence for easy detection. The as synthesized nanoparticles were used for diagnosis as well as for checking the glioma after operation (Tang et al., 2017). There are research articles of gold nanoparticles being used for imaging studies in the case of brain cancers. The authors’ group of researchers biosynthesized gold nanoparticles with the help of Zinnia elegans plant extract that displayed green fluorescence at 350 nm excitation and red fluorescence at the NIR region at 710 nm (Kotcherlakota et al., 2019). The fluorescence was due to the presence of some fluorescent molecules in the extract that was present on the surface of the nanoparticles during the synthesis of the nanoparticles. Even when injected in C57BL6 mice, they showed accumulation in the brain, and red fluorescence was observed at the red portion of the NIR region. Fig. 2.4A
B depicts the biodistribution of the nanoparticles in the injected mice, which clearly depicts their accumulation in the brain region when excited at 710 nm and emitted at 825 nm. The image further shows that after the injected mice were sacrificed, the organs were imaged in an in vivo imager that clearly displayed the nanoparticles accumulated in the brain along with the kidney and liver. Hence the biosynthesized nanoparticles can be used for theranostic applications in brain cancers (Kotcherlakota et al., 2019). Table 2.1 depicts the diagnostic applications of various nanoparticles through different modes and methods either acting as contrast agents, carriers of fluorescent dyes, or as fluorescent dyes themselves.

Nano Drug Delivery Strategies for the Treatment of Cancers

FIGURE 2.4 (A and B) In vivo biodistribution of ZE and AuZE in C57/BL6 female mice using an in vivo imager. (A) Biodistribution of i.p. injected ZE and AuZE in C57BL6 mice, which shows the distribution of both ZE and AuZE from 4 to 24 h of observation. The mice were imaged at 710 nm excitation and collected at 820 nm emission. (B) Ex vivo imaging of ZE- and AuZE-treated mice organs under an in vivo imager. The brain, liver, and kidney show fluorescence from ZE and AuZE, indicating their maximum distribution into those respective sites. Source: Reprinted with permission from Kotcherlakota, R., Nimushakavi, S., Roy, A., Yadavalli, H.C., Haque, S., Patra, C.R. (2019). ACS Biomaterials Science & Engineering, 5(10), 5439
5452, Copyright r 2019 American Chemical Society.

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TABLE 2.1 Nanoparticles for diagnosis. Nanoparticle

Target moiety

Function

References

1.

Gadolinium-PEG nanoparticles




Contrast agents

Mekuria et al. (2017)

2.

Gadolinium metallofullerene

Interleukin-13 peptide

MRI

Li et al. (2015)

3.

Iron oxide
doped tungsten nanoparticles




MRI

Clavijo Jordan et al. (2014)

4.

Galium-BNOTA-PRGD2 (68GaPRGD2)

Integrins

PET/CT SCAN

Li et al. (2014)

5.

Pegylated dimeric isoDGR

Radiotracers

NanoScan SPECT/CT

Gao et al. (2019)

6.

IR780-phospholipid micelles

Phospholipids

Carriers for fluorescent dye

S. Li et al. (2017)

7.

Polymeric nanoparticles

CTX

Carriers for fluorescent dye

Han et al. (2016)

8.

Silver nanoplate

Fluorescent dye with F3 peptide

Photoacoustic contrast agents

Ray et al. (2014)

9.

Biosynthesized gold nanoparticles




Fluorescence imaging

Kotcherlakota et al. (2019)

RGD peptide

Imaging of gliomas

Liu et al. (2017)

10. Quantum dots

2.8 Nanomedicine for the treatment of brain cancer There are new advancements taking place for the treatment of brain cancer through nanotechnology. As discussed previously, nanoparticles have helped to overcome several problems associated with surgery, immunotherapy along with radiation therapy, and chemotherapy (Senapati, Mahanta, Kumar, & Maiti, 2018). There have been instances where nanoparticles are loaded or attached with therapeutic agents and biological substances (e.g., targeting agent) for their accumulation in site-specific tumor regions and they enhanced the activity of the attached moieties (Patra et al., 2018; Rosenblum et al., 2018). Some nanoparticles such as gold, magnetic nanoparticles, and other inorganic nanoparticles have the ability to respond to environmental cues such as temperature, pH, and magnetic fields, resulting in a slow discharge of the attached drugs and, thus, increasing their healing efficacy (Bruschi & de Toledo, 2019). Various nanoparticles (metal-based, liposomal, lipid-based, polymeric) and nanoparticle-based targeted drug delivery systems have been used for the treatment of brain cancers under different conditions that are discussed in the subsequent sections.

2.8.1 Metal nanoparticles There are wide ranges of inorganic nanoparticles (copper, gold, carbon, titanium dioxide, iron oxide, silicon dioxide, etc.,) that are being tested for the treatment of brain cancers

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(Teleanu, Chircov, Grumezescu, Volceanov, & Teleanu, 2018). The unique features for which they are recruited for use as therapeutic agents includes their biosafety, the fact that they are well functionalized, and their efficient stability (Kumar, Sharma, & Maitra, 2017; Wu et al., 2019). 2.8.1.1 Silica nanoparticles To overcome the challenge of crossing the BBB and to deliver drugs to the central nervous system, Lungare et al. synthesized mesoporous silica nanoparticles (MSNs) conjugated with hydrophobic chrysin and curcumin, which is a phytochemical. The formed nanoparticles could easily cross the BBB and the antioxidant feature of the phytochemical helped them to act as an active agent for the CNS targeted through olfactory pathways. Several characterization techniques were used for the confirmation of the nanoparticles, which included Fourier transformation infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), high performance liquid chromatography (HPLC), and differential scanning calorimetry (DSC). At a low pH (5.5), the curcumin exhibited enhanced chemical stability and its release was pH dependent. The percentage of release for curcumin and chrysin were 53.2% 6 2.2% and 9.4% 6 0.6% respectively. The bare nanoparticles without the phytochemicals were nonhazardous to olfactory neuroblastoma cells (OBGF400), but upon conjugation with curcumin and chrysin, there was a considerable decrease in cell viability. The buildup of the nanoparticles was also observed inside the cells in both the membrane and cytoplasm with the help of confocal microscopy after 2 h of incubation. Hence silica nanoparticles act as an excellent delivery vehicle for hydrophobic phytochemicals to reach the CNS in order to cure brain cancers (Lungare, Hallam, & Badhan, 2016). Another work was reported by Hu et al., where they designed MSNs coated with polydopamine (PDA) and functionalized with Asn-Gly-Arg (NGR) ligand, which targets the cluster of differentiation 13 (CD13). The formed nanoparticles act as a carrier for doxorubicin (DOX) and are sensitive to pH. The as synthesized nanoparticles exhibited more permeability inside the BBB in vitro along with enhanced accumulation inside the primary brain capillary endothelial cells (BCECs) and in the C6 cells. Also, the tumor tissues in the in vivo and ex vivo tests showed increased gathering. Hence the nanoparticles act as an excellent drug delivery vehicle and are useful for therapeutic application in brain cancers (Hu et al., 2016). 2.8.1.2 Titanium oxide nanoparticles Other than silica nanoparticles, there are cases of titanium oxide (TiO) being used for the treatment of brain cancers. Wang et al. used TiO, which when irradiated with ultraviolet A (UVA), exhibited a strong antiglioma property. The proliferation of the glioma cells decreased when the UVA irradiated nanoparticles were used. The anticancer activity of the nanoparticles was attributed to the BCL2 family of genes revealed during RT-PCR. The in vivo activity of the nanoparticles showed similar results of a decrease in proliferation of glioma tumors along with enhanced apoptosis, broadened area of necrosis, and admirable survivability of the treated group with respect to the control. Therefore these photo-induced TiO nanoparticles act as a potential candidate for glioma therapy (Wang et al., 2011).

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2.8.1.3 Carbon nanodots Carbon nanodots are currently being widely used for the treatment of brain tumors. In this context, Qian et al. fabricated highly crystalline carbon nanodots (HCDDs) for the photothermal therapy (PTT) of brain cancers (Qian et al., 2018). The as synthesized nanoparticles exhibited good photothermal and photoacoustic properties and also possess fluorescence emission, which can be changed. When these carbon dots are irradiated by NIR radiation, it results in the killing of cancer cells. The nanodots, when applied to U87 cell tumor bearing mice, exhibited dual-modal imaging guided PTT along with accumulation and regression of the tumor. Fig. 2.5A
D depicts the localization of the formed nanoparticles in the brain of the injected tumor bearing mice with respect to the control and saline groups. The figure depicts the organs of the sacrificed mice, showing the presence of the nanoparticles in the brain along with the liver and kidney. The photoacoustic images are displayed at different concentrations. Hence the as synthesized nanoparticles can perform as therapeutic and diagnostic agents (Qian et al., 2018). 2.8.1.4 Magnetic nanoparticles Several scientists have reported the use of iron oxide nanoparticles for the treatment of brain cancers as they can easily cross the BBB (Teleanu, Chircov, Grumezescu, & Teleanu, 2019). Magnetic hyperthermia (MHT) is a new way of treating solid tumors, which are difficult to treat with chemotherapy (Spirou, Basini, Lascialfari, Sangregorio, & Innocenti, 2018). The underlying mechanism of the treatment of cancer includes escalating the temperature of the local tumor without affecting the surrounding normal tissues (Goedegebuure, de Klerk, Bass, Derks, & Thijssen, 2019). Utilizing this mechanism, Sanz et al. incorporated magnetic nanoparticles into human neuroblastoma cells (SH-SY5Y), fabricated them in the form of solid tumors, and applied MHT. The results revealed that there was a decline in cell viability in comparison to those cells that had undergone exogenous heating sources (EHT). The treated cells, when viewed with confocal microscopy, revealed that the MHT caused the destruction of the cells locally with the help of magnetic nanoheaters. Hence this proves to be an excellent method for the treatment of brain cancers (Sanz et al., 2017). With reference to magnetic properties, Shah et al. designed magnetic core
shell nanoparticles (MCNPs) functionalized with amphipathic tail-anchoring peptide (ATAP). This formed nanoparticles that target the mitochondria and are proapoptotic. Thus the formed nanoparticles accumulate in the metastatic tumors of the brain and this increases the chemotherapeutic activity of the ATAP since it is delivered to its desired site. The MCNPs were further utilized for hyperthermia activity and they enhanced the therapeutic efficacy of ATAP. Overall, the MCNPs along with the ATAP resulted in increased mitochondrial disorder leading to the enhanced apoptosis of the cancer cells (Shah et al., 2014). Similarly, Saalik et al. designed iron oxide nanoworms functionalized with glioblastoma-targeting ligand LinTT1 (Sa¨a¨lik et al., 2019). The fabricated nanoparticles exhibited colocalization with the macrophages and lymphatic vessels of the tumor. The in vivo mice model having glioblastoma tumors exhibited increased survivability when injected with the formed nanoparticles due to increased anticancer activity. Fig. 2.6 depicts confocal images of the brain tumor sections of the glioma injected mice. The tumor sections of the nanoparticle-treated mice clearly show greater uptake of the targeted ligand

Nano Drug Delivery Strategies for the Treatment of Cancers

FIGURE 2.5 (A) Confocal fluorescence images of U87 glioma cells incubated with 150 μg/mL HCCDs for 2 h under different excitations.

Bar 5 100 μm. (B) In vivo fluorescence images of glioma-bearing mice at different time points after intravenous administration of saline and HCCDs respectively. The ex vivo images of major organs were taken at 120 min after administration. (C) Photoacoustic images of HCCDs solution with different concentrations. (D) Real-time photoacoustic images of glioma in mice at different time points after intravenous administration of HCCDs. Source: Reprinted with permission from Qian, M., Du, Y., Wang, S., Li, C., Jiang, H., Shi, W., . . . Huang, R. (2018). Highly crystalline multicolor carbon nanodots for dual-modal imaging-guided photothermal therapy of glioma. ACS Applied Materials & Interfaces, 10(4), 4031
4040, Copyright r 2018 American Chemical Society.

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FIGURE 2.6 FAM-LinTT1-iron oxide nanoworms home to mouse and human GBM. Mice bearing GBM xenografts of mouse (005, WT-GBM, VEGF-KO-GBM, intracranial) or of human origin (NCH421k, intracranial; U87MG, subcutaneous) were injected intravenously with 7.5 mg/kg FAM-LinTT1-NW or FAM-NW, and allowed to circulate for 5 h followed by cardiac perfusion of the animals. Cryosections from subcutaneous tumor or coronal cryosections from brain with GBM were stained by anti-FAM (NWs), anti-CD31 (blood vessels), and DAPI (cell nuclei), and visualized by confocal microscopy. Tu 5 tumor, BP 5 brain parenchyma. Insets show the FAM channel alone. Arrowheads indicate LinTT1-NW signal. Scale bars 5 100 μm in low magnification panels; 50 μm in high magnification panel. FAM-LinTT1-NW and FAM-NW signal intensity in GBM tissue was quantified from 6 to 9 confocal images and analyzed by Image J. Statistical analysis was performed by one-way ANOVA. Error bars: standard deviation. Source: Reprinted with permission from Sa¨a¨lik, P., Lingasamy, P., Toome, K., Mastandrea, I., Rousso-Noori, L., Tobi, A., . . . Teesalu, T. (2019). Peptide-guided nanoparticles for glioblastoma targeting. Journal of Controlled Release, 308, 109
118, Copyright r 2019 Elsevier.

with respect to the untargeted free nanoparticles. Since the iron oxide nanoworms are proapoptotic, their increased accumulation in tumors due to the targeted peptide increased the killing of the tumor cells. Therefore the LinTT1-conjugated nanoparticles could easily accumulate in the brain tumors of mice and exhibited enhanced regression of tumors (Sa¨a¨lik et al., 2019). 2.8.1.5 Gold nanoparticles Gold nanoparticles are extensively used for the treatment of brain cancers. They are used as an excellent drug delivery vehicle and exhibit admirable therapeutic and targeting properties (Singh et al., 2018). Utilizing the properties of gold nanoparticles, Ruan et al. designed a complex nanosystem abbreviated as AUNP-A&C (comprising of AUNP modified with Ala-Ala-Asn-Cys-Lys and AUNP modified with 2-cyano-6-aminobenzothiazole). As a result, the retention of the formed nanoparticles within the tumor increased. The underlying mechanism is that the gold nanoparticles are protected from exocytosis and this prevents the nanoparticles from flowing back into the blood. They eventually conjugated DOX with the help of a linker that was pH sensitive to the nanoparticles, which increased the survivability of the mice having tumors in comparison to the control group.

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The formed nanoparticles were even exploited for imaging purposes. With the tumor accumulation property of the nanoparticles they can be used in future for brain cancer therapy (Ruan et al., 2016). Khonkow et al. designed gold nanoparticles and conjugated them with membranes derived from exosomes and targeted the formed nanoparticles to brain cells. The membranes were formed from mammalian cells that were genetically engineered with the help of extrusion and mechanical methods. The testing of the nanoparticles was done under laminar flow by their cohering to brain cells and their increased transport across the BBB. In vivo imaging of the formed nanoparticles revealed that they accumulated in the brain of the mice that were administered through intravenous injection. Hence the formed nanoparticles can act as a potential approach for treating brain cancers and other brain-related diseases (Khongkow et al., 2019). In another application, Cheng et al. functionalized gold nanoparticles with a transactivator of transcription (TAT) peptide and used them as a delivery agent. The formed nanoparticles further acted as a delivery vehicle for DOX and contrast agent Gd31, which could easily cross the BBB and reach the brain tumor. In vivo studies of the formed nanoparticles were performed in a mice model and were accomplished through xenografts of intracranial glioma through intraperitoneal injection. The results demonstrated that it increased the survivability of the treated mice. The nanoparticles increased the retention of the contrast agent inside the tumor as compared to the free form of the Gd(3 1 ) chelates. Therefore the overall work exhibited the potential of using these nanoparticles as a drug delivery vehicle along with their contribution in imaging (Cheng, Dai, et al., 2014; Cheng, Morshed, et al., 2014). There is a variety of work that has been done using gold nanoparticles for the treatment of brain cancers. Bobyk et al. used gold nanoparticles for exploiting their radiosensitization property by irradiating them with synchrotron radiation having relatively low energy in order to treat gliomas (Bobyk et al., 2013). The effects of the formed nanoparticles were checked in vitro in F98 glioma cells and in vivo in tumor bearing mice after intracerebral injection. In both cases, after irradiation of the nanoparticles, there was a regression of tumors and the survivability of the tumor bearing mice increased. Fig. 2.7A
B shows the internalization of the gold nanoparticles by transmission electron microscopy (TEM). The TEM images indicate that the gold nanoparticles were accumulated in the intracellular medium, near the lysosomes along with endosomes. This suggests that the gold nanoparticles were responsible for the tumor regression in the mice when irradiated with low energy radiation (Bobyk et al., 2013).

2.8.2 Liposomes Liposomes are widely used for the treatment of gliomas, in which they are primarily used as vehicles for carrying drugs and other therapeutic agents to the targeted sites since they can easily cross the BBB (Nam et al., 2018). Shaw et al. designed nanoliposomes conjugated with docetaxel and delivered them to solid brain tumors since the formed liposomes can easily cross the BBB. The nanoliposomes were synthesized by hydration method and several characterization techniques were employed for their characterization. In vitro studies in C6 glioma cells exhibited the desired results. Since the size of the liposomes was small, it resulted in sustained drug release. Also, in vivo studies in the brain

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FIGURE 2.7 Microscopy electron imaging of biopsies of brain rats 1 day (A) and 6 days (B) after injection of 15 μL of 15 nm AuNPs (15 mg/mL). Scale bars 5 1 μm (A) and 2 μm (B). Source: Reprinted with permission from Bobyk, L., Edouard, M., Deman, P., Vautrin, M., Pernet-Gallay, K., Delaroche, J., . . . Elleaume, H. (2013). Photoactivation of gold nanoparticles for glioma treatment. Nanomedicine: Nanotechnology, Biology and Medicine, 9(7), 1089
1097, Copyright r 2013 Elsevier.

tumor model of rats showed a greater amount of drug retention in the tumors with the formed nanoliposomes as compared to the free drug. Hence the liposomes can be used to deliver therapeutic agents in the future (Shaw et al., 2017). Scientists have discovered that another way of combating cancer is by targeting thermoresponsive therapeutic agents that work under hyperthermic circumstances (Senapati et al., 2018). In this context, Rehman et al. designed thermoresponsive lipid nanoparticles (TLNs) for therapeutic application in brain cancer since most available thermoresponsive agents find it difficult to cross the BBB. The process of the formation of TLNs involves a hot melt encapsulation process. The characterization of the TLNs was done by various techniques, which revealed a ,270 nm size along with a spherical morphology. The TLNs were further loaded with paclitaxel and they exhibited a faster rate of diffusion at 39 C than at 37 C and proved to be more cytotoxic to glioblastoma cells at higher temperatures. At increased temperatures they formed therapeutic particles that took a liquid state and could easily cross the BBB, proving their potential as a therapeutic agent in killing glioblastoma cells (Rehman et al., 2017). Gliomas are known to be extremely invasive, which is one of the major drawbacks in treating them. Therefore Ying et al. developed liposomes that can penetrate the BBB and can induce apoptosis of cancer stem cells. They conjugated anticancer ursolic acids (UA), which decrease the proliferation of glioma cells, and epigallocatechin 3-gallate (EGCG) to the liposomes for the induction of the apoptosis of C6 glioma cells. The liposomes could easily cross the BBB and accumulated inside the brain tumors since p-aminophenyl-α-D-manno-pyranoside (MAN) was used as a targeting ligand. In vitro as well the in vivo experiments revealed that the formed liposomes upregulated the anticancer ability of the drugs on C6 glioma cells as well as glioma stem cells. The survivability of the treated mice was also increased as compared to the control untreated ones. Hence the targeted liposomes serve as admirable candidates for the

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treatment of brain cancer (Ying et al., 2017). A new method of treating gliomas through radiosensitizers is being explored. Hua et al. (2018) designed liposome-based nanoparticles that are used as targeted radiosensitizers (hypoxia-responsive lipid-poly-nanoparticles for glioma and radiotherapy). They fabricated angiopep-2-lipid-poly-(metroniadazoles)n (ALP-(MIs)n) as a drug that was sensitive to the hypoxic conditions of the tumor and increased the killing of the glioma through both radiation as well as chemotherapy. Fig. 2.8A
I depicts all the activities of the formed nanoparticles on the gliomas in a C6GFP-Luci glioma mouse model. The figures exhibit that the nanoparticle-injected mice showed inhibition of the gliomas as compared to the control group. Ki67 and tunnel assay images also depict the regression of the tumors of the treated group. H&E staining images clearly show that the nanoparticle-treated mice had smaller gliomas compared to the other groups. Therefore these lipid nanoparticles can act as an excellent candidate for treating glioma (hypoxia-responsive lipid-poly-nanoparticles for glioma and radiotherapy). Liposomes that are FDA approved are widely recommended for the treatment of glioma since they can easily cross the BBB and are less toxic to the systemic circulation. Lam et al. developed pegylated transferring nanoparticles and conjugated them with temozolomide and bromodomain inhibitor JQ1 (Lam et al., 2018). When the as synthesized nanoparticles were injected into two intracranial orthotopic mice models, they exhibited decreases in the tumor content and increases in the survivability of the tumor bearing mice. In Fig. 2.9A
E, multiphoton imaging and confocal images visibly depict that the functionalized liposomes could easily cross the BBB and the leaky microvessels of the endothelium, and accumulate more in the tumor tissues of the mice brain as compared to the other groups. Hence the work evidently demonstrates that the liposomal formulation possesses the potential to be used for glioma therapy along with other nervous diseases (Lam et al., 2018).

2.8.3 Polymeric nanoparticles Polymeric nanoparticles are considered to be an efficient targeted drug delivery agent for treating brain cancers (Patra et al., 2018). Some polymeric nanoparticles include poly (lactic acid) (PLA), poly(glycolic acid) (PGA), and PLGA. Taking advantage of the properties of polymers, Li et al. designed small-sized micelles based on poly(2-ethyl-2-oxazoline)b-poly(ε-caprolactone) (PEtOz-SS-PCL), which is an amphiphilic copolymer block. The formed micelles were further conjugated with DOX, and because of the reduced tumor environment, there was rapid release of the drug. This was further proved by in vivo experiments in an orthotopic glioblastoma mouse model where the small-sized, fabricated polymers loaded with DOX exhibited excellent anticancer activity with reference to largesized micelles. This study opens new avenues for changing the size of polymers and forming new bonds with drugs, resulting in the treatment of brain cancers (Y. Li et al., 2017). There are searches for new mechanisms for treating brain cancer, and one of them is the inhibition of the enzyme aromatase; in this context, Tivnan et al. synthesized PLGA encapsulating letrozole inhibitor, which inhibits aromatase. Moreover, the formed nanoparticles were further linked with anti-GD2 antibody ch14.18/CHO, which helps in the targeting of glioblastoma cells that are GD2 positive. The overall as synthesized nanoparticles along with temozolomide resulted in a decrease in the cell proliferation of glioblastoma cells that

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FIGURE 2.8 In vivo efficacy in a C6-GFP-Luci glioma mouse model. (A) C6-GFP-Luci-bearing mice received three injections of PBS, PBS and RT, free DOX and RT, AL-PLGA and RT, ALP-(MIs)25 and RT, ALP-(MIs)48 and RT, AL-PLGA/DOX and RT group, ALP-(MIs)25/DOX and RT, and ALP-(MIs)48/DOX and RT at a dose of 3 mg/kg DOX and 14.1 mg/kg P-(MIs) on days 12, 14, and 16 with 2 Gy RT. (B) Bioluminescence signal change correlating to tumor growth over time following inoculation. (C) Quantification of the tumor bioluminescence signal (n 5 5 mice per group); **P , .01, one-way ANOVA; n.s. indicates no statistical significance. (D) Relative

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2. Nanomedicine: future therapy for brain cancers

were cocultured with colorectal cancer cells. Hence the formed nanoparticles can be used as an efficient therapeutic agent for brain tumors (Tivnan et al., 2017).

2.8.4 Dendrimers Dendrimers can serve as excellent drug delivery vehicles because of their ability to transverse the BBB (Santos et al., 2018). In this context, Li et al. synthesized polyamidoamine (PAMAM) dendrimers that were conjugated with tamoxifen on the interior and transferrin on the exterior. The G4-DOX-PEG-Tf-TAM was pH sensitive and showed higher rates of drug release in weak acidic conditions. The dendrimers showed a highly superior ability to cross the BBB and induce the death of glioblastoma cells. Furthermore, they lead to a significant reduction in the tumor volume (up to 38%) as compared to the control owing to the increase of DOX concentration in the avascular C6 glioma spheroid, which makes these an excellent candidate for the treatment of brain tumors (Li et al., 2012). In another study, Zhao et al. fabricated dendrimers with chlorotoxin, and they used radionuclide 131I for labeling. The formed dendrimers were used for SPECT imaging as well as for cancer radiotherapy. The dendrimers used were generation five amine-terminated poly(amidoamine). The as synthesized dendrimers exhibited admirable biocompatibility and target cancer cells, specifically those that express greater matrix metallopeptidase 2 (MMP2). They showed good stable properties along with improved radiochemical purity. The dendrimers exhibited an enhanced accumulation inside the tumors and showed an increased SPECT signal intensity. Also, tumor regression was observed in the tumor bearing mice that were treated with the dendrimers and their survivability was also increased. Therefore these multifunctional dendrimers have the capability to be used for both diagnostic and therapeutic purposes (Zhao et al., 2015). Table 2.2 depicts the therapeutic properties of different nanoparticles in the treatment of brain cancers. The surface of the nanoparticles has been modified in some reports enhancing their targeting abilities along with their therapeutic efficacy.

2.9 Nanomedicines for brain cancer using a combinatorial approach The previous discussions focused mainly on the single application of nanoparticles. But to meet the current needs for the treatment and diagnosis of brain cancers, multifunctional nanoparticles that exhibit theranostic features are mostly explored (Singh et al., 2018).

L

tumor inhibitory rate for each treatment; **P , .01, one-way ANOVA; n.s. indicates no statistical significance. (E) Representative H&E-stained images of coronal sections from mouse brains with orthotopic tumors. (F) Ki67 staining of coronal sections from mouse brains with orthotopic tumors. Scale bar 5 50 μm. (G) TUNEL staining of coronal sections from mouse brains with orthotopic tumors. Scale bar 5 50 μm. (H) Kaplan
Meier survival curves for mice (n 5 10), ***P , .001, one-way ANOVA. (I) Body weight change. Data are presented as the mean 6 SD. Source: Reprinted with permission from Hua, L., Wang, Z., Zhao, L., Mao, H., Wang, G., Zhang, K., . . . Liu, H. (2018). Hypoxia responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo-and radiotherapy. Theranostics, 8(18):5088
5105, Copyright r 2019 Ivyspring International Publisher.

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61

FIGURE 2.9

Transferrin-functionalized nanoparticles cross the intact BBB. (A) Schematic representation of a pegylated dual drug-loaded liposome that can be functionalized to enhance transport across the BBB and targeted to glioma cells. (B) Cranial window (black oval delineating region of craniotomy) exposing the brain for in vivo multiphoton imaging. Multiphoton images of (C) a brain microvessel showing lack of transport of hemagglutininPEG2K-Cy5.5 liposomes across the BBB; (D) diffusion of transferrin-PEG2K-Cy5.5 (Tf-NP) liposomes across the endothelium of a brain microvessel (outlined in white) with nanoparticle aggregates in the subarachnoid space (white arrows); and (E) composite image showing the accumulation of Tf-NP liposomes in the endothelial wall of a brain microvessel (white arrows) with diffusion across the BBB and aggregation of liposomal nanoparticles in the surrounding brain milieu. White outline depicts bony edge of the cranial window with bone second harmonic signal in blue. Images were taken 24 h following a single tail vein injection of nanoparticles. All scale bars 5 25 μm. Source: Reprinted with permission from Lam, F. C., Morton, S. W., Wyckoff, J., Vu Han, T.-L., Hwang, M. K., Maffa, A., . . . Hammond, P. T. (2018). Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nature Communications, 9(1), 1991, Copyright r 2018, Springer Nature.

Gold nanoparticles, carbon nanodots, and magnetic nanoparticles are a few such nanoparticles that exhibit dual properties.

2.9.1 Combination of magnetic resonance imaging and therapy Due to the aggressive nature of glioblastoma, treatments using a combination of therapeutic methods would have a greater effect as compared to a single treatment regime (Shergalis, Bankhead, Luesakul, Muangsin, & Neamati, 2018). Ganipineni et al. developed pegylated PLGA-based nanoparticles that were conjugated with paclitaxel (PTX) and superparamagnetic iron oxide (SPIO). The superparamagnetic properties of the nanoparticles resulted in the increased accumulation of the nanoparticles in the tumor in a dose-dependent manner

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TABLE 2.2 Nanoparticles for treatment of brain cancer. Sr. No

Nanoparticle

Target moiety

Function

References

1.

Mesoporous silica nanoparticles

Chrysin and curcumin

Olfactory neuroblastoma

Lungare et al. (2016)

2.

Mesoporous silica nanoparticles

Asn-Gly-Arg ligand

Brain cancer

Hu et al. (2016)

3.

Titanium oxide

Irradiated with UVA

Apoptosis and necrosis of glioma tumors

Wang et al. (2011)

4.

Highly crystalline carbon nanodots




Regression of gliomas

Qian et al. (2018)

5.

Magnetic nanoparticles

Exogenous heating sources

Destruction of gliomas

Sanz et al. (2017)

6.

Iron oxide nanoworms

LinTT1

Apoptosis of the tumors

Sa¨a¨lik et al. (2019)

7.

Gold nanoparticles

DOX with pH sensitive linker

Regression of gliomas

Ruan et al. (2016)

8.

Gold nanoparticles

Brain targeted exosomes

Enhanced transportation across the BBB

Khongkow et al. (2019)

9.

Gold nanoparticles

Transactivator of transcription

Delivery vehicle for DOX and contrast agents Gd31

Cheng, Dai, et al. (2014); Cheng, Morshed, et al. (2014)

10.

Thermoresponsive lipid nanoparticles




Cytotoxic to gliomas

Rehman et al. (2017)

11.

Liposomes

Ursolic acids and Induction of apoptosis of EGCG brain cancer cells

Ying et al. (2017)

12.

PEtOz-SS-PCL

DOX

Anticancer activity

Y. Li et al. (2017)

13.

PLGA nanoparticles

Letrozole

Decrease in cell proliferation of gliomas

Tivnan et al. (2017)

14.

Poly(amidoamine) dendrimers

Transferrin and tamoxifen

Inhibition effect on drug efflux transportation

Y. Li et al. (2012)

along with increased antitumor effects. Therefore the survivability of the tumor-induced mice increased as compared to those treated by passive treatments and treatments using saline solutions. This was demonstrated by MRI, which showed a disruption of the BBB in the area of the tumor, while ex vivo studies for biodistribution showed an increased accumulation of PTX/SPIO nanoparticles in the tumor area. Thus these PTX/SPIO nanoparticles act as an efficient anticancer agent as well as a diagnostic tool for brain cancer theranostic studies (Ganipineni et al., 2018). There are certain reports of resistance to temozolomide occurring in brain cancer patients due to O6-methylguanine
DNA methyltransferase (MGMT). Therefore to overcome this, O6-benzylguanine (BG) is used, but it has been reported that BG has poor pharmacokinetics. In this context, Stephan et al. synthesized SPIO nanoparticles coated with a chitosan
PEG copolymer, to which BG and chlorotoxin were covalently linked. These

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63

nanoparticles exhibited excellent physicochemical properties that allowed for the proper release and exchange of the nanoparticles within the glioma cells. Also, there was a significant reduction in MGMT activity in the brain cancer cells comparable to free BG
treated cells. The treatment with the formed nanoparticles led to a significant increase in the sensitivity of the cells to temozolomide treatments. The treatment led to a good biodistribution of the nanoparticles within the brain tumor with a threefold increase in the survivability of brain cancer xenograft mice as compared to the untreated ones. Pharmacological studies exhibited similar results for liver toxicity for saline and nanoparticle treatments. Overall, the as synthesized nanoparticles could be used as a feasible nanomedicine in the current treatment routines for patients with brain cancer cells expressing MGMT (Stephen et al., 2014).

2.9.2 Combination of optical imaging and therapy Reports suggest the use of nanoparticles for optical theranostic applications. Xu et al. synthesized biocompatible silk fibroin nanoparticles with indocyanine green (ICG) encapsulated in them. Due to the strong binding efficiency of the silk to most colorants, the ICG was easily encapsulated in the nanoparticles with a high efficiency and slow release profile. Also, indocyanine green-silk fibroin nanoparticles (ICG-SFNPs) were proven to be more photothermally stable as compared to free ICG. Additionally, in vitro studies showed that the nanoparticles were easily up taken by C6 tumor cells. In vivo imaging studies also showed the accumulation of the nanoparticles at the tumor site in mice bearing C6 cells. Exposure to NIR increased the temperature of the ICG-SFNPs, which increased the temperature of the tumor site, thereby killing the tumor cells. Treatment of the mice with the nanoparticles yielded a significant reduction in tumor growth as compared to the control groups. Thus ICP-SFNPs could be used as an effective agent for tumor therapy and imaging (Xu et al., 2018). Conjugated polymer nanoparticles are increasingly becoming used as theranostic nanoplatforms with photoacoustic imaging (PA) and PTT properties. Their applications are, however, limited by the availability of design guidelines with good PA and PTT properties. Guo et al. designed three different conjugated polymer nanoparticles with different electron acceptors (A) and a planar electron donor (D), and they demonstrated that the PA and PTT performance was affected by the D
A strength (Guo et al., 2017). These nanoparticles had superior biocompatibility and also had good cytotoxicity to tumor cells. Fig. 2.10A
F depicts infrared thermal images of the xenograft tumor mice. The tumor groups showed increases in temperature upon treatment, but the control groups exhibited little increase, indicating the effects of nanoparticles on tumors. The survivability graphs represent the increased survivability of the nanoparticle-treated mice with respect to the control. Even the H&E staining shows a decreased tumor size when the nanoparticle irradiation was given to the tumor bearing mice due to increased necrosis. Moreover, they exhibited excellent PA contrast and deeper tumor tissue imaging (Guo et al., 2017).

2.9.3 Combination of multimodal imaging and therapy Qian et al. synthesized multicolor HCCDs through an in situ solid-state transformation procedure with a hydrophilic surface, which gave them decent photoacoustic and

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2. Nanomedicine: future therapy for brain cancers

FIGURE 2.10

In vivo PTT of mice bearing subcutaneous U87 xenograft tumors, which were divided into four groups, including a PBS group, nanoparticle group, laser group, and laser and nanoparticle group. (A) Infrared thermal images of mice under NIR laser irradiation (808 nm, 0.8 W/cm2). (B) Tumor growth curves. (C) Survival curves. (D) Mice body weight curves. (E) H&E-stained images of tumor sections from mice after 4 h of PTT treatment (magnification: 400 3 ). (F) Representative photos of mice. Source: Reprinted with permission from Guo, B., Sheng, Z., Hu, D., Li, A., Xu, S., Manghnani, P. N., . . . Liu, B. (2017). Molecular engineering of conjugated polymers for biocompatible organic nanoparticles with highly efficient photoacoustic and photothermal performance in cancer theranostics. ACS Nano, 11(10), 10124
10134, Copyright r 2017, American Chemical Society.

photothermal characteristics along with tunable fluorescence emission. Owing to their small size, the HCCDs could easily transverse the BBB and get accumulated in the glioma cells. Furthermore, these carbon nanodots were biocompatible to normal cells, but were cytotoxic to tumor cells. The results were successfully demonstrated in U87 gliomabearing mice and also by CCK-8 assay (Qian et al., 2018).

2.10 Future perspectives and challenges With the advent of nanotechnology, there has been an increase in the potential to reach success in the field of biomedical applications. Nanoparticles are being used both as diagnostic and therapeutic agents. Nanoparticles, with their admirable properties and features, can be used as an excellent alternative for the commercially available diagnostic agents and treatments, which have their own disadvantages and difficulties (Barui, Nethi, Haque, Basuthakur, & Patra, 2019). Several critical diseases are being cured with the help of nanotechnology such as brain cancer, which is one of the leading causes of mortality and morbidity worldwide. The commercially available therapeutic agents available have many drawbacks that can be overcome by the potential use of nanomedicine. Numerous reports have been cited where nanoparticles were used as an excellent alternative in theranostic applications in brain cancers. A large number of nanoparticles are under experimental

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65

processes, receiving FDA approvals, and under clinical trials for the treatment of diseases (Martinelli, Pucci, & Ciofani, 2019). But in order to enhance the activity of nanoparticles, a few things need to be considered, which are discussed here. The first and foremost is the surface functionalization of nanoparticles. This is to enhance the ability of nanoparticles in order for new drug targets and moieties to be attached onto their surface. As a result, they reaches tumor sites more efficiently by crossing the BBB (Navya et al., 2019). The second step is to increase the usage of lipids and polymer-based nanoparticles such as liposomes, polymers, dendrimers, and micelles since these nanoparticles possess less significant toxicity, are effective against various pH values and temperatures, and some are FDA approved (Ventola, 2017). The third step is that more protein-based and inorganic nanoparticles need to be synthesized as they have wide potential to act as vectors. Inorganic nanoparticles have various structural properties that can be exploited for the treatment and diagnosis of brain cancers since they have magnetic, thermal, and fluorescent properties (Wang, Li, Cheng, & Yuan, 2016). This makes them potential candidates for use as contrast agents in diagnosis and as targeting agents in therapeutics. Additionally, the size of the formed nanoparticles should be small enough to cross the BBB and their stability has to be maximal in order to be retained inside tumors and enhance their therapeutic time. But there are still many drawbacks and challenges that prevail, which need to be addressed in order to enhance the treatment efficacy in brain cancers. The first and the foremost challenge is the route of administration of nanoparticles to cross the BBB. It has been found that by employing certain routes, nanoparticles do not reach the desired site. The second challenge refers to the toxic effects of nanoparticles, which must be considered in order for their long-term usage (Patel & Patel, 2017). Most nanoparticles possess toxicity due to their different structures or surface modification. The third challenge that needs to be addressed is their process of synthesis, production costs, manufacturing problems, and their ultimate entry into the world market of clinical trials. The fourth issue is that during their long production time, the containers or the manufacturing units used need to be cleaned so that they do not hamper the quality of the nanoparticles and their properties (Rogers & Jensen, 2019). Fifth and finally, the time of retention of nanoparticles within tumors along with normal organs should be assessed and an easy clearance method of nanoparticles has to be employed. The retention of nanoparticles within the body is further checked by pharmacokinetics and pharmacodynamics studies, which are the toxicity tests. Even the immunological response generated by nanoparticles inside the body is verified by different immunologic assays and tests for their further potential use in the fields of therapeutics and diagnostics (Zottel et al., 2019).

2.11 Conclusion Brain cancers are considered to be the most invasive type of cancers and a large number of methods are being evaluated in order to eliminate and curb them. Nanoparticles have emerged as new age materials for the treatment and diagnosis of brain cancers. In order to treat brain cancers, a large number of nanoparticles are in the FDA preapproval phases. In this chapter, brain cancers, their global market value, and current research circumstances

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have been highlighted. Furthermore, the properties of nanoparticles for the efficient treatment of brain cancers, the different mechanisms employed to reach targeted tumor sites, and different types of nanoparticles for the treatment and diagnosis of brain cancers have also been discussed. Finally, the chapter ends with a discussion of the future perspective and challenges to be met in order to utilize nanoparticles for future clinical biomedical applications in brain cancers.

Acknowledgment Financial support from Nano Mission-DST (SR/NM/NS-1252/2013; GAP 570), New Delhi, to C.R.P. is duly acknowledged. S.H is thankful to CSIR, New Delhi, for supporting the Junior Research Fellowship. The authors are thankful to the Director, CSIR-IICT for his support, encouragement and keen interest in this work. IICT Manuscript No. IICT/Pubs./2019/400 dated November 14, 2019 for this book chapter is duly acknowledged.

Abbreviations ATP ATAP AuNP A32 BBB BCECs BCL2 CAGR CBTRUS CD13 CNS CT CTX DLS DOX DSC EGCG EGFRvIII EHT EPR FT-IR GBM 68Ga-PRGD2 HCDDs HPLC IL-13 IR MAN MCNP MHT MRI MSNs NGR NIRF

Adenosine triphosphate Amphipathic tail-anchoring peptide Gold nanoparticle Aptamer 32 Blood
brain barrier Brain capillary endothelial cells B-cell lymphoma 2 Compound annual growth rate Central Brain Tumor Registry of the United States Cluster of differentiation 13 Central nervous system Computed tomography Chlorotoxin Dynamic light scattering Doxorubicin Differential scanning calorimetry Epigallocatechin 3-gallate Epidermal growth factor receptor variant III Exogenous heating sources Enhanced permeability and retention Fourier transformation infrared spectroscopy Glioblastoma multiforme Gallium-BNOTA-PRGD2 Highly crystalline carbon nanodots High-performance liquid chromatography Interleukin-13 Infrared spectroscopy P-aminophenyl-α-D-manno-pyranoside Magnetic core
shell nanoparticles Magnetic hyperthermia Magnetic resonance imaging Mesoporous silica nanoparticles Asn-gly-arg Near-infrared fluorescence

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References

PAMAM PDA PEG PET PEtOz-SS-PCL PGA PLA PLGA PTT RGD RT-PCR TAT TGA TiO TLN UA UVA XPS WHO

67

Polyamidoamine Polydopamine Polyethylene glycol Positron emission tomography Poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) Poly(glycolic acid) Poly(lactic acid) Poly(lactic-co-glycolic acid) Photothermal therapy Arginylglycylaspartic acid Reverse transcription polymerase chain reaction Transactivator of transcription Thermogravimetric analysis Titanium oxide Thermoresponsive lipid nanoparticles Ursolic acids Ultraviolet A X-ray photoelectron spectroscopy World Health Organization

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Nano Drug Delivery Strategies for the Treatment of Cancers

C H A P T E R

3 Nano drug delivery strategies for the treatment and diagnosis of oral and throat cancers Sandra J. Perdomo1, Angela Fonseca-Benı´tez1, Andre´s Cardona-Mendoza1, Consuelo Romero-Sa´nchez1 and Jenny Pa´rraga2 1

Cellular and Molecular Immunology Research Group (INMUBO), Universidad El Bosque, Bogota´, Colombia 2Biomaterials and Tissue Engineering group, BioMediTech, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

3.1 Oral and throat cancers Mouth and throat cancers are part of a group of tumors that arise at different anatomical sites in the head and neck, including the oropharynx, hypopharynx, and larynx (Marur & Forastiere, 2016; Stransky et al., 2011). Head and neck squamous cell (HNSC) carcinomas (HNSCC) comprise the seventh most common type of cancer worldwide. The incidence rates are 5.7% in Latin America and the Caribbean and 2.3 per 100,000 worldwide (Siegel, Miller, & Jemal, 2019) with a mortality rate of 4.5%, according to the World Health Organization (WHO). HNSC is a heterogeneous disease, and the significant risk factors associated with it include the use of tobacco and alcohol and infection with high-risk genotypes of the human papillomavirus (HPV). Other risk factors may be associated with poor oral hygiene and microbiome, diet, and epigenetic changes (Rettig & D’Souza, 2015). The disease is mainly present in older males. However, women can also suffer from this type of cancer.

3.1.1 Conventional therapies for the management of oral cancers Current therapeutic strategies for oral cancer are based on tumor, nodule, and metastasis (TNM) classification of the primary tumor, the patient’s general state of health, and the

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3. Nano drug delivery strategies for the treatment and diagnosis of oral and throat cancers

histological subtype. However, management is limited to surgery, chemotherapy, radiotherapy, or combined treatment. The choice of therapy depends on the stage of the cancer. Patients with early-stage tumors are treated with surgery and radiotherapy alone (Marur & Forastiere, 2016), although most are treated with adjuvant chemotherapy before and after surgery. The most common chemotherapeutics used in the treatment of oral cancer are cisplatin, 5-fluorouracil (5-FU), paclitaxel, doxorubicin, docetaxel, and methotrexate. However, the protocol for choosing the appropriate chemotherapeutic treatment is unclear, and all patients can be candidates for radiation and drug therapies (Hartner, 2018). The adverse effects of chemotherapeutics that can occur in patients with different types of oral cancer include mucositis, cardiac ischemia, thromboembolic complications, conjunctivitis, interstitial pneumonitis, nausea, and vomiting (Livshits, Rao, & Smith, 2014). These side effects can be related to the drug pharmacokinetics and pharmacodynamics as well as their bioavailability in tissues. Moreover, surgery is highly invasive, because the procedure is based on the excision of the lesion, that is, mandibulectomy, maxillectomy, glossectomy, and/or neck dissection (Shanti & O’Malley, 2018). In general, conventional treatments decrease the quality of life for patients. Radiotherapy can also be offered either before or after surgery. This treatment is a coadjuvant to chemotherapy when patients have a poor prognosis; for example, when a positive margin has been found in the biopsy after surgery. However, this choice for therapy depends on the size of the tumor and the presence of cancer-positive lymph nodes (Huang, 2013). All patients diagnosed with any oral or throat cancer are treated with one or more chemotherapeutic drugs. The combination most used is cisplatin, 5-FU, and Taxol (paclitaxel
docetaxel) or cisplatin, bleomycin, and methotrexate. The treatment begins with the administration of cisplatin (Alvarez, Garcı´a, Iruegas, & Garcı´a-Garcı´a, 2015).

3.1.2 Cisplatin Cis-diamminedichloroplatinum is an antineoplastic agent widely used in numerous human cancers such as sarcomas and ovarian, breast, oral, head and neck, lung, and testicular cancers (Lacas et al., 2017). The mode of action is related to its capacity to damage DNA by crosslinking the purine bases, interfering with the DNA restoration mechanism, and finally inducing cell death (Dasari & Tchounwou, 2014).

3.1.3 5-Fluorouracil Fluoropyrimidine 5-FU, a uracil analog, is a type of antimetabolite medication. It enters cells quickly using the uracil transport mechanism and incorporates into essential DNA or RNA structures, and prevents the normal synthesis of these molecules by inhibiting thymidylate synthase enzymes (Longley, Harkin, & Johnston, 2003).

3.1.4 Paclitaxel/docetaxel Taxane is a microtubule-stabilizing drug used in combination with other chemotherapy agents. Its mechanism of action is based on its apoptotic effects. Paclitaxel reduces microtubule polymerization in cells during mitosis (Yardley, 2013).

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Chemotherapy agents used in oral and throat cancer therapy may be administered by drug delivery systems, which offer means of reducing the associated adverse events. Nanomedicine platforms can target different components of the TME such as the extracellular matrix (ECM), tumor vasculature, pH, and oxygen gradients. It allows the generation of therapies with low toxicity and high specificity to tumor cells and the compounds in their microenvironment.

3.2 Transport barriers to drug delivery in head and neck tumors The limitations of chemotherapy for use on solid tumors have been attributed mainly to genetic and epigenetic alterations affecting the proteins that influence the uptake, metabolism, and export of drugs to tumor tissues (Nishimura et al., 2014; Senthebane et al., 2017). However, during the distribution, medications for head and neck cancer (HNC) must pass through critical transport barriers present in the TME. These barriers can interfere with or control the permeation and biodistribution of drug compounds and signaling molecules between different tumor compartments. These biological transport barriers include tumor-associated vasculature, the ECM, cell
cell interaction molecules, the oxygen gradient, and the acidic pH from the hypoxic TME (Huang & Gao, 2018). Nevertheless, the distribution of various chemotherapeutics within tumors is heterogeneous, and a low proportion of tumor cells, mainly those in the proliferative compartment, are exposed to a cytotoxic drug concentration. The TME is characterized also by gradients of tumor proliferating cells, tumor quiescent cells, cancer stem cells (CSCs), and nonmalignant cells (fibroblasts and immune cells) immersed in regions with low oxygen concentrations and acidic extracellular environments. All those features influence the sensitivity of tumor cells to chemotherapeutic agents (Griffith & Swartz, 2006). Here, the physiological barriers in HNC TMEs to cancer drug delivery are summarized. First, poor vascular organization and a lack of or poor lymphatic drainage in oral and throat TMEs constitute critical physicochemical barriers to drug delivery. Accordingly, a limited blood supply due to a difference in pressure between the vessels and the tissues cannot ensure the correct tumor blood perfusion, resulting in poor penetration of the drug or immune cells present in the bloodstream through the tumor vessels, which impacts on the efficacy of the drug (Le Guelte, Dwyer, & Gavard, 2011; Tre´dan, Galmarini, Patel, & Tannock, 2007). It has been suggested that more direct administration of drugs to tumors can be carried out by changing the size and load of the administered molecule. Molecules larger than 40
70 kDa could easily penetrate tumors through vessels to act on cancer cells (Dreher et al., 2006). Second, the complex ECM in HNC, which is composed of a collagen scaffold linked with glycoproteins (e.g., elastin, laminin, fibronectin, and proteoglycans) and glycosaminoglycans (e.g., heparan sulfate and chondroitin sulfate) leads to drug adsorption and/or quick clearance from the TME and from the body (Lammers, Kiessling, Hennink, & Storm, 2012). In addition, changes to the composition and organization of the ECM led by tissuespecific metalloproteinases may influence the drug response by altering the local drug availability. Alterations in ECM interactions may lead to changes in the cell signaling associated with cellular defense mechanisms and mediating mechanical cues “mechanotransduction,” consequently inducing chemoresistance (Holle, Young, & Spatz, 2016). Changes to the ECM increase tumor stiffness by raising the hyaluronic acid content, thus, elevating

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the hydrostatic pressure during the carcinogenesis process. This process has a substantial impact on cancer progression by activating oncogenic intracellular signaling pathways and inhibiting tumor suppressor genes. ECM changes have been implicated in the resistance to therapy of solid tumors and reductions of intratumoral drug delivery effectiveness (Mouw et al., 2014; Peltanova, Raudenska, & Masarik, 2019). Nevertheless, ECM reorganization and composition may lead to drug accumulation in tissue compartments, which can be critical for drug extravasation and distribution in the TME (Tannock, Lee, Tunggal, Cowan, & Egorin, 2002). Then, drug diffusion in the ECM is determined by the concentration gradient in the tumor tissues and the characteristics of the drug used such as molecular size, shape, and solubility in water and lipids (Minchinton & Tannock, 2006). Third, tumor cells interact with various other cells in the stroma such as fibroblasts, endothelial cells, and immune cells through physical contact, surface receptor
ligand interaction, cellular junctions, and stimulus secretion from neighboring cells in the TME (Lyssiotis & Kimmelman, 2017). Chemoresistance mediated by receptor
ligand interactions on cancer cells is called cell adhesion
mediated drug resistance (Meads, Gatenby, & Dalton, 2009). Tumor cell interaction with other cells or ECM components induces a quiescent state and the production of pro- and antiapoptotic molecules, which lead to chemoresistance (Castells, Thibault, Delord, & Couderc, 2012; Correia & Bissell, 2012). Fourth, weak diffusion and perfusion of nutrients in the tumor as a result of aberrant angiogenesis and a high rate of tumor cell proliferation leads to the generation of hypoxia and extracellular acidosis in the TME (Mistry, Thomas, Calder, Conway, & Hammond, 2017). Hypoxia in tumors leads to the activation of genes that are associated with angiogenesis and cell survival. This effect is mediated by the transcription factor hypoxiainducible factor 1 (HIF-1) (Pouysse´gur, Dayan, & Mazure, 2006). HIF-1 expression results in the expansion of populations of cells with altered biochemical signaling pathways—the “Warburg effect”—resulting in a drug-resistant phenotype and clonal selection. This is the case of platinum-based chemotherapeutic agents for cells that have lost sensitivity to p53mediated apoptosis and are deficient in DNA mismatch repair abilities (Kinoshita, Johnson, Shatney, Lee, & Mochizuki, 2001). This metabolic shift in tumor cells results in the intracellular accumulation of lactic and carbonic acids, which increases acidity in the TME. Reductions in pH in the TME seems to protect tumor cells from chemotherapeutic agents. This acidification results in the extracellular accumulation of drugs that ought to enter cells via passive diffusion (Kolosenko, Avnet, Baldini, Viklund, & De Milito, 2017). Strategies using nanotechnology to improve the selective distribution and bioavailability of antitumor drugs to altered cells have been developed to optimize therapeutic effects, overcoming and preventing adverse side effects (Maranha˜o, Vital, Tavoni, & Graziani, 2017). These new cancer therapies must (1) deliver a high dose of selective medication directly to the site of the tumor using systemic dose rates, (2) improve drug absorption by malignant cells or their microenvironment, and (3) reduce cytotoxic effects on healthy cells (Alexander-Bryant, Berg-Foels, & Wen, 2013).

3.3 Nanotechnology in head and neck cancer detection and diagnosis Here, several strategies involving nanomedicine that have been developed for oral and throat cancer detection, diagnosis, and treatment are highlighted. Efficient and sensitive Nano Drug Delivery Strategies for the Treatment of Cancers

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detection and diagnosis of HNSCC is a critical challenge for patients and clinicians, and the WHO has emphasized the need to focus its attention on early detection and diagnosis to reduce morbidity, mortality, and high associated treatment costs (Brockstein & Vokes, 2013). To achieve this, diagnostic strategies based on the emerging field of nanotechnology have been developed, which use nanoscale materials to better visualize pathologies and increase sensitivity to enable earlier detection of disease (Jaishree & Gupta, 2012; Jokerst & Gambhir, 2011). This technology applies tools and materials that are on the same size scale as biological and physiological systems and can detect even a single cancerous cell in vivo (Jaishree & Gupta, 2012). Nanotechnology-based strategies have the advantage of being selective for tumors because they are designed to identify the morphology and characteristics of malignant cells by determining the specific expression of cell surface antigens, rapid proliferation, and other components of the TME (vasculature, ECM, stroma, hypoxia, etc.) (Bhandare & Narayana, 2014). Additionally, nanotechnology offers several advantages for the detection and diagnosis of oral and throat tumors at early or late stages. Among these are (1) analytical sensitivity, (2) multiplexing capacity, (3) the use of liquid biopsies, (4) disease monitoring and follow-up, (5) early detection through cell and molecule visualization, (6) providing solutions for visualizing oncologic pathogenesis and the response to medical intervention, and (7) cost benefits for patients and healthcare systems (Chen, Zhang, Liu, Zhang, & Zhou, 2018).

3.3.1 Nano-based molecular imaging Current nanoimaging agents and modalities for HNC detection and diagnosis are summarized here. Patients with HNSCC require careful evaluation and a multidisciplinary approach to determine the most appropriate form of therapeutic management. Treatment depends, as mentioned previously, on TNM classification, which is evaluated by physical examinations, endoscopies, and cross-sectional images that reflect anatomical changes that differentiate pathological from healthy tissues (Dammann et al., 2005; James & Gambhir, 2012). However, currently available imaging techniques such as computed tomography, magnetic resonance imaging (MRI), and positron emission tomography, have limits of sensitivity, resolution, and differential depth profiles. Consequently, new strategies that allow for the imaging of tumors across multiple platforms for the early diagnosis of cancer are required (Cai & Chen, 2007). Molecular imaging enables the visual representation, characterization, and measurement of biological processes at the cellular and molecular levels, which are fundamental to premalignant and cancer states (Gillies, Anderson, Gatenby, & Morse, 2010). Molecular imaging applications promise to promote new therapeutic approaches for oncologic diseases. Table 3.1 summarizes the main methods used based on nanotechnology for HNC detection and diagnosis. 3.3.1.1 Magnetic resonance imaging MRI is a noninvasive diagnostic imaging tool that relies on the electromagnetic response of tissues to a combination of magnetic and radio energy. MRI allows for tissue imaging with enhanced resolution in both space and time, acquiring information about the anatomy and functionality of structures simultaneously. In many cases, it is necessary to

Nano Drug Delivery Strategies for the Treatment of Cancers

TABLE 3.1 A summary of nanotechnology-based methods for head and neck cancer detection and diagnosis. Detection method MRI

OCT

Nanoparticle type

Surface functionalization/ conjugation

Cell line/sample/model

Advantages

Reference

Oral KB cells

Shortened T2 relaxation time and better imaging contrast

Shanavas, Sasidharan, Bahadur, and Srivastava (2017)

Multifunctional gold Monoclonal antibody nanoshells encapsulated epidermal growth factor with superparamagnetic receptor (EGFR) iron oxide (SPIO
Au NS)

HNC cell lines overexpressing EGFR: HN5, FaDu, and OSC19 In vivo mice Sprague Dawley bearing A431 tumors

Estimation of the spatiotemporal heat profile for more robust treatment planning safety and efficacy of therapy delivery

Melancon et al. (2011)

Ultrasmall superparamagnetic iron oxide (USPIO)

Nasopharyngeal carcinoma CNE1 cells

Noninvasive detection in early stages using an MRI contrast agent that can target EGFR

Liu et al. (2011)

Hybrid nanoparticles with magnetic PLGA nanoparticle core

Folate-chitosan (fol-cht) conjugate “shell”

Cetuximab (C225)

Encapsulated Gd within Biotin modulated liposome particles antiEGFR antibody

HNC cancer cell line, 15B Discrimination of high and low (high EGFR EGFR-expressing cells overexpression) and a human embryonic kidney cell line, HEK293 (low EGFR)

Kuo, Hung, Raghavan, and D’Souza (2012)

Gold nanoparticles (Au NPs)

Codoped with Gd2O3 mesoporous silica nanocomposite (Au/ Gd
MCM-41)

Nasopharyngeal High optical resolution for FLIM carcinoma cell line (CNE- imaging, which differentiates 2) normal and high-grade precancers

Wang et al. (2016)

MSN-dendron

Gd conjugate

Normal female BALB/c mice 6
8 weeks old

Higher relaxivity rates and an 11fold increase

Guo et al. (2016)

Au NPs (71 nm in diameter)

Monoclonal antibody EGFR

Standard golden Syrian hamster (Mesocricetus auratus) cheek pouch model

Identification of early neoplasia with Au NPs with meaningful quantitative signal analysis

Kim et al. (2009)

KB cells (a human epithelial carcinoma cell line)

FA-Cys-Au NPs can be used as promising nanoprobes for molecular tumor CT imaging in vivo

Khademi et al. (2018)

Blood serum samples were collected from a total of 135 OSCC patients in different tumor stages and histologic grades

Potential to carry out the preoperative assessment and prediction of the OSCC patients in different tumor stages and histologic classifications

Xue et al. (2018)

Au NPs with a core size Folic acid (FA) cysteamine of 15 nm (Cys) linking (FA-Cys-Au NPs) Surface-enhanced Au NPs with a diameter Raman of 55 nm spectroscopy (SERS)

Au NPs

AntiEGFR

Au NPs (nanorods
plasmonic paper)

Surface plasmon resonance scattering

Photoacoustic imaging (PAI)

Nasopharyngeal Increased the Raman scattering carcinoma cell line (CNE- spectra to discriminated between 2) (Saliva samples were cancerous and normal cells from healthy individuals and oral cancer patients.)

Kah, Kho, Lee, and Richard (2007)

OSCC cell line CAL-27, oral keratinocytes, normal healthy individuals, and oral cancer patients

Noninvasive and effective cancer screening, and reproducible SERS spectra from normal and cancerous cells

Liu et al. (2014)

Catheter device model of TiO2 nanostructures

Coated with Ag NPs

Oral tissue samples from buccal mucosa OSCC, verrucous carcinoma, leukoplakia, and normal tissue specimens

Characterization of oral tumors into three grades with an accuracy of 97.84%

Chundayil Madathil et al. (2019)

Colloidal Au NPs

Conjugated to monoclonal antiEGFR

Nasopharyngeal epithelium carcinoma CNE2 cell line and normal human lung fibroblast (NHLF) cell lines

Optical contrast to discriminate between cancerous and normal cells and biomarkers for molecular imaging

Kah et al. (2007)

Colloidal Au NPs with an average size of 35 nm

Conjugated to monoclonal antiEGFR

Nonmalignant epithelial Distinguish between cancerous cell line (HaCaT) and two and noncancerous cells malignant oral epithelial cell lines (HOC 313 clone 8 and HSC 3)

Lipid film of porphysomes

Plasmonic nanosensors (MAPS) of 40 nm spherical Au NPs Porphysome: porphyrin
lipid building blocks that self-assemble into liposome-like NPs (100
150 nm diameter)

Buccal mucosa squamous cell carcinoma rabbit model and a hamster cheek carcinogenesis model AntiEGFR or antiRG16 monoclonal antibodies

Metastatic murine model of oral squamous cell carcinoma Buccal tumor in rabbit and hamster model

El-Sayed, Huang, and El-Sayed (2005)

Muhanna et al. (2015) Porphysome not only enabled photoacoustic and fluorescence imaging of oral cavity carcinomas in rabbit and hamster models, but also allowed for tumor-localized effective therapeutic temperature. Luke, Myers, Emelianov, and Sokolov (2014) Muhanna et al. (2015) Guide HNSCC surgeries and intervention showing the primary tumor and metastatic lymph nodes around the head and neck regions (Continued)

TABLE 3.1 (Continued) Detection method

Quantum dots (QDs) imaging

Nanoparticle type

Surface functionalization/ conjugation

Cell line/sample/model

Advantages

Spherical Au NPs (MAPS)

AntiEGFR or antiRG16 monoclonal antibodies

Balb/c nude mice with a submucosal injection of FaDu cells for tumor model

Luke et al. (2014) Noninvasively identify micrometastases as an alternate to sentinel node biopsy analysis

Near-infrared quantum dots with an emission wavelength of 800 nm

Labeling BcaCD885 cells with QD800

OSCC cell line BcaCD885 BALB/c nu/nu mice aged 5
6 weeks

Promising prospects in in vivo imaging of OSCC and development of personalized surgical therapies

K. Yang et al. (2010)

Near-infrared QDs with Peptide containing an emission wavelength arginine
glycine
aspartic of 800 nm acid (RGD) to target integrin αvβ3

BcaCD885 cells transplanted into nude mice cheek to establish an HNSCC model

Potential application for personalized HNSCC patient treatment and diagnosis

Huang, Bai, Yang, Tang, and Wang (2013)

QDs (goat antirabbit QD655nm-IgG)

Binds to survivin and HSP70

Human tongue cancer cells Tca8113

QDs have good fluorescence intensity and photostability and are appropriate for studies that require a long dynamic observation of physiological changes in cells

Zhao, Chen, Wang, Pan, and Huang (2011)

QDs (goat antimouse QD525nm-IgG and goat antimouse QD655nm-IgG)

Binds to HSP70 and HSF-1 Human tongue cancer cells SCC25

Chen et al. (2013) HSF-1 may serve as a novel therapeutic target in the treatment of oral cancer

QD-IHF

Label E-cadherin, vimentin, and EGFR

Multiplexed subcellular QD Hu et al. (2016) quantification of EGFR and Ecadherin is a potential strategy for the prediction of HNSCC patients

Patients diagnosed with HNSCC

Reference

Image in EGFR, Epidermal growth factor receptor; FLIM, Fluorescence lifetime imaging; HNSCC, Head and neck squamous cell carcinoma; MAPS, Molecularly activated plasmonic nanosensors; MRI, magnetic resonance imaging; OSCC, Oral squamous cell carcinoma, PEG, Polyethylene glycol.

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use contrast agents (CA) to increase the magnetic signal and sensitivity of the detector to resolve a reduced number of cells (75
300 μs) (Jung & Lee, 2015). In patients with HNC, conventional anatomical MRI is used to identify primary lesions, assess structural distortion, identify the presence of metastatic lymph nodes, and evaluate treatment response (Payabvash, 2018; van der Hoorn, van Laar, Holtman, & Westerlaan, 2017). MRI is the method of choice for studying tumors in the tongue, oropharynx, and other oral cavity locations since it is superior in the detection of tumor metastasis into bone marrow (Rumboldt, Gordon, Bonsall, & Ackermann, 2006). However, its main shortcomings are limited sensitivity and toxic side effects due to the necessity of using CAs to enhance the signal difference between the region of interest (disease) and the background (healthy tissues) (Jung & Lee, 2015). CAs have been developed to change the longitudinal and transverse relaxation times selectively (T1 and T2) of the hydrogen atoms (1 H) in biological tissues. Most clinically approved CAs used in MRI are based on small molecules that sequester the paramagnetic ion gadolinium (Gd31). Gd31 is complexed with diethyl triamine-pentaacetic acid (Gd-DTPA; Magnevist) or tetra azacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA; Dotarem) (Caravan, 2006). Gd31 has seven unpaired electrons in its 4f orbitals, giving it a large magnetic moment (Cheng, Ping, Zhang, Chuang, & Liu, 2013). However, the blood circulation lifespan of Gd-DTPA or Gd-DOTA is short (1
1.5 h) and these complexes to not specifically accumulate in tumors (Bennett, Jo, Cabral, Bakalova, & Aoki, 2014). Manganese (LumenHance) has been used in MRI applications, although its magnetic moment is weaker than that of Gd31 (Gale, Atanasova, Blasi, Ay, & Caravan, 2015). In this regard, nanoscale MRI is a new tool that enhances the resolution of MRI measurements from the micrometer to the nanometric scale and has the capacity to analyze the individual biomolecules involved in cancer processes (Boretti, Rosa, & Castelletto, 2015). Applications of nano-CA for MRI is based on the fact that nanoscale materials exhibit unique physical and chemical properties due to improvements in surface/volume ratios, in addition to tune via functionalization. The synthesis of nano-CAs has been carried out in two ways, namely by conjugating the paramagnetic center onto nanocarrier components or by encapsulating the CA into nanoparticles (NPs) as nanoscale liposomes, mesoporous silica, polymers, or plasmonic NPs (Pitchaimani et al., 2017; Pitchaimani, Nguyen, Wang, Bossmann, & Aryal, 2016). Liposomes are sphere-shaped vesicles composed of one or more phospholipid bilayers with an aqueous core. They are excellent carriers of probes for in vivo applications. The size of liposomal NPs varies between 50 and 200 nm, which can significantly increase the blood circulation of probes loaded with CA. Liposomes can lead to increased CA accumulation in target tumor tissues by passive targeting through the enhanced permeation and retention effect (Pattni, Chupin, & Torchilin, 2015; Xia et al., 2019). Gd-complexes (GdDTPA and Gd-DOPA) associated with liposomes for MRI applications can be classified into three categories, namely (1) conjugation at the free-floating polyethylene glycol corona, (2) entrapment in the inner hydrophilic core, and (3) infusion in the lipid bilayer of the liposomal system (Aryal et al., 2016; Villaraza, Bumb, & Brechbiel, 2010). Epidermal growth factor receptor (EGFR) is overexpressed in 90%
100% of HNSCC cases. The overexpression of EGFR and its ligands is associated with reduced survival rates (Agarwal, Subash, Nayar, & Rao, 2019). Kuo et al. developed a tumor-targeting

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nanoprobe that selectively binds to EGFR-overexpressing tumor cells by encapsulating a Gd
CA complex and conjugating an EGFR-specific monoclonal antibody within the liposome particle. They concluded that the nanoprobe could function as a targeting tracer for tumor cells, potentiating it in improving treatment efficacy through MRI (Kuo et al., 2012). Mesoporous silica NPs (MSN) are one of the most promising types of nanocarrier for use in MRI applications (Zhang et al., 2014) due to their excellent biocompatibility, biodegradability, and three-domain structure comprising a silica framework, internal pore walls, and an outer surface (Cha & Kim, 2019). MSNs are composed of periodic arrangements or uniformly-sized mesopores (2 to .20 nm in diameter) embedded within an amorphous silica framework. To increase the efficiency and sensitivity of probes, the large surface area is functionalized for cellular labeling with MRI CAs. Furthermore, paramagnetic ions are directly included in the silica framework to give probes high levels of stability and efficacy (Lee et al., 2009). The inclusion of Gd complexes into MSN facilitates the exchange of water hydrogen atoms with a magnetic center, hence, reducing T1 and T2 relaxation times. Guo et al. developed a novel nanoprobe-based MRI CA by combining MSN and peptide dendrons using click chemistry reactions. The nanoprobe showed an 11-fold increase in its relaxivity value compared with small Gd-DTPA complexes, and an enhancement of MRI contrast images (Guo et al., 2016). Gd31
gold (Au) nanohybrids have afforded enhanced contrast capabilities in MRI applications. In this regard, Wang et al. reported that Au NPs codoped with a Gd2O3 mesoporous silica nanocomposite (Au/Gd
MCM-41) could produce a pronounced contrast enhancement for T1 weighted images for MRI to detect nasopharyngeal carcinoma cells (CNE-2), which may be an ideal diagnostic probe for early diagnosis (Wang et al., 2016). Polymer-based magnetic NPs are considered to be attractive and feasible tools for simultaneous cancer diagnosis and treatment because of their controllable size and biocompatibility (Wang, Niu, & Chen, 2014). Dendrimers are highly branched synthetic polymers that form spherical macromolecules of a specific size. Several researchers have developed nanosized MRI CAs with different dendrimer cores such as polypropylenimine diaminobutane of various sizes to enhance contrast (Kobayashi & Brechbiel, 2005). Shanavas et al. combined folate preconjugated chitosan and magnetic poly(lactide-coglycolic acid) (PLGA) NPs to create an MRI CA with a shorter T2 relaxation time and better imaging contrast. In this study, oral cancer folate receptor
positive cells showed an increase in NP uptake, which provoked a significant enhancement of cytotoxicity for cancer therapy (Shanavas et al., 2017). Image-guided thermal ablation of HNC is a minimally invasive tool for patients with advanced-stage tumors and is an alternative to conventional surgical intervention. This technique induces heating and destroys tumor tissues using small laser fibers directed into the tumor. However, laser-induced heating is not limited exclusively to tumor tissues, and there is a possibility of damaging the adjacent tissue (Hirsch et al., 2003). To avoid these limitations, Melancon et al. proposed the use of multifunctional superparamagnetic iron oxide coated with an Au nanoshell (SPIO
Au NS) conjugated with the targeting agent monoclonal antibody C225 (cetuximab) against EGFRs. They showed that C225-SPIO
Au NS, both in vitro and in vivo, are MRI-active and can selectively be heated for simultaneous imaging and photothermal ablation therapy, thereby enhancing safety and efficacy

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(Melancon et al., 2011). Liu et al. designed ultrasmall superparamagnetic iron oxide NPs (USPIO) that target specific tumor-associated EGFRs for the application of radiotherapy in nasopharyngeal carcinoma treatment. It has been proven that C225-USPIO has potential as an MRI CA and can be used to detect noninvasive early-stage HNC showing EGFR overexpression (Liu et al., 2011). 3.3.1.2 Optical coherence tomography Optical coherence tomography (OCT) is a real-time imaging tool capable of providing noninvasive cross-sectional images of biological tissues (Fercher, Drexler, Hitzenberger, & Lasser, 2003). OCT produces images with high resolution at the micrometer scale in realtime. The depths of penetration into soft tissue are approximately 2
3 mm, allowing for the in vivo imaging of the macroscopic characteristics of epithelial and subepithelial structures, including depth and thickness, histopathological appearance, and peripheral margins (Drexler & Fujimoto, 2008). In oral cavities, the potential for OCT-based diagnostics is promising because of the penetration depth into hard and soft tissues. Due to the high effective atomic weight of bone, OCT has a sensitivity between 80% and 83% and a specificity between 90% and 98% for differentiating oral premalignant lesions and squamous cell carcinoma from healthy mucosa (Ridgway et al., 2006; Tsai et al., 2009). However, early cancer detection using OCT is limited by the low contrast levels in biological tissues, particularly between normal and neoplastic tissues (Rollins, Yazdanfar, Barton, & Izatt, 2002). The utilization of new CAs for OCT applications includes nanorods (Wang, Ma, Wang, & Su, 2006), nanospheres (Rayavarapu et al., 2007), nanoshells (Gobin et al., 2007), nanocages (Chen et al., 2005), and nanostars (Zhu et al., 2017). Au NPs are particularly promising for OCT applications owing to their biocompatibility, ease of synthesis, and ability to be delivered both systemically or topically (Loo et al., 2004). Kim et al. topically injected Au NPs conjugated with antiEGFR monoclonal antibodies and polyethylene glycol to enhance the contrast of in vivo OCT images of oral dysplasia in a hamster cheek pouch model. The Au NPs overcame the stratum corneum and epithelial barriers, resulting in a B150% increase in the OCT contrast level in this standard model of oral carcinogenesis (Kim et al., 2009). Khademi et al. synthesized folic acid (FA) Au NPs through cysteamine (Cys) linked (FA-Cys-Au NPs) to target human nasopharyngeal HNC. Cancer cells require more FA due to their higher metabolic rate, and there are more FA receptors on their surfaces compared with those on healthy cells (Beik et al., 2017). Cys is a nontoxic linker that easily attaches to Au NPs through sulfhydryl groups (Khademi et al., 2018). Because of the increased attenuation in X-ray intensity and the excellent biocompatibility of FA-Cys-Au NPs, these can be used as effective nanoprobes for OCT targeted imaging (Khademi et al., 2019). 3.3.1.3 Photoacoustic imaging Photoacoustic imaging (PAI) is a hybrid imaging tool based on a near-infrared (NIR) laser (Shi, Gu, Fei, & Zhao, 2017) that combines the high contrast of optical imaging (spatial resolution , 100 μm) and the high penetration depth of ultrasound imaging (up to 5 cm), resulting in elastic expansion and the generation of an acoustic signal (Xu & Wang, 2006; Yao, Xing, He, & Ueda, 2001). PAI has several related advantages that include (1) imaging depths of up to centimeter and down to submillimeter resolutions, (2) high

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contrast-to-noise ratios and spectroscopic imaging, (3) real-time acquisition, (4) integration with ultrasound scanners, (5) noninvasive imaging for longitudinal studies, and (6) monitoring of cancer progression and drug delivery (Wang & Gao, 2014). The photoacoustic signal is provided mainly by endogenous molecules such as hemoglobin, oxygen, melanin, lipids, and collagen or by molecularly targeted exogenous CAs conjugated with antibodies or peptides, which display NIR optical absorption properties between 700 and 1100 nm (Kim, Favazza, & Wang, 2010; Pu et al., 2014). These photoacoustic agents include organic dyes (Sheng et al., 2014), semiconductors (Song et al., 2015), and noble metal materials (Huang et al., 2014). Hypoxia may affect prognosis and chemotherapeutic and radiotherapeutic efficacies in cancer patients. In this regard, Rich and Seshadri used patient-derived xenograft models of HNC to describe the utility of PAI to measure changes of total hemoglobin and oxyhemoglobin in order to evaluate tumors following radiation therapy alone or in association with chemotherapy. The authors reported that PAI was able to detect early changes in the oxygenation of tumors in vivo. This is, therefore, a potential tool for predicting individual responses to chemotherapy and radiotherapy in vivo (Rich & Seshadri, 2016). Muhanna et al. described preclinical evidence of HNSCC cell fluorescence and photoacoustic image-guided detection in both buccal mucosa squamous cell carcinoma rabbit and hamster cheek carcinogenesis models (Muhanna et al., 2015). They reported a novel multifunctional NP, a porphysome, which consists of porphyrin
lipid building blocks that self-assemble into liposome-like NPs (100
150 nm in diameter) (Lovell et al., 2011). Therefore the porphyrin agent combines photoacoustic and fluorescence imaging to guide HNSCC cell surgeries and interventions. Additionally, porphysomes achieved high tumorto-tissue ratios of fluorescence with lower background signals at 24 h post injection, showing the primary tumor and metastatic lymph nodes around the head and neck regions (Muhanna et al., 2015). Luke et al. developed a novel method based on spectroscopic PAI for molecular-specific detection of micrometastasis with enhanced specificity and sensitivity with molecularly activated plasmonic nanosensors (MAPS). MAPS consist of 40 nm spherical Au NPs targeted to EGFRs with specific interactions for tumor cells and change the spectroscopic signal to enable highly sensitive detection of micrometastasis in HNC (Luke et al., 2014). 3.3.1.4 Surface plasmon resonance scattering The main clinical protocols for the evaluation of HNC tumors are based on tissue biopsy using special needles or surgery for examining the structure and the features of invasive tumor lesions (Crowley, Di Nicolantonio, Loupakis, & Bardelli, 2013). However, the disadvantages of this method in HNC are related to the accessibility of tissue for biopsy due to the oropharynx location. Tissue extraction may augment the risk of metastatic lesions and injury to the facial nerve, jugular vein, and carotid arteries (McKnight, Glastonbury, Ibrahim, Rivas-Rodriguez, & Srinivasan, 2017). The analysis of cancer cells in body fluids is an alternative for the detection of cancer-related biomarkers such as nucleic acids, proteins, and microvesicles in combination with their microenvironment profiles (Nonaka & Wong, 2018). Surface plasmon resonance scattering is a molecular sensing tool that can examine the interactions between biomolecules at extremely low concentrations based on affinity binding analysis. Examples include antibody
antigen interactions

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(Hearty, Leonard, & O’Kennedy, 2012), enzyme
substrate reactions (Miyazaki, Shimizu, Mejı´a-Salazar, Oliveira, & Ferreira, 2017), ligand
receptor kinetics, exosomes (Carroll, Raum, Forsten-Williams, & Ta¨uber, 2016), and specific DNA sequences and mutations (Hu & Zhang, 2012). Using antiEGFR antibody
conjugated Au NPs (average size of 35 nm) in in vitro models, El-Sayed et al. discovered that scattering images and absorption spectra can distinguish between oral cancerous and noncancerous cells. This tool makes both techniques potentially useful for anatomic imaging location and molecular sensing of oral squamous cell carcinoma for cancer diagnostics (El-Sayed et al., 2005). 3.3.1.5 Surface-enhanced Raman spectroscopy Surface-enhanced Raman spectroscopy (SERS) is a powerful analytical technique used in the identification of molecular structures and chemical and biological samples and the early diagnosis of cancer. This technique is based on the Raman effect, which consists of an inelastic proton dispersion that exits at high energy levels, thereby producing spectral characteristics similar to those of the investigated sample. However, Raman dispersion is not highly efficient (Vo-Dinh, Yan, & Wabuyele, 2005). Silver (Ag) and Au are the most used NPs in SERS; however, nanostructures with different coating materials and biomolecules can be aimed at various biomarkers and tumors (Kiefer, 2015a). Nanostructures that have been studied include Au
Ag nanoshells and Ag NPs, which have been characterized in terms of size, surface plasmon resonance wavelength, surface charge, and chemical composition (Kiefer, 2015b). Metallic NPs for the enhancement of Raman signals are utilized for the noninvasive detection of cancer and associated biomarkers (Indrasekara et al., 2013), circulating tumor cells (Wang et al., 2011), and tumor-associated exosomes (Park et al., 2017). The spectral detection of biofluids using SERS is considered to be a noninvasive and convenient method for diagnosing HNC (Vo-Dinh et al., 2005). Xue et al. demonstrated that SERS with Au NPs based on blood serum tests had the potential to be used in the preoperative assessment and prediction of oral squamous cell carcinomas in patients at different tumor stages and with different histologic classifications (Xue et al., 2018). Moreover, using colloidal Au NPs conjugated with antiEGFR antibodies, Kah et al. increased the Raman scattering spectra in saliva samples to discriminate between cancerous and healthy cells (Kah et al., 2007). Conventional cytology for oral tumors is considered to be a technique of insufficient sensitivity due to heterogeneity in the sampling of altered cells and subjectivity in cytological interpretations (Weigum et al., 2010). By combining exfoliative cytology and SERS, Liu et al. established a paper-based plasmonic SERS substrate as a rapid, sensitive, and noninvasive platform for oral cancer screening. The platform includes Au nanorods due to their strong surface plasmon resonance extinction in the NIR, high stability, and low toxicity (Sun et al., 2008). The results demonstrated that paper-based SERS, in conjunction with exfoliative cytology, is a useful tool for noninvasive detection and screening for oral cancer in patients (Liu et al., 2014). Madathil et al. developed a point-of-care rapid diagnostic SERS catheter device model for the rapid detection, classification, and grading of normal, premalignant, and malignant tissues with high sensitivity and accuracy. The catheter consists of a sensor made from

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TiO2 nanostructures coated with Ag NPs to generate an electromagnetic field on the catheter surface. The researchers showed that the device could classify oral tumors into three grades with an accuracy of 97.84%, which correlates with current pathological data (Chundayil Madathil et al., 2019). 3.3.1.6 Quantum dots imaging and biomarkers Quantum dots (QDs) are NPs that exhibit optical and electronic properties that are susceptible to size and have the potential to be used as novel nanomaterials for both cancer diagnosis and therapy. They are able to link with biomolecules such as peptides, antibodies, nucleic acids, and small molecules through covalent attachments (Smith, Gao, & Nie, 2004). QDs have been applied in the molecular and cellular imaging of oral squamous cell carcinomas, both in vitro and in vivo. The advantages of QDs over organic fluorophores include their broad excitation, tunable emission, and high resistance to chemical and metabolic degradation. They also have the capacity to be modified with a targeting ligand such as EGFR or HIF-1 for labeling oral cancer cells (Medintz, Uyeda, Goldman, & Mattoussi, 2005; Tao et al., 2017). In this type of cancer, QDs show high fluorescence intensity and low nonspecific binding patterns for the in vitro imaging of the human oral cancer cell lines Tca8113, SCC-25, and BcaCD885. These properties have applications in immunohistochemistry techniques for biomarker identification, prognosis, and treatment (Chen et al., 2013; Zhao, Chen, Wang, Pan, & Huang, 2011). Moreover, QDs coupled with other biomolecules such amino acids are efficient in the diagnosis of HNSCC. QDs have been combined with proteins of sanguineous blood vessels. In this regard, researchers showed that QDs coupled to the arginylglycylaspartic acid (RGD) peptide target αvβ3 integrin on endothelial cells enabled vascularization targeting in an in vivo tumor (Huang et al., 2013). Also, QDs combined with EGFR, E-cadherin, and cytoplasmic vimentin are useful in the prognosis of metastasis (Hu et al., 2016; Liu, Zhao, Luo, Liu, & Wu, 2017).

3.3.2 Nanotechnology-based drug delivery systems for the treatment of head and neck cancer Table 3.2 summarizes the main methods used based on nanotechnology for drug delivery in head and neck TME. 3.3.2.1 Cell targeting with nanoparticles Chemotherapeutic drugs applied in clinical settings produce toxic side effects. For this reason, researchers have loaded NP cores with chemotherapeutic drugs such as cisplatin, paclitaxel, cetuximab, doxorubicin, and 5-FU as a controlled method of inducing cytotoxicity locally and improving drug efficacy. Cisplatin has been nano-encapsulated in different lipid-based nanocarriers, liposomes, and micelles. These have been evaluated in clinical trials, and indications are that these formulations can reduce cytotoxicity and drug resistance when cisplatin is combined with other medications. Known nanopharmaceuticals such as Nanoplatin, Aroplatin, Lipoplatin, and SPI-077 are registered, but have yet to be marketed (Farooq et al., 2019).

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TABLE 3.2 A summary of nanoparticle-based targeted therapies for tumor microenvironment in head and neck cancer. Category

Description

Target effects

Cell line/model

References

Vasculature

Lipid
calcium
phosphate nanoparticles (LCP NPs)

Deliver VEGF-A small interfering RNA (siVEGF-A)

Human HNSCC SCC4 and SAS xenograft models

Lecaros, Huang, Lee, and Hsu (2016)

a-Tocopheryl succinatebased polymeric NP with a hydrodynamic diameter of 164.3 6 4.9 nm

a-TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells

FaDu cell line

Sa´nchezRodrı´guez et al. (2018)

Integrin-targeted nanoparticle (ITNP) encapsulated rhodamine-B and multiple copies of the integrin αvβ3 with a mean diameter of 104.4 6 3.3 nm

The ITNPs SCC 7 murine accumulated in the squamous cell angiogenic vessels after carcinoma model systemic administration in a murine squamous cell carcinoma model, targets the tumor angiogenic vessels

Xie, Shen, Li, and Danthi (2007)

UCNP: Au NPs coated with silica shells and modified with amino groups

MMP-based biosensor may serve as sensitive and specific molecular fluorescent probe in biological applications

Cal27, HSC3, HSC4, CA922, SAS, YD15, and TW2.6 cell lines

Chan et al. (2016)

Chemical pH-responsive aerobic NPs High efficiency for environment inhibiting proliferation (hypoxia and acidic pH)

CAL-27 and L929 cells, CAL-27 oral squamous cell carcinoma tumorbearing mice BALC/c model

Shen et al. (2017)

ECM

Immune

HPAE(NaAsO2 1 TH287) NPs

Effective inhibition of CAL27 cells tumor cell proliferation and synergistic effect of NaAsO2 and TH287

Li et al. (2017)

Iron oxide magnetic NPs hyperthermia (mNPHT)

The cells in these hypoxic tumors internalize NPs

Chen et al. (2013)

PLGA NPs loaded with TAA

CD8 1 T cell responses FaDu and FAT7 cell evoked by degradable lines, tumor and blood NPs loaded with TAA samples

Prasad et al. (2011)

PLGA NPs as potential for efficient tumor antigen delivery to dendritic cells

Encapsulated antigens are immunogenic and evoke favorable TILmediated antitumor responses.

Prasad et al. (2012)

FaDu and SCC-25 cells, NOD-SCID mice

FaDu and FAT7 cell lines

(Continued)

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TABLE 3.2 (Continued) Category

Description

Target effects

Cell targeting

Folate-decorated lipid carriers

Highest cytotoxicity FaDu cell line and synergistic effect of two drugs in HNC (FaDu cells) in vitro

Poly 2-(methacryloyloxy) ethylphosphorylcholine (PMPC)
poly 2(diisopropylamino)ethyl methacrylate (PDPA) polymersomes loaded with paclitaxel and doxorubicin

A strong cytotoxic effect in 2D cell culture model Penetrated deep into the center of 3D spheroid model resulting in extensive cell damage

FaDu, NOF, or HDF ce1l line. FaDu spheroids

Selenium NPs with EGFR as targeting molecule, Gd as MRI contrast agent, and 5-Fu drug

CNE-bearing xenograft nude mice model

Human nasopharyngeal J. Huang et al. carcinoma cell line CNE (2019) 1, CNE-bearing xenograft nude mice model

Albumin-sericin (Alb-Ser) NPs as a novel siRNA delivery system

HA/PLL-siRNA/AlbSer (2:1) systems have an apoptotic effect

Human epithelial type 2 (Hep-2) cells

Yalcin et al. (2019)

Folic acid (FA) modified, gefitinib (GEF) and yttrium 90 (Y90) coloaded, core
shell structured lipid
polymer hybrid NPs (FA-GEF-Y90-LPNP)

In vivo tumor inhibition ability and safety system for treatment

Nasopharyngeal carcinoma cell line HONE1, nasopharyngeal cancer bearing mice model

Yugui, Wang, Sun, and Zhang (2019)

CD44-SPIONPs induced cancer stem cells to undergo programmed death

Cal-27 cells, Male BALB/c nude mice model

Su et al. (2019)

Cancer stem- AntiCD44 antibodylike cell modified superparamagnetic iron oxide NPs (SPIONPs)

Cell line/model

CD44-coated superparamagnetic iron oxide NPs functionalized with HA (HA-DESPIONs)

Increase of cell death in UT-SCC-14 cells the CD44-positive population

CSC-platelet hybrid membrane-coated iron oxide magnetic NPs

Characteristics for immune evasion, active cancer targeting, magnetic resonance imaging, and photothermal therapy

References Yang, Ju, and Dong (2017)

Colley et al. (2014)

Thompson et al. (2017)

CAL27 cells and Bu et al. (2019) murine macrophagelike cells RAW 264.7. Tumor-tissue cells from 2cKO HNSCC mic, ICR mice in vivo model

Au NPs, Gold nanoparticles; CSC, cancer stem cells; HA, hyaluronic acid; HPAE, cationic hyperbranched poly(amine-ester); HPV, human papillomavirus; NaAsO2, anticancer drug sodium arsenite; NPs, nanoparticles, PLGA, poly(lactic-co-glycolic acid); UCNPs, upconversion nanoparticles; TAA, tumor-associated antigens; TH287, MTH1 inhibitor; TIL, tumor infiltrating lymphocytes.

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Nanostructured lipid carriers have been used to encapsulate combinations of drugs for cancer therapy. This method was probed using a mouse model and a FaDu cell line. The NPs contained folate, cholesterol, and 3-[4,5-dimethyl-2 thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide and were combined with docetaxel
paclitaxel encapsulated in lipid carriers named folate-cisplatin-plus paclitaxel. The results from the in vitro model demonstrated inhibition in the viability and proliferation of the HNC FaDu cells. This indicated improved anticancer drug efficiency in the in vivo model, and exposed a synergetic effect of the two drugs (Yang et al., 2017). Other drugs and drug combinations have been evaluated. For example, paclitaxel, doxorubicin, and a combination of the two have been encapsulated using polymersomes and tested in monolayer (2D) and 3D spheroid-like cultures. In the evaluation of cell cytotoxicity, a cell line for oral and hypopharyngeal cancer was used. The 2D model demonstrated that paclitaxel was responsible for cell cytotoxicity, whereas doxorubicin showed less of an effect. However, when these drugs were combined, the antiproliferative effect increased. Likewise, in 3D cultures, the results indicated that modifications to the spheroid architecture had occurred because of a loss of cell viability (Colley et al., 2014). In another study, selenium NPs using EGFR as targeting molecules and Gd31 chelate as an MRI CA were used to investigate the use of combined drug delivery. In this case, the major drugs were 5-FU and cetuximab. This study of model mouse xenografts demonstrated the antiproliferative potential of selenium NPs loaded with 5-FU/cetuximab due to their high levels of biocompatibility with tissues (Huang et al., 2019). Similarly, strategies based on gene silencing such as the use of small interfering RNA (siRNA) have indicated the potential of suppressing specific molecular targets. Albuminsericin NPs as vehicles for administering siRNA have been formulated. These NPs are composed of albumin-sericin and decorated with hyaluronic acid to target Hep2 cell lines (laryngeal cancer) and are modified with poly-L-lysine for siRNA binding. This novel NP is called HA/PLL-siRNA/Alb-Ser. The study indicated that HA/PLL/Alb-Ser as a siRNA carrier exhibited a capacity to induce apoptosis and silence cyclin proteins, specifically CK2a (Yalcin et al., 2019). In the same way, some EGFR inhibitors such as gefitinib (GEF) were coloaded with radiotherapeutics such as yttrium 90 to build a structured lipid
polymer hybrid NP (FAGEF-Y90-LPNP). Its efficacy was evaluated in HONE1 cells (carcinoma nasopharyngeal) and a mouse model. The cytotoxicity results indicated that this nanoformulation was effective in tumor cell inhibition. Most importantly, when measured in vivo, plasma concentration profiles over 2 h showed that the free GEF was cleared rapidly, whereas GEF loaded in LPNP was retained in the plasma for 48 h (Yugui et al., 2019). 3.3.2.2 Drug delivery using nanoparticles for cancer stem-like cell targeting In several types of cancer cells, including HNSCC, CSCs play an integral role in tumor initiation, disease progression, metastasis, and treatment resistance. The development of new therapeutic approaches that target CSCs that are resistant to chemotherapy and radiotherapy are key to the success of cancer treatment (Zhao et al., 2013). In this sense, NPmediated laser hyperthermia can act on CSCs to induce cell death. This technology uses magnetic NPs under an alternating magnetic field (AMF) to generate heat via magnetic fluids injected into the bloodstream of patients (Kobayashi, 2011). The use of specific

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biomarkers for targeted CSCs with magnetic NPs constitutes an alternative therapy for HNC. Su et al. used antiCD44 antibody-modified superparamagnetic iron oxide NPs (SPIONPs), AMF, and magnetic fluid hyperthermia to induce CSCs to undergo programmed death in tumors in a mouse model (Su et al., 2019). Moreover, Thompson et al. used dextran CD44-coated SPIONPs functionalized with hyaluronan (HA-DESPIONs) to demonstrate that cell death only increased in the CD44-positive population (Thompson et al., 2017). Cell-membrane coating nanotechnologies for drug delivery have attracted attention due to their excellent biocompatibility properties and capacity to interact with their surrounding environments (Fang, Kroll, Gao, & Zhang, 2018). Bu et al. developed a new fused CSC-platelet membrane-coated Fe3O4 NP with membrane materials derived from CSCs and platelets to demonstrate enhanced antitumor activity and growth inhibition in a mouse model with a complex TME (Bu et al., 2019). 3.3.2.3 Tumor microenvironment targeted nanotherapy Delivering an effective treatment to the HNC microenvironment involves multiple physiological, biochemical, and biophysical barriers that influence the therapeutic efficacy of anticancer drugs (Zhan, Alamer, & Xu, 2018). The make-up of the HNC microenvironment such as the vasculature, ECM, and hypoxic and acidic conditions makes significant differences to cell proliferation and cell cycle regulation that can lead to chemotherapeutic drug resistance. As conventional drugs used for HNC treatment show only modest effects in patients mainly due to their limited penetration into tumor tissues (Minchinton & Tannock, 2006), a variety of microenvironment treatment strategies are currently being considered to improve HNC treatment. These efforts have involved the pharmacological suppression of proliferation and metastasis, tumor vasculature modification/intervention, ECM targeting, angiogenesis, and hypoxic modulation. Approaches for specific targeted delivery of therapeutics in HNC involve the systemic administration of drugs encapsulated in NPs to the tumor-tissue site. Encapsulated antitumor drugs in NPs can enhance their solubility and bioavailability and facilitate entry into the target cell (Blanco, Shen, & Ferrari, 2015). Fig. 3.1 shows an example of NPs intended to target the TME. 3.3.2.3.1 Nano-chemotherapeutics in targeting tumor vasculature

Tumor angiogenesis and neovascularization play fundamental roles in tumor growth, invasion, and metastasis. However, new tumor blood vessels are highly accessible to cancer therapeutics. Treatments for targeting tumor vasculature have several advantages over conventional anticancer therapies because endothelial cells have high proliferation rates and express specific angiogenic markers in the TME that allow for the delivery of chemotherapies with minimal side effects for patients (Banerjee, Harfouche, & Sengupta, 2011). Also, nanoscale drug delivery systems use alterations in the tumor vasculature to promote the accumulation of NPs in the perivascular tumor region—the so-called enhanced permeability and retention effect (Golombek et al., 2018). To facilitate the translation of nanomedicines to HNC patients in the clinical setting, it is crucial to understand the heterogeneity of the enhanced permeability and retention effect in order to administer the required single or multimodal therapy (Greish, Mathur, Bakhiet, & Taurin, 2018).

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FIGURE 3.1 Nanoparticle targets in head and neck cancer tumor microenvironment components. This illustration shows nanoparticles intended to target the vasculature, ECM, immune system, and chemical microenvironment. (A) Lipid
calcium
phosphate nanoparticles (LCP NPs) that deliver a siRNA that inhibits VEGF (siVEGF-A). (B) Upconversion nanoparticles conjugated with gold nanoparticles (UCNP-Au), coated with silica shells, and modified with amino groups that sense matrix metalloproteinase 2 (MMP-2). (C) Polylactic-co-glycolic acid nanoparticles deliver tumor-associated antigens to dendritic cells (DCs). (D) Cationic hyperbranched poly(amine-ester) nanoparticles (HPAE NPs) codelivery of sodium arsenite (NaAsO2) and MTH1 inhibitor TH287, which induce tumor cell apoptosis.

Altered vascular permeation and leakiness favor the release of NPs into the TME, near to tumor vessels, giving the opportunity for drugs to accumulate selectively in the tumor space (Maeda, 2012). HNSCC tumors are highly angiogenic and express angiogenic cytokines such as a vascular endothelial growth factor (VEGF), interleukin-1a, and fibroblast growth factor. Additionally, the high expression of matrix metalloproteinases (MMPs) has been linked with tumor invasion, metastasis, and poor survival (Ruokolainen, Pa¨a¨kko¨, & Turpeenniemi-Hujanen, 2006). However, the drugs bevacizumab and sorafenib, which work as specific inhibitors of both VEGF and its receptor VEGFR, have not been successful in treating HNSCC tumors (Yao et al., 2015). Sa´nchez-Rodrı´guez et al. used nanoencapsulated tocopheryl succinate (a-TOS) to enhance the hydrophobic nature of the drug, its bioavailability, and therapeutic activity. The molecule was incorporated into NPs with

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a hydrophilic segment of copolymers based on N-vinyl pyrrolidone, and the hydrophobic segment mostly incorporated PEG-b-poly MTOS (methacrylic derivative of α-TOS) [poly (VP-co-MTOS)]. In a previous study, the inner core of the NPs used enhanced the proapoptotic activity of the nanocarrier on hypopharynx carcinoma squamous FaDu cells (Palao-Suay et al., 2016). Additionally, a-TOS-based NPs decreased the production of the proangiogenic growth factor VEGF, downregulated the expression of its receptor VEGFR, and diminished the migration and secretion of proteases (MMP-2 and MMP-9) of FaDu cells in vitro (Sa´nchez-Rodrı´guez et al., 2018). During angiogenesis, αv integrins are overexpressed on the endothelial cell surface to enhance the growth and survival of newly forming vessels; among these, integrin αvβ3 is the most abundantly expressed in angiogenic endothelial cells in remodeled and pathological tissues (Brooks et al., 1995; Weis & Cheresh, 2011). Several research groups have developed αvβ3-targeted nanomaterials for imaging and therapy (Winter et al., 2003). Xie et al. developed a novel integrin-targeted NP system that consists of two lipids with encapsulated rhodamine-B and multiple copies of the integrin αvβ3 compound conjugated onto the NP surface that targets tumor angiogenic vessels specifically localized within the endothelial cells for cancer therapy. They used a mouse model implanted with HNC cell line SCC7 (Xie et al., 2007). 3.3.2.3.2 Nano-chemotherapeutics to target the chemical environment (hypoxia and acidic pH) of tumors

Hypoxia and acidic pH are important aspects of the TME. Solid tumors have a hypoxic environment, and this is related to the low clinical effectiveness of therapeutics in tumor cells. Studies have shown that the oxygen gradient in the TME also affects the absorption of NPs (J. Chen et al., 2013). To overcome this obstacle, techniques such as photodynamic therapy (PDT), which is a noninvasive oxygen-dependent treatment related to the promotion of hypoxic conditions that leads to the overexpression of VEGF, have been combined with different NPs. For example, pH-sensitive aerobic NPs produced by electrostatic interactions between biopolymers such as chitosan and H2O2 reduction enzyme or catalase protein enable the reduction of high concentrations of H2O2 in solid tumors. These NPs self-assembled in micelles that enter the tumor through mechanisms such as macropinocytosis (Shen et al., 2017). Similarly, PDT has been combined with calcium phosphate and lipid NPs to release siRNAs that inhibit vascular endothelial growth factor (VEGF-A). This technique resulted in an increase in the number of apoptotic cells and a reduction in the expression of the VEGF factor (Lecaros et al., 2016). Other combinations seek to establish synergistic relationships with NaAsO2 and TH287 chemotherapeutic drugs and MTH1 inhibitors through a pHsensitive system. In vitro evaluation has demonstrated that NPs synergistically inhibit tumor cell proliferation effectively (Li et al., 2017). Therefore these strategies may be promising in the treatment of the hypoxic microenvironment and, especially, of superficial tumors. Other techniques such as magnetic NP hyperthermia are promising because NPs exposed to AMFs can be injected and specifically target hypoxic tumor cells to induce hyperthermia (E. Y. Chen et al., 2013). Different tools such as PAI, involving light and ultrasound, have also been evaluated to measure oxygen concentrations in tumors in vivo. These oxygen concentrations have

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demonstrated the potential to be used as a prognostic biomarker for therapy response. This technique has been evaluated in HNC associated with HPV(1) and HPV(2) showing differential response patterns, demonstrating that PAI can be a promising tool in the measurement of tumor hemodynamics in HNC (Rich, Miller, Singh, & Seshadri, 2018). 3.3.2.3.3 Nano-chemotherapeutics targeting metastasis

Patients with HNC have distant metastases with ranges between 4% and 26%, which limit their quality of life and survival. The main risk factors associated with the development of distant metastasis are related to the primary site, tumor differentiation, nodal involvement, and TNM classification (Wiegand, Zimmermann, Wilhelm, & Werner, 2015). However, the treatment strategy for patients with distant metastasis in HNC remains unclear (Wiegand et al., 2015). Src, a member of the nonreceptor tyrosine kinases, is often activated by different classes of cellular receptors, including receptor protein tyrosine kinases and G protein-coupled receptors as well as cytokines and integrins (Irby & Yeatman, 2000). The overexpression of Src has been found in HNSCC, which correlates with malignant potential and patient survival. Also, Src-activated signaling cascades can induce epithelial
mesenchymal transition, which promotes tumor cell metastasis (Summy & Gallick, 2003; Teng, Cai, Pi, Gao, & Shay, 2017). The chemotherapeutic molecules that target the signaling of Src receptors in cancer include dasatinib and saracatinib. Dasatinib inhibits migration and invasion in HNC, whereas saracatinib has potent antimigratory and antiinvasive effects in breast cancer cells and a modest effect in HNC (Teng et al., 2017). To enhance the antimetastatic activity of saracatinib in HNC, Lang et al. developed novel multifunctional NP formulations loaded with saracatinib for the selective release of the drug into tumor cells in mouse models and demonstrated that this complex has superior antimetastatic effects compared to the free drug (Lang et al., 2018). During metastasis, adhesion molecule-mediated cell interactions with the ECM and neighboring cells are lost and cancer cells are released into the lymphatic system or the bloodstream to invade tissues and organs (Sahai, 2005). The maintenance of adhesion between tumor cells and the surrounding ECM can be an approach for targeting tumor cell migration and metastasis. Moustafa et al. developed Au nanorods to target integrins using RGD peptides activated with NIR light to generate heat for photothermal therapy. The Au nanorods enhanced the remodeling of cytoskeletal proteins and decreased migration in human OSCC (HSC-3) modulating Rho GTPases, actin, microtubules, and kinaserelated pathways, which are the downstream regulators of integrins (Ali et al., 2017). 3.3.2.3.4 Potential of nanoparticles in head and neck cancer immunotherapy

One of the hallmarks of cancer is the avoidance of tumoral immune destruction (Hanahan & Weinberg, 2011). As in other types of cancer, tumoral immune suppression is a vital factor in the development of HNC, and this is evidenced by the higher incidence of squamous cell carcinomas in immunosuppressed people than that in immunocompetent individuals (Duray, Demoulin, Hubert, Delvenne, & Saussez, 2010; Herman, Rogers, & Ratner, 2007). The role of the immune system is critical in the identification and elimination of tumoral cells. Its response is represented by the cancer immunity cycle. Once a tumoral cell dies, it releases tumoral antigens that are taken up and processed by

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antigen-presenting cells such as dendritic cells, which migrate to the lymph nodes to present the tumoral antigen and induce the priming and activation of tumor-specific T cells. Once the T cells have been activated, they migrate through the blood vessels to the tumor and infiltrate it. There the T cells identify tumoral cells and destroy them. This initiates the immune cycle again (Chen & Mellman, 2013). Along with the coordinated participation of other effector cells of the immune response as natural killer cells, macrophages M1, ɣδ T cells, and proinflammatory mediators such as interferon-gamma (IFNɣ), IL-12p70, IL-1β, tumor necrosis factor-α, and other effector molecules constitute an effective antitumoral immune response (Mittal, Gubin, Schreiber, & Smyth, 2014). However, tumors have several ways to evade the immune system using different immunosuppressive mechanisms to generate a tolerogenic microenvironment that allows them to proliferate and grow freely, as in HNC (Duray et al., 2010). For example, tumor cells produce a large amount of immunosuppressive factors such as transforming growth factor-beta (TGF-β), indoleamine dioxygenase, prostaglandin E2, and arginase (Liu & Guo, 2018). The regulation of immune responses in TME is mediated by the production of the regulatory cytokine IL-10 (both TGF-β), and, in immune cells such as dendritic cells, induces the upregulation of coinhibitory receptor programmed death-ligand 1 (PDL-1) and in T cells the upregulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). In addition, many other tolerogenic strategies together blockade antitumoral mechanisms and promote tumor development (Tran Janco, Lamichhane, Karyampudi, & Knutson, 2015). In this context, cancer immunotherapy (CIT) arises. It is focused on restoring the antitumoral function of the immune system and repotentiating its ability to eliminate tumors. Currently, there are several immunotherapeutic strategies that have different targets in the cancer immunity cycle. Among the most important are the immune checkpoint inhibitors (monoclonal antibodies) anti-PDL1 and anti-CTLA-4, cancer vaccines, cellular immunotherapy, and CAR-T therapy (autologous T cells genetically modified with chimeric antigen receptors). CIT has contributed to the treatment of HNC patients (Ferris et al., 2016; Ferris et al., 2018) and related projects as one of the most promising therapeutic strategies. Because of the ability to protect molecules from degradation and maintain them for controlled release, the use of NPs in CIT seeks to improve its effectiveness through the design of strategies that overcome limitations in the delivery of antigens, adjuvants, and other immune potentiators into the TME and immune cells (especially antigen-presenting cells). In particular, the delivery of these factors to the TME of solid tumors (as in HNC) is more difficult than that of liquid tumors (Melero, Rouzaut, Motz, & Coukos, 2014) due the complexity of the TME. Several aspects such as size, shape, charge, and hydrophobicity are essential to the consideration of NPs for CIT (Fan & Moon, 2015; Irvine, Hanson, Rakhra, & Tokatlian, 2015). One key point in CIT is the efficient delivery of tumor-associated antigens (TAA) and/or tumor-specific antigens (TSA) to antigen-presenting cells. TSA are ideal for the induction of specific tumor immune responses. To achieve the delivery of these antigens into the lymph nodes, medium-sized NPs (5
100 nm) are the best option. Small NPs could be lost through blood vessels, and larger ones could be retained by the ECM (Park, Heo, & Han, 2018). Another critical aspect of CIT is the surface charge of the NPs. Cationic surfaces are the most suitable because antigen-presenting cells absorb them better when they are at the injection site (Hamdy, Haddadi, Hung, & Lavasanifar, 2011; Saleh & Shojaosadati, 2016),

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which could be applied in mouth cancer. However, cationic NPs present some difficulties with trafficking such as low tissue permeability, which must be taken into account and reviewed (Foged, Brodin, Frokjaer, & Sundblad, 2005). Finally, shape, along with size and charge, is another critical aspect of NPs in CIT due to the capability of antigen-presenting cells to sense different kinds of particles and, using this information, to execute several actions (Underhill & Goodridge, 2012); nonspherical NPs with higher aspect ratios are more easily accepted (Park et al., 2018). As the main objective of CIT, both in HNC and other types of cancer, is to restore the antitumoral activity of the immune system, the use of NPs is focused on releasing antigens such as peptide antigens and nucleic acid-based tumor antigens, among others (Mi, Hagan, Vincent, & Wang, 2019). The most used strategies are targeted at dendritic cells due to their high capacity to active T cells and direct the antitumor adaptive immune response. PLGA NPs have been used widely to active dendritic cells, along with chitosan, micelles, and liposomes (Surendran, Moon, Park, & Jeong, 2018). PLGA NPs have been used in models of HNC to deliver to patient-derived dendritic cell TAA both from FaDu and FAT7 cell lines and tumor-tissue lysates. This showed that dendritic cells stimulated with TAA-loaded NPs were more efficient at producing IL-2 and INF-ɣ and activating CD8 1 T cells compared with tumor-tissue lysates alone (Prasad et al., 2012; Prasad et al., 2011). Although to date there are only a few investigations of NPs for CITs in HNC and their use is quite limited, the potential of NPs to improve CITs in this cancer is large as seen in other types of cancers; however, this is an emerging field and, therefore, its true utility will only be seen in some years. 3.3.2.3.5 Nanomedicine as a strategy for natural compound delivery for cancer treatment

Our research group explores methods to target HNC with new bioactive molecules from natural sources. The incorporation of nanostructures in delivery systems for natural compounds would be a major advance to increase their therapeutic effects. Our projects are focused on the design of natural medicines for controlled and sustained release of bioactive compounds to use in cancer prevention, control, and therapy.

3.4 Conclusion Nanotechnology offers the capability to new strategies in the early diagnosis, control and treatment of head and neck cancer - Nanotechnology has the potential to profoundly impact cancer patient management with its capacity to provide diagnostic sensitivity and specificity, multiplexing and flexibility.

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Nano Drug Delivery Strategies for the Treatment of Cancers

C H A P T E R

4 Nanoparticles and lung cancer Sudha Vengurlekar and Subhash Chandra Chaturvedi Sri Aurobindo Institute of Pharmacy, Indore, MP, India

4.1 Introduction Lung cancer emerged as the most common cancer in the last century from an uncommon disease. Lungs perform a vital function in the body—the exchange of the gases between air and blood. Lungs purify the blood by expelling carbon dioxide and by absorbing oxygen. Lung cancer can be defined as the abnormal growth of cells present in lungs. These cancerous cells stick together and form a lump known as a tumor. Tumors can be removed from the body during the early stage of growth (Williams, Mackenzie, & Magnuson, 2016). In the majority of fatal cases, metastasis of various cancers like that of the lungs, liver, and bone occurs. Lung cancers can be classified in two main categories: small-cell and non-small-cell lung carcinoma. Small-cell lung cancer look like oats under microscopic view and is also known as oatcell cancer. These cancers originate in the inner layer of the wall of the bronchi, then grow and quickly spread to other parts of the body. This type of lung cancer is not very common. The main cause is smoking tobacco and initial symptoms are chest pain, respiratory infection, sore throat, difficulty in breathing, and so forth. Small-cell lung cancer is difficult to treat as it has more capacity to grow compared to non-small-cell lung cancer (Edwards, Noone, & Mariotto, 2014). Non-small-cell lung cancer is more common and usually grows at a slower rate than small-cell lung cancer. According to the World Health Organization there are three main categories of non-small-cell lung cancer: (1) adenocarcinoma (AD), (2) squamous cell carcinoma, and (3) large-cell carcinoma. ADs are found centrally in the lung at the joint of the bronchi and trachea, the part of the lung that secretes mucus and helps us to breathe. Squamous cell lung cancer is more common and is mainly linked to smoking. Large-cell cancer is usually found anywhere in the lungs, grows fast, and spreads quickly (Edwards et al., 2014).

Nano Drug Delivery Strategies for the Treatment of Cancers DOI: https://doi.org/10.1016/B978-0-12-819793-6.00005-9

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4.1.1 Cause, molecular target Various factors are responsible for lung carcinogenesis such as smoking and long-term exposure to toxic chemicals through inhalation. Certain other factors such as genetic susceptibility may also cause lung cancer. Cancer susceptibility is significantly higher in the presence of rare germ line mutations like p53, retinoblastoma, epidermal growth factor receptor (EGFR), and others. Compromised immunity and a low rate of repair of genetic materials such as DNA also play important roles in lung cancer (Burstein & Schwartz, 2008). Tyrosine kinases is a key enzyme that is involved in lung cancer. Due to mutation, autocrine incitement, and overexpression of kinases, activation occurs which leads to lung cancer. Tyrosine kinase like PIK3CA, EGFR, and others, are frequently activated by mutants and are important targets for cancer therapeutics (Burstein & Schwartz, 2008; Paul & Mukhopadhyay, 2004). Another target is through immune response such as activation of programmed cell death protein 1 (PD-1) receptor of lymphocytes, activation of T cells, and others. Anaplastic lymphoma kinase is also an important target for lung cancer. Through blocking the activity of ROS1 and enzyme B-Raf (a growth enzyme) lung cancer can be targeted.

4.1.2 Traditional therapies for treatment Treatment of lung cancer is very challenging and mainly depends on the severity stage, type of cells involved, and early diagnosis. Cancers that are detected at very early stage may be curable. Various treatment options are available—some treatments are used to control the growth of cancer and others reduce symptoms. Chemotherapy involves the use of a drug candidate which kills the cancer cells. In this therapy a single drug or a combination of drugs is directly injected into the veins. Chemotherapy is applicable for advanced stages of non-small-cell cancer and in all stages of small-cell cancer (NCCN, 2016). The various drugs approved by US FDA for lung cancer are shown in Table 4.1. Another popular therapy is radiation therapy in which an X-ray beam of high energy is focused on the cancer cells to reduce their effect on normal cells. This therapy may be employed at the primary stage of cancer or it can be combined with chemotherapy. There are various types of radiation therapy, including 3-D conformal radiation therapy (3-D CRT), hypofractionated radiation therapy, stereotactic body radiotherapy, intensity-modulated radiation therapy, and others. For non-small-cell lung cancer brachytherapy is used. This is an internal radiation therapy in which a radioactive material (radioactive isotope) is focused on the tumor or very near to it (Detterbeck, Decker, Tanoue, & Lilenbaum, 2015). Surgery is another way of treating cancer and is considered as a standard treatment for lung cancer when detected at an early stage. The tumor is removed completely from the lungs so that the surrounding tissue has a better chance for cure. Targeted therapy is used for non-small-cell lung cancer which has spread to other body parts or lymph nodes. The choice of targeted therapy depends on the type of mutations in the cancer cells, which are identified through molecular tissue tests. Immunotherapy is also used for metastatic lung cancers. Immunotherapy is used when patients do not respond to any of the other therapies (Tyson & Ginex, 2012).

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4.1 Introduction

TABLE 4.1 US FDA-approved drugs used for the treatment of lung cancer. Name of drug

Therapy

Mechanism

References

Pembrolizumab Chemotherapy for metastatic small-cell lung cancer

It targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes

Pembrolizumab Monograph (2019)

Atezolizumab

Chemotherapy for the first-line treatment metastatic nonsquamous, non-small-cell lung cancer

It targets programmed cell death-ligand 1 (PD-L1)

Shields (2016)

Lorlatinib

Chemotherapy for metastatic non-small-cell lung cancer

Inhibitor of anaplastic lymphoma kinase and receptor tyrosine kinase (encoded by the gene ROS1)

European Commission Report (2019)

Dacomitinib

First-line treatment for metastatic An irreversible EGFR tyrosine kinase non-small-cell lung cancer inhibitor (chemotherapy)

Lau, Batra, Mok, and Loong (2019)

Nivolumab

Chemotherapy for metastatic small-cell lung cancer

European Commission Report (2019)

Osimertinib

Chemotherapy of metastatic non- Epidermal growth factor receptor tyrosine small-cell lung cancer kinase inhibitor

Minari, Bordi, and Tiseo (2016)

Durvalumab

Chemotherapy for stage III nonsmall-cell lung cancer

It is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell deathligand 1 (PD-L1) with the PD-1 (CD279)

www.fda.gov

Afatinib

Chemotherapy for metastatic non-small-cell lung cancer

Harbor mutations in the epidermal growth US Food and factor receptor gene Drug Administration (2013)

Alectinib

Chemotherapy for metastatic non-small-cell lung cancer

Blocks the activity of anaplastic lymphoma INN (2017) kinase

Blocks a signal that would have prevented activated T cells from attacking the cancer

Dabrafenib and Chemotherapy for metastatic trametinib non-small-cell lung cancer

An inhibitor of the associated enzyme B-Raf, which plays a role in the regulation of cell growth

Gibney and Zager (2013)

Ceritinib

Chemotherapy for metastatic non-small-cell lung cancer

Inhibitor of anaplastic lymphoma kinase

INN (2014)

Brigatinib

Non-small-cell lung cancer

An anaplastic lymphoma kinase and epidermal growth factor receptor inhibitor

Uchibori et al. (2017)

4.1.3 Shortcomings with existing treatments Existing non-small-cell cancer drugs have several side effects despite much research and development into the treatment of lung cancer. Chemotherapy, radiation therapy is associated with their own set of adverse effects on cancer patients and results into reduced efficacy of medication. One of the most common therapies, chemotherapy, has an effect on

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all cells, not just the cancer cells. Radiation therapy results in a reduction of white blood cells and causes fatigue. It may also cause nausea, vomiting, and skin irritation (Rani, Somasundaram, Nair, & Koyakutty, 2012). Surgery is a tedious process and requires expertise as small-cell lung cancers are present at specific sites (Rani et al., 2012). Current forms of chemotherapy lack target specificity and so frequent recurrence of the disease occurs. Chemotherapy by oral route further causes damage to the drug efficacy by altering drug structure as a process of pH dependent degradation or by drug molecule alteration during first pass metabolism (Schmid, 2005). The heterogeneity of tumor cells (e.g., primary tumor or metastatic) also plays a vital role in the success of therapy. The main challenge in the selection of a cancer therapy is the ability of cells to develop resistance (Jamal-Hanjani et al., 2017).

4.2 Nanotechnology and lung cancer Nanoparticles (NPs) possess different physical and chemical properties. The size of NPs varies between 1
100 nm, they may have active functional groups on the surface, they can exist in different shapes (e.g., rod, sphere, etc.), and they may contain different materials such as organic or inorganic (Fig. 4.1). The surface of NPs plays an important role for the delivery of drugs at the site. The surface can be made hydrophilic by adding appropriate polymers on it. Hydrophilic surfaces play vital role in the life span of NPs in circulation (Srinivasan, Rajabi, & Mousa, 2015; Sun, Zhang, Pang, Hyun, & Yang, 2014). Due to their very small size, NPs pass easily to tumor sites without getting affected by the vascular defects of cells. This characteristic of NPs is known as fenestration. This property allows NPs to deliver even high concentrations of the therapeutic molecule to the cancer tissue directly (Cho, Wang, Nie, & Shin, 2008). NPs are able to encapsulate drugs with different natures (i.e., whether hydrophobic or hydrophilic) and can achieve controlled delivery of the drugs. Nanocarriers are very effective in chemotherapy as it is possible to deliver the drugs accurately to the desired site. NPs possess various remarkable properties such as their low dosage requirement and hence low side effects, as well as targeted drug delivery, controlled delivery of drugs, improved stability and less toxicity, effective diagnostic tool, fast onset of drug action, and so forth. NPs are available in different types as illustrated in Fig. 4.2. Advancements in nanotechnology have developed various new nano forms made up of different materials according to the requirements. Nanoparticle offers to manipulate numerous physical, chemical and biological properties which have emerged in many possibilities such as effective drug action and low toxicity. FIGURE 4.1 Physicochemical properties of nanoparticles.

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FIGURE 4.2 Types of nanomaterials employed in lung cancer therapies.

4.2.1 Organic nanoparticles for lung cancer Organic NPs possess many important features such as nontoxicity, biodegradability, compatibility with biological systems, and others. Various polymeric materials such as chitosan (CS), poly (lactide-co-glycolide) (PLGA), poly (lactic acid) (PLA) nanogels made up of PEG, diallyl phthalate, divinylbenzene, and so forth, are common materials employed in organic NPs. Chitosan NPs along with DNA makes a complex known as polyelectrolyte, which is an effective drug delivery form. Chitosan and carboxymethyl chitosan were found to be excellent carriers for delivery of many drugs. PLGA NPs have been approved as an effective tumor suppressor of A549 lung cancer cells by the US FDA. A potential drug delivery strategy for anticancer drugs has been reported by preparing NPs of doxorubicin with chitosan, and showed improved absorption of drug. Haitao, Hao, and Baorui (2013), have also worked on polymeric NP development and prepared curcumin (CM) loaded NPs. CM has well-documented anticancer potential for various types of cancers. However, some limitations associated with CM are related to its poor solubility, which limits its possible uses. CM-loaded NPs such as amphilic methoxy poly(ethylene glycol) (mPEG)
polycaprolactone showed the highest loading efficiency along with the sustained release of drugs. Nanoscaled systems are one of the polymeric approaches to improve the drugs targeting lung cancer cells. Guowen et al. (2018) prepared RGD peptide-modified, dual-drug loaded, paclitaxel (PTX) prodrug-based and redox-sensitive lipid-polymer NPs and evaluated them for their in vitro and in vivo efficiency to kill lung cancer cells. RGD-modified PTX and cisplatin (CDDP) loaded LPNs (RGD-ss-PTX/CDDP LPNs) have shown remarkably higher antitumor activity of LPNs than free drugs. Fahad, Almutairi, and Abd-Rabou (2019), prepared a novel drug delivery system to reduce drug resistance in lung cancer by using complexing hyaluronic acid (HA) and chitosan to improve the half-life and activity of the drug raloxifene. The nano system developed exhibited the proapoptotic and cytotoxic effects against NSCLC (A549) and HCC (HepG2 and Huh-7) cell lines.

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A novel chemotherapeutic (CDDP)-siRNA (HuR) in combination with folic acid conjugated dendrimer-polyethlyeneimine (Den-PEI) NPs were developed and evaluated for its efficacy in lung cancer cells. This Den-PEI-CDDP-HuR-FA system showed targeted drug delivery and increased cell uptake in folate receptor alpha (FRA). The targeted NP delivery system exhibited apoptosis, and was found to be an efficient combined potency of CDDP and HuR siRNA in lung cancer cells (Narsireddy et al., 2018). Mohammad et al. (2017) developed low dose disulfiram (DSF) loaded PLGA NPs in order to improve efficacy of DSF. DSF metabolizes rapidly in the bloodstream and thus its anticancer effects against lung cancer cells were limited. A low dose of DSF-loaded PLGA NPs was shown to reduce metastasis in a lung cancer model. Other PLGA
PEG NPs have been developed by Claudia et al. (2018), as new redoxresponsive NPs (RR-NPs). These NPs are programmed in a way to have altered surface properties when reaching tumor microenvironments. These PEGylated nanocarriers enter the mucus layer of the tissues that results in increased cellular uptake and drug cargo by extra- and intra-cellular cleavage of protein and cell shielding hydrophilic blocks. Jung et al. (2012), reported PEG-modified poly NPs in addition to taxanes as effective chemoradiotherapy system for A549 cells when tested on in vitro and in vivo xenograft model of lung cancer.

4.2.2 Inorganic nanoparticles for lung cancer Inorganic NPs have been used in lung cancers for the delivery of drugs, diagnostics, imaging, delivery of nucleic acid, biosensing, and so forth, due to their wide range of physicochemical properties. The most common inorganic NPs employ gold, silver, iron oxides, silica, rare earth oxides, carbon dots, and nano diamonds (Knights & McLaughlan, 2018; Silva et al., 2019). Silver NPs are commonly employed as a bactericide and gold NPs show lots of potential in drug delivery targeted delivery because of its catalytic activity. Inorganic NPs exhibit excellent cytotoxic properties on a variety of lung cancer cells and also are nontoxic, biocompatible, hydrophilic, and highly stable compared to organic materials. Inorganic NPs have widespread use in nearly all imaging techniques (e.g., MRI, photoacoustic imaging, and optical imaging). They can further be utilized as a potential medical imaging technique by incorporating organic dyes to have improved diagnostics, disease characterization, and so forth. Inorganic NPs such as those from gold and iron oxide are potential probes in thermal lung cancer therapies. Photocatalyzed titanium dioxide (TiO2) NPs have been developed by Thevenot, Cho, Wavhal, Timmons, and Tang (2008), and exhibited antitumor properties against lung cancer. Peng, Tisch, and Adams (2009), developed a biosensor gold NP to detect lung cancer. The sensors use a combination of an array of chemiresistors based on gold NPs and pattern recognition methods. Priyanka et al. (2018) reported gold NPs in the treatment of cancer by tumor detection, drug delivery, imaging, photothermal, and photodynamic therapy (PDT) and their current limitations in terms of bioavailability and the fate of the NPs. Silver NPs (AgNPs) were also employed as an effective antitumor agent against lung cancer for in vitro H1299 lung cancer cells and an in vivo xenograft immunodeficient (SCID) mouse model. Mechanistic studies showed that AgNPs caused apoptosis (increase

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in caspase-3 and decrease in bcl-2) in lung cancer cells that connected well with an inhibition of NF-_B activity (He et al., 2016). Notably, HIF-1 protected AgNPs act by inducing apoptosis and by regulating autophagic flux through the ATG5, p62, and LC3-II. Hence, AgNPs have emerged as a potential lung cancer therapy (Jeong et al., 2016). Vaikundamoorthy, Krishnamoorthy, Vilwanathan, and Rajendran (2018) reported gold NPs (AuNPs) as an effective delivery system when conjugated with anticancer drug doxorubicin (DOX) on the surface of AuNPs with polyvinylpyrrolidone (dox@PVP-AuNPs). The system ensured effective cellular intake and intracellular release of DOX. The nano system dox@PVP-AuNPs inhibited the proliferation of human lung cancer cells, produced an in vitro cytotoxic effect, and can be considered as a potential drug delivery system for the effective treatment of human lung cancer. Inorganic material selenium has been used to prepare NPs against lung cancer. Selenium NPs (SeNPs) MTT assay was performed to evaluate the radio-sensitizing effect under X-ray against lung cancer cells as well as normal healthy cell lines. SeNPs indicated remarkable potency against cancer cells and additionally showed relatively less toxic effects in normal healthy cells (Liza, Cruz, & Wang, 2019). Inorganic material mesoporous silica was utilized to develop mesoporous silica NPs (MSN) as a drug delivery system. This system is an inhalation system which effectively delivers drugs like DOX and cisplatin into lung cancer cells. In this system, drugs are combined with two siRNA targeted to MRP1 and NCL2 m RNA and act by suppressing pump and nonpump resistance in lung cancer cells. MSN delivery to the local area by inhalation causes preferential collection of NPs in mouse lungs, which eventually prevented the diversion of MSN to systemic circulation, and as a result limited its reach to other organs (Taratula, Garbuzenko, Chen, & Minko, 2011). Gadolinium-doped zinc oxide NPs (Gd-doped ZnO NPs) were also developed for lung cancer (Masoumeh, Hassan, Hossein, & Aziz, 2019). Zinc oxide NPs have an important photocatalytic feature that enables them to kill cancer cells under UV light. Gadolinium (Gd), being element of high atomic number, was selected for doping as it increases the absorption of radiation and enhances the imaging visualization capabilities of ZnO NPs. Another inorganic metal, platinum, also has versatile therapeutic effects. Nanotechnology has developed many platinum drug delivery nanoforms. Platinum NPs including polymeric AP5280, AP5346, and NC-6004 have been developed for better lung cancer cell killing effects, less side effects, and less drug resistance (Ping et al., 2015). DOX is a widely used chemotherapeutic drug and cetuximab is an EGFR inhibitor combined with NPs and coconjugated to dextran-coated Fe3O4 magnetic NPs (DOX-NPs-Cet) and evaluated on the NSCLC cell line A549. DOX-NPs-Cet suppress cell proliferation of A549 cells more compared with A549 cells treated with NPs only conjugated with DOX (Qinlu et al., 2019).

4.2.3 Natural or biomaterials as nanoparticles Bio-NPs are widely applied for lung cancer treatments as they have remarkable biocompatibility and biodegradability. Yuzhou and Wentao (2018) reported HA and human serum albumin modified erlotinib NPs (ERT-HSA-HA NPs) delivery systems. MicroRNAs (miRNAs) are important in the development of lung cancer as they are small noncoding

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RNAs that regulate several cancer-related genes. They are utilized in many ways for the development of anticancer agents and are an interesting therapeutic approach for cancer treatment. Massimo et al. (2019), has developed cationic lipid NPs by entrapping miR-660 (CCL660) for systemic delivery of CCL660. This system causes increased miRNA levels in tumors and remarkably reduced growth of tumors without off-target effects. Mesenchymal stem cells (MSC) also have potential as a drug delivery vehicle. Xusheng et al. (2019), utilized MSC as lung cancer-targeted drug delivery vehicles with NPs loaded with anticancer drugs. MSC indicated a better drug uptake capacity than fibroblast. The MSC/NP drug delivery system is an encouraging system for lung-targeted drug delivery for lung cancer treatment. Juglanin is extracted from green walnut husks of Juglans mandshurica, a natural product with numerous bioactivities. Reduction in multiple drug resistance can be achieved through the combination of drug, gene, and NP which also inhibits lung cancer progression. Zhong et al. (2017), developed a self-assembled NP formula of amphiphilic poly [juglanin (Jug) dithiodipropionic acid (DA)]-b-poly (ethylene glycol) (PEG)-siRNA Kras with DOX in the core (DOX/PJAD-PEG-siRNA). Juglanin, as a chemosensitizer, increases the anticancer activity of DOX in drug-resistant cancer cells. Albumin NPs are also well-known drug carriers for delivery of hydrophobic anticancer molecules. Albumin NPs are used to encapsulate various potent anticancer drugs such as CM and doxorubicin. Albumin NPs have reduced side effects by gradually releasing the drugs over a period of 24 h rather than the burst effect (Bomi et al., 2017). Hideki et al. (2019), have developed porphyrin
high-density lipoprotein (HDL) NPs which are ultrasmall in size and called porphyrinHDL. Presence of high density of porphyrin molecules causes its rapid dissociation upon tumor cell accumulation to be fluorescent and photoactive. This nano system is used extensively in image-guided PDT. These NPs are targeted to scavenger receptor class B type I (SR-BI) present on lung cancer cells and applicable for the treatment of peripheral lung cancer and metastatic lymph nodes of advanced lung cancer. Virus NPs are commonly used systems for in situ vaccination in lung cancer therapy. Among different viruses, cowpea mosaic virus (CPMV) has wide utility in a wide range of vectors. CPMV has an icosahedrons shape, its size is approximately 28.4 nm, and is made of nearly 60 subunits which makes it suitable to withstand the temperature of about 60 C and pH range of 3
9. Their structure is polyvalent, symmetrical, and can conjugate with various drugs, target specific reagent, and so forth (Robertson, Soto, Archer, Odoemene, & Liu, 2011).

4.2.4 Other novel nanoparticles systems for lung cancer Nanotechnology has developed many new categories of nanosystems to treat lung cancers. Magnetic NPs have been extensively utilized and applied in diagnosis and treatment of various cancers. Magnetic hyperthermia is a therapeutic approach that causes heat-induced excision of the desired tumor tissue for lung cancer. When tumor cells are subjected to magnetic materials (superparamagnetic iron oxide) it generates sublethal heat that damages the local tissues. Wang, Zhang, Du, Wu, and Zhang (2012) have developed magnetic NPs to detect micrometastasis in lung cancer. Magnetic NPs are conjugated with epithelial tumor cell

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isolated from circulating tumor cells from patients diagnosed with lung cancer. The cells were later identified by quantum dots coupled to the NSCLC micrometastasis marker lungspecific X protein (LUNX) and surfactant protein-A(SP-A) antibody. Magnetic NPs have also been used to overcome drug resistance. A cisplatin-resistant A549 lung tumor xenograft model was chemosensitized with cisplatin-loaded magnetic NPs. Molecular studies demonstrated that cisplatin-loaded magnetic NP
treated tumors had a significant reduction in localization of drug resistance related proteins and enhanced cytotoxicity of cisplatin (Li, Chen, & Xu, 2013). Smart nanomaterials (NP drones) have also been developed recently and have opened up new ways for lung cancer diagnosis and therapy. These drones are constructed with the capacity to specifically target tumor cells with remotely radiation activation to emit micrometerrange missile-like electrons that target and destroy the tumor cells. Nanoparticle drones may also be utilized for the delivery of therapeutic agents to tumor cells. These drones have recently been utilized to deliver cannabinoids, which are the natural bioactive moiety of Cannabis sativa. This drone drug delivery reduces toxicities associated with cannabinoids and their derivatives. Fatemeh, Mehdi, Yousef, Fatemeh, and Rassoul (2019), generated hybrid nanosystems that are a combination of organic, inorganic, metallic, and polymeric nanoparticulate with the aim to achieve a synergistic effect. Combining various organic and inorganic components in a single hybrid nanosystem is a novel concept and has multifunctional properties, as well as their own advantages and disadvantages. A novel pH-sensitive system that has a codelivery property for the treatment of metastatic lung cancers through pulmonary delivery of doxorubicin and survivin siRNA have been developed (Caina, Huayu, Ping, Yanbing, & Xuesi, 2016) using some conjugates of polyethylenimine (PEI), doxorubicin, and pH-sensitive hydrazine bond (3-maleimidopropionic acid hydrazide (BMPH)). This nanosystem has effectively delivered doxorubicin and survivin siRNA into the same cells and improved the cytotoxicity in B16F10 cells. When it is tested on B16F10 tumor-bearing mice models, PMD/siRNA complex NPs by pulmonary delivery resulted in local delivery and preferential accumulation of DOX and siRNA in the lung tumor cells. Currently optical imaging along with polymer-based fluorescent NPs is being extensively studied in order to achieve detection of lung tumors at molecular levels. As the majority of cancer patients are detected at metastatic and advanced level cancer, there are limited therapeutic options. This new technology is very helpful in early cancer detection, therapeutic monitoring, and in image-guided surgeries (Venkatesan et al., 2019).

4.3 Conclusion NPs, due to their high-invasive property and small size, can effectively be used in the treatment of cancers. Novel physical and chemical properties make NPs very useful in enhancing solubility and stability through surface modification. The unified approach of adding ligands drugs, imaging agents, and biomolecules into an NP enables diagnostics and targeted drug delivery. NP-based targeting of therapeutic drugs to specific tumor cells and the delivery of therapeutic agents to cancer sites play important roles in reduction of toxicities and side effects. The literature discussed in this chapter provide a variety of

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forms of NPs that have been extensively explored for the treatment of different forms of lung cancers. Many advanced techniques such as magnetic NPs, NP drones, hybrid NPs, and so forth, are under study. Many approaches are still at preclinical stages. In spite of the many advantages, there are a lot of challenges including economical production, scaleup problems, pharmacokinetics of drugs, and the imaging construct. Additional issues with nanotoxicity and regulatory guidelines and other hurdles need to be resolved in order to see lung cancer therapies in clinics.

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C H A P T E R

5 Nanoparticles and liver cancer Mohammad Bayat1 and Davood Ghaidari2 1

Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran 2Department of Chemistry, Faculty of Science, University of Guilan, Rasht, Iran

5.1 Introduction Hepatocellular carcinoma (HCC) is one of the most pernicious malignancies worldwide, and, unfortunately, the incidence of HCC has significantly increased over the past few decades (Li, Farmer, Yang, & Martin, 2016). The standard treatment of HCC includes chemotherapy, ablation (alcohol injection to tumor or radiofrequency ablation), or surgical resection followed by chemotherapy (Lin, Hoffmann, & Schemmer, 2012). Metastases and relapses cannot be efficiently cured by surgical resection and require versatile diagnosis and chemotherapy approaches. The survival rate of liver cancer patients is low, which is largely due to late diagnosis and poor sensitivity to common chemotherapeutic formulations (Greco & Vicent, 2009). In this regard, because of the lack of efficient diagnostics approaches, most HCC patients are diagnosed at late and advanced stages, which leads to unsuccessful treatment outcomes. Thus innovations in efficient medical diagnostics accompanied by therapeutic agents with fewer side effects can present an elegant solution to the mentioned problems. In the past few years, there has been a growing focus on the application of theranostic nanomedicine, which is a new strategy that combines therapeutic and diagnostic agents in delivery systems. Theranostics is emerging as a promising approach to assist cancer chemotherapy, the early detection of cancer, and the measurement of the real-time therapeutic response of patients. A new era of nanomedicine that uses devices of nanoscale size to address urgent needs for the improved diagnosis and therapy of diseases is being etched in the 21st century. Polymeric micelles, quantum dots, liposomes, polymer
drug conjugates, dendrimers, biodegradable nanoparticles, silica nanoparticles, etc., are just a few examples of nanoparticulate materials that are researched in laboratories, undergoing preclinical development, or already being used in clinics (Davis, Chen, & Shin, 2008; Duncan, 2003; Farokhzad & Langer, 2006; Kabanov & Alakhov, 2002; Peer et al., 2007; Tasciotti et al., 2008). These nanomaterials are collectively called “nanomedicines” or “classical” drug delivery systems. Nanomedicines are submicrometer-sized carrier materials designed to improve the biodistribution of systemically administered

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FIGURE 5.1 Theranostic nanomedicines. Liposomes and liposomal bilayers are shown in gray; polymers and polymer-coatings in green; solid (lipid) nanoparticle components in brown; antibodies in purple; linkers allowing for drug release and for sheddable stealth coatings in blue; targeting ligands in yellow; imaging agents in orange; and conjugated or entrapped pharmacologically active agents in red.

therapeutic agents. By delivering pharmacologically active agents more effectively and more selectively to pathological sites (site-specific drug delivery) and/or by guiding them away from potentially endangered healthy tissues (site-avoidance drug delivery), nanomedicines aim to improve the balance between efficacy and the toxicity of systemic therapeutic interventions (Lammers, Hennink, & Storm, 2008; Sanhai, Sakamoto, Canady, & Ferrari, 2008). Besides, for drug targeting to pathological sites and for therapeutic purposes, nanomedicine formulations have also been used increasingly for imaging applications as well as, in the past few years, for theranostic approaches, that is, for systems and strategies in which disease diagnosis and therapy are combined (Caruthers, Wickline, & Lanza, 2007; Sun, 2010; Xie, Lee, & Chen, 2010). Classical drug delivery systems, and antibodies (Lammers, Aime, Hennink, Storm, & Kiessing, 2011), are being coloaded with drugs and contrast agents; examples of which are shown in Fig. 5.1. On the other hand, nanomaterials with an intrinsic ability to be used for imaging purposes such as gold and iron (inorganic particles) oxide
based nanoparticles are increasingly being loaded with drugs and used for combining disease diagnosis and therapy.

5.2 Drug delivery to the liver with nanoparticles An example of a colloidal drug carrier system that can be employed for the delivery of drugs to the liver is nanoparticles. Many clinically approved nanoparticle formulations are used for treating various cancers at a variety of stages. Interestingly, all but one of these systems (Abraxane) are liposomal systems that encapsulate an anticancer drug. On the other hand, nanoparticles are defined as polymeric particles made of natural or artificial polymers ranging between about 10 and 1000 nm (1 mm) in size. Drugs can be bound in the form of a solid solution or a dispersion, or they can be adsorbed onto the surface or be chemically attached (Kreuter, 1994). For instance, Doxil, which is polyethylene glycol (PEG)-functionalized liposomal doxorubicin (DOX), was the first approved (FDA, 1995) cancer nanomedicine (Barenholz, 2012). Soon after, other liposomal formulations such as liposomal daunorubicin (DaunoXome) (Fox, 1995), liposomal vincristine (Marqibo) (Silverman & Deitcher, 2013), and most recently, liposomal irinotecan (Onivyde) (Carnevale & Ko, 2016) were approved by the Food and

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Drug Administration (FDA), whereas nonPEGylated liposomal DOX (Myocet) (Leonard, Williams, Tulpule, Levine, & Oliveros, 2009) and liposomal mifamurtide (MEPACT) (Ando, Mori, Corradini, Redini, & Heymann, 2011) were approved by the European Medicines Agency (EMA). The lone nonliposomal nanoparticle system currently approved for cancer treatment is Abraxane, an albumin-bound paclitaxel nanoparticle (Miele, Spinelli, Miele, Tomao, & Tomao, 2009). The majority of these formulations are not PEGylated, with the exception of Doxil and Onivyde (Chang, Shiah, & Yang, 2015), which is perhaps surprising given the widely known advantages that even small amounts of PEG have shown to confer to nanoparticle delivery systems (Gref et al., 1994; Otsuka, Nagasaki, & Kataoka, 2003; Suk, Xu, Kim, Hanes, & Ensign, 2016). Additionally, all of these formulations are passively targeted, with no active- or chemical-based targeting moieties; again, this is despite the proven advantages of active-targeting in preclinical settings (Byrne, Betancourt, & Brannon-Peppas, 2008). It is likely that the other advantages, notably the reduced toxicity stemming from the ability to preferentially accumulate at tumor sites and limit off-target side effects via the enhanced permeation and retention (EPR) effect, are responsible for the success and increased efficacy that these approved particles have over their free drug counterparts. Ever since its discovery (Fire et al., 1998), siRNA has been widely recognized as being capable of silencing many or perhaps all genes, thereby modulating or selectively blocking the biological processes that are the defining hallmarks of cancer. A tremendous amount of effort has been spent on developing siRNA cancer therapeutics over the past 10 years, and much progress has been achieved in research and development, both in academics and the pharmaceutical industry. Nanotechnology has had an important role in siRNA cancer therapy, and many nanovector strategies have been developed for siRNA delivery. Nanovectors for siRNA delivery can be divided into two groups, namely lipid-based consisting of liposomes, stable nucleic acid, lipid particles, and lipidoid nanoparticles and nonlipid organic-based consisting of chitosan, cyclodextrin-containing polycations, dendrimers, polyethylenimine, and other polymer conjugates. Lipidoids are lipid-like delivery molecules. Lipidoid nanoparticles contain lipidoids, cholesterol, and PEG-modified lipids specific for siRNA delivery. Most research laboratories and biotechnological/pharmaceutical companies have used lipidbased nanovectors for siRNA delivery so far. Liposomes have been the default choice for the majority of studies. In the existing systems, siRNAs delivered by liposomes have obtained promising results and represent the first successful clinical trial against liver cancer (Bochicchio, Dalmoro, Barba, Grassi, & Lamberti, 2014; Tabernero et al., 2013). RNA interference is currently a therapeutic strategy with broad application prospects. siRNA is a double-stranded RNA molecule with typically 21
23 nucleotides per strand. The ability of siRNA to be loaded in an RNA-induced silencing complex (RISC) to recognize a target mRNA sequence through base-complementary pairing results in efficient cleavage and degradation, leading to gene knockout (Jinek & Doudna, 2009). A large number of experiments have been carried out to prove that siRNA therapy can achieve gene silencing and treat tumors (Lee, Kim, Kwon, & Roberts, 2016; Scarabel et al., 2017). Survivin is an apoptosis-inhibiting gene with tumor specificity. So anti-survivin siRNA can specifically target the survivin gene and downregulate survivin protein expression, which has become a new cancer treatment option (Chen et al., 2017; Salzano et al., 2014). However, the clinical translation of siRNA therapeutics is limited by the lack of an efficient delivery system that protects them from degradation and can be targeted to liver cancer

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cells (Li et al., 2016). Therefore a therapeutic strategy based on finding a suitable delivery vector for loading siRNA is feasible for treating liver cancer (Wang et al., 2014). Polyethylenimine (PEI) is a cationic polymer that has been used extensively in nucleic acid delivery (Breunig et al., 2008; Zhang et al., 2018). Its high buffering capacity can facilitate endosomal release through the proton sponge effect (Chen et al., 2016; Xie, Xinyong, Xianjin, & Yayu, 2013). PEI 25 kDa is highly active in transfection, but is cytotoxic (Farra et al., 2018; Xie et al., 2013). PEI has been chemically modified to further improve its properties (Hobel & Aigner, 2013). The hydrophobic modification of PEI can enhance its transfection activity (Gunther et al., 2011). Teo et al., studied the effect of different hydrophobic functional groups on the transfection efficiency of Low-molecular-weight (LMW) PEI. The research confirmed that modified PEI 21.8 kDa polymers are capable of condensing the size of cationic nanoparticles and increasing the ζ-potential of polymer/DNA complexes (Teo et al., 2013). Importantly, the modified PEI 21.8 kDa showed an improved transfection efficiency over its unmodified counterpart. The bioreduction responsive delivery strategy relies primarily on the presence of redox potential changes both inside and outside cells. The intracellular glutathione concentration (2
20 μM) is more than 1000-times the extracellular glutathione concentration (2
20 μM) (Cheng et al., 2011). In addition, tumor tissue cells are more hypoxic than normal tissue cells, resulting in a more reducing environment. A large number of studies have been conducted to deliver nucleic acids using various carriers prepared by crosslinking a disulfide bond with a cationic polymer to achieve an intracellular reduction response, thereby promoting drug release. Christensen et al., designed poly(amidoamine)s (PAAs), disulfidecontaining poly(amidoethyl enamine)s (SS-PAEIs) as potential gene delivery vehicles (Christensen et al., 2006). The results demonstrated that SS-PAEIs are a new class of gene transfection reagents with high transfection efficiency that have low levels of toxicity. Jia Liu et al., evaluated a reducible disulfide-containing crosslinked polyethylenimine (PEI-SS-CLs) as a nonviral gene delivery vector (Liu et al., 2010). In vitro experiments demonstrated that the gene transfection of reducible PEI-SS-CLs (LMW) PEI (1.8 kDa) was effective and less cytotoxic. Gene therapy strategies for liver cancer have broad application prospects, but still lack a stable and efficient delivery vehicle. To overcome this obstacle, a novel multifunctional lipid vector system was designed for the delivery of siRNA to liver cancer cells. To formulate and optimize carriers, PEI-OA and PEI-SS-OA were separately mixed with lipids according to different molar ratios to prepare a delivery vehicle system. A cationic lipid (DODMA) was incorporated in the lipid carrier system. DODMA is a conditionally ionized cationic phospholipid that has a low positive charge or no charge at a physiological ph. In addition to PEI, the strategy of using DODMA in lipid carriers is to avoid an excessively positive charge during blood circulation, leading to clearance by the reticuloendothelial system (RES). In the acidic tumor environment, an increase in positive charge can increase cellular uptake. The average particle size and surface charge were determined by dynamic light scattering on a particle size analyzer. The results showed that the average particle size of the lipid carrier system prepared based on PEI-SS-OA was higher than that of the lipid carrier system based on the PEI-OA preparation. With a ratio of 25/20/18/35/2, both of the average particle sizes were the smallest compared to the ratio of the other compositions (127.57 6 1.81 nm and 161.33 6 2.12 nm) with the smallest polydispersity indexes (0.164 6 0.01 and 0.073 6 0.04).

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The reason for this might be that the hydrophobic fatty chain in the PEI derivative was optimally combined with the components in the lipid phase at a ratio of 25/20/18/35/2. A particle size below 200 nm contributed to the accumulation of the carrier at solid tumor sites depending on the EPR effect of the tumor (Wang et al., 2016). The ζ-potentials at different composition ratios were positive and had little difference. Higher intensity cations from PEI and DODMA were effective in binding to negatively charged siRNA, helping to achieve a higher degree of loading and promoting fine uptake based on enhanced electrostatic interaction with cell membranes. Therefore this ratio is the most suitable composition for constructing a lipid carrier system. Based on this composition ratio, a multifunctional lipid carrier system was prepared using surface-embedded transferrin polyethylene glycoldistearoylphosphatidylethanolamine (Tf-PEG-DSPE). Scanning electron microscopy was used to observe the morphology and structure of POLP, PssOLP, and TPssOLP and two conclusions were reached. First, the lipid nanoparticle carriers all had spherical morphologies, and second, the particle size of the three carriers was basically no larger than 200 nm. As shown in previous studies, PEI has a significant cytotoxicity. Here, the cytotoxicity of HepG2 and SMMC cells treated with two lipid carrier systems based on PEI derivatives was investigated by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Respectively, PEI, POLP, PssOLP, and TPssOLP (8 μg/mL) were applied to HepG2 and SMMC cells for 24, 48, and 72 h. As shown in Fig. 5.2, the viability of cells treated with POLP, PssOLP, and TPssOLP was significantly increased relative to cells treated with PEI, indicating that the novel lipid carrier systems prepared based on PEI derivatives reduced the cytotoxicity caused by PEI. Therefore a multifunctional lipid carrier system for in vivo delivery was prepared, in which PEI derivatives and DODMA were the main components of the system bilayer structure, other lipids were used as auxiliary components, and the outer layer had PEGylated Tf added to it for the purpose of increasing the cycle life and targeting tumor cells expressing the Tf receptor. In order to evaluate whether the lipid vector system could serve as a delivery vector for effective siRNA delivery, the binding effect of the vector to siRNA was examined. Xie and Teng prepared a series of siRNA-loaded formulations at different charge ratios and then performed agarose gel blocking experiments. The results showed that the free siRNA produced a bright band on the agarose gel, and the band disappeared after the siRNA was completely bound by the carrier. It is noteworthy that the binding efficiency of POLP and PssOLP to siRNA increased with increases in the nitrogen/phosphate (N/P) ratio. When the N/P ratio was higher than 4, both the POLP and PssOLP were fully bound to the siRNA. To investigate the degradation of sPOLP and sPssOLP induced by dithiothreitol (DTT), a gel retardation assay was used after reacting a complex of POLP and PssOLP with siRNA for 1 h by adding DTT (10 mM). It was deduced from the results that the complex of POLP and siRNA was not affected by DTT, and the vector prepared based on the disulfide crosslinked PEI-SS-OA responded to the reducing agent DTT. At an N/P ratio of 4:1, free siRNA was still present, indicating that the siRNA was released in the reducing environment. Three siRNA-loaded lipid vector systems, including sPOLP, sPssOLP, and sTPssOLP, were loaded according to the optimal composition ratio of lipid carrier systems and N/P, which just completely binds to siRNA. The average particle diameters of the three formulations were all less than 200 nm. The particle sizes of sPssOLP and sTPssOLP gradually increased with the crosslinking of disulfide and the introduction of transferrin. The results of the ζ-potential indicated that the effect of the PEG ligand on the surface charge of the lipid carrier system was significant. Furthermore,

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FIGURE 5.2 MTT assay to evaluate the cytotoxicity of multifunctional drug carriers based on PEI derivatives on HepG2 and SMMC cells. Carriers at a concentration of 8 μg/mL were added to cells, which were incubated for 4 h. Then the medium was replaced by a fresh medium. The cells were then incubated for another 20, 44, and 68 h. Cell viability was determined at 24 h (A), 48 h (B), and 72 h (C) on HepG2 and SMMC cells respectively. Data are presented as mean 6 SD (n 5 6). *P , .05, **P , .01 versus control.

the electronegativity of transferrin had a critical effect on the surface charge of sTPssOLP. It is worth mentioning that the structure of sTPssOLP under transmission electron microscopy was revealed to be a solid sphere with a bright shell on the surface. It was indicated that PEI-SS-OA is tightly bound to siRNA inside and the outer layer is a lipid layer.

5.3 Cellular uptake in vitro The PEI, POLP, PssOLP, and TPssOLP loaded with fluorescein amidite (FAM)-labeled siRNA were treated with HepG2 and SMMC cells for 4 h. The cellular uptake of the

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FIGURE 5.3 Cellular uptake of PEI, POLP, PssOLP, and TPssOLP combined with siRNA in HepG2 and SMMC cells. The complexes were prepared with FAM-labeled siRNA (final concentration 100 nM) at an N/P ratio of 4:1. The mean fluorescence intensity (MFI) of cells was analyzed by flow cytometry at 4 h after treatment. ***P , .001, **P , .01, *P , .05 versus control; ##P , .01 versus sPEI.

FAM-siRNA in both cells was examined by flow cytometry. As shown in Fig. 5.3, compared with the control group, the cells treated by the three complexes had higher average fluorescence intensities, especially sPssOLP and sTPssOLP, similar to the results of sPEI. The trends in both cell lines were consistent. The reason may be that the PEI-SS-OA-based lipid vector system delivers siRNA into the reducing environment within cells, and the disulfide bond cleaves into small PEI and OA-SH, resulting in carrier degradation. Therefore the FAM-siRNA was capable of exhibiting a strong fluorescent signal in cells. It was observed that sTPssOLP had a higher average fluorescence intensity than that of sPssOLP, indicating that the surface Tf helped to enhance the uptake of sTPssOLP by HepG2 and SMMC. To achieve multifunctional carriers of three complexes, HepG2 and SMMC cells were treated with PEI, POLP, PssOLP, and TPssOLP loaded with FAM-siRNA. Free FAM-siRNA was used as a control. The results obtained using a confocal laser scanning microscope after 4 h of treatment showed more green fluorescence than in the free siRNA, with sTPssOLP showing a higher fluorescence than sPssOLP and sPOLP. The higher transfection ability of TPssOLP for siRNA was confirmed. This was consistent with the results of cellular uptake assays exhibited by flow cytometry. In addition, the result of the colocalization of sTPssOLP and lysosomes showed that green and red signals did not coincide, demonstrating that siRNA escaped from lysosomes. Further clinical studies were performed to distinguish whether functional lipid nanoparticles could accede survivin-specific gene silencing in vitro, in which survivin mRNA levels were measured by real-time polymerase chain reaction (RT-PCR) (Fig. 5.4). sTPssOLP was shown to downregulate survivin mRNA expression. The downregulation of mRNA by sPEI was only 24.44% and 16.32% in HepG2 and SMMC cells respectively. The downregulation of mRNA by sTPssOLP reached 54.41% and 49.92% in the HepG2 and SMMC cell lines respectively. Free siRNA showed only a slight downregulation. Survivin protein levels were analyzed by western blot analysis. sTPssOLP showed a higher downregulation in HepG2 and SMMC, reaching 49.41% and 59.45% respectively, indicating

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FIGURE 5.4 Downregulation of survivin mRNA expression by RT-PCR. (A) HepG2 cells. (B) SMMC cells. **P , .01 versus control.

that it has potent gene silencing activity. In vitro assay results indicated that the multifunctional lipid vector system for the delivery of siRNA was less cytotoxic than the lipid vector system prepared from common PEI derivatives. Experiments showed that the siRNAs in these carriers were able to escape from lysosomes and had an effective gene silencing effect after being taken up by cells.

5.4 Antitumor efficacy in vivo To further investigate whether the multifunctional lipid vector system could efficiently deliver siRNA to tumor cells and exert its effects in vivo, Zhao et al., established a nude mouse HepG2 cell xenograft model. Body weight and tumor growth curves for the nude mice were obtained through the intravenous injection of normal saline, sPOLP, sPssOLP, and sTPssOLP (Fig. 5.5A, B). The tumor growth curves demonstrated that the tumor growth in the treated group was significantly slower compared to the saline-treated control group. The tumor inhibition rates of the sPOLP, sPssOLP, and sTPssOLP treatment groups were 28%, 42%, and 56% respectively. The effects of tumor suppression in the sPssOLP and sTPssOLP groups were significantly higher than those of the saline and sPOLP groups. This may be due to the introduction of PEI-SS-OA and Tf, which can target tumor cells and promote the transfection of siRNA to improve the therapeutic effect of sTPssOLP. In addition, the body weight of the nude mice in the treatment group did not decrease significantly, and there was no significant dysfunction in behavior, eating, response to external stimuli, or mental state. The average weight measurement of tumors obtained subcutaneously from nude mice showed that the sPssOLP and sTPssOLP treatment groups were significantly lower than the saline group (Fig. 5.5C). Zhao et al. measured the distribution of cyanine dye 5 (Cy5)-siRNA-loaded as well as the sPOLP, sPssOLP, and sTPssOLP in mice. The results showed that after 4 h of sTPssOLP injection into the tail vein, the distribution of fluorescence intensity in the nude mice was mainly concentrated at the sites of xenograft tumors. There were no additional

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FIGURE 5.5 Intravenous delivery of siRNA-loaded POLP, PssOLP, and TPssOLP suppresses growth of HepG2 xenografts in nude mice. (A) The relative body weight of nude mice in the process of treatment. (B) Growth curves of xenograft tumors in nude mice, which were injected every 3 days with saline, sPOLP, sPssOLP, and sTPssOLP treatments at a concentration of 2.5 mg/kg siRNA per injection. *P , .05, ***P , .001 versus control. The weight of xenograft tumors in each nude mouse harvested at the end of treatment (*P ,.05, ** P ,.01 versus control). (C) Photographs of xenograft tumors harvested at the end of treatment (n 5 4).

accumulations in other parts of the nude mice. In addition, the tissue distribution of fluorescence-labeled sTPssOLP and other vectors was evaluated in vivo. The observations showed that the siRNA-loaded sTPssOLP showed a higher delivery to xenograft tumors than the sPOLP group, and it was able to promote the accumulation of Cy5-labeled siRNA in the liver more strongly than sPssOLP. The level of siRNA in the sTssOLP group was highest in the liver and tumors, with a small amount of accumulation in the lungs. The fluorescence intensity of other tissues was much lower. Therefore TPssOLP was effective in delivering siRNA to tumor and liver sites in vivo. Histological studies showed that there were no significant histological differences between the three treatment groups and the saline group. Although the sPOLP and sTPssOLP groups showed a similar phenomenon to the control group, the lung interval was thickened, but it was normal for the feeding process. No other tissue showed any obvious damage. The results indicated that the multifunctional lipid carrier system

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delivers siRNA in vivo without causing damage to normal tissues, but accumulates at tumor sites to inhibit tumor growth. This lipid vector system can, therefore, be considered a safe and effective way to deliver siRNA (Zhao et al., 2019).

5.5 Doxorubicin and lovastatin co-delivery liposomes DOXis an anthracycline chemotherapeutic agent widely used for the treatment of various cancers. DOX has been extensively applied in the clinical chemotherapy of liver cancer. The mechanism of action is thought to be associated with DNA damage and the inhibition of nucleic acid synthesis, which means that DOX can cross the cell membrane and reach the nucleus where it induces cell death. Unfortunately, DOX cannot distinguish between cancerous cells and normal cells, and this usually results in serious adverse effects. One approach to address the issue is to construct multifunctional nanocarriers for tumor-targeted drug delivery (Gautier, Allard-Vannier, Munnier, Souce, & Chourpa, 2013; Wang, Wei, Zhang, Zhang, & Liang, 2010). Newly, 3-hydroxy-3-methylglutaric coenzyme A (HMG-coA) reductase inhibitor lovastatin (LOV) has drawn great attention as an anticancer drug. The experimental results have shown that LOV had the abilities of antiproliferative, induction proapoptotic, anti-invasion, and antiangiogenesis. LOV has been proven to reduce the incidence and mortality of many kinds of cancers. The main anticancer mechanisms of LOV involve reducing the level of prenylated protein and inhibiting cholesterol synthesis. According to the biopharmaceutics classification system (BCS), LOV was categorized as a class compound. Because of its low aqueous solubility and rapid metabolism in the gut and liver, LOV exhibits poor oral bioavailability and a short half-life (1
2 h). Studies showed that the concentrations required for the inhibition of cholesterol biosynthesis were in the range of 0.1 IM, while the concentrations required for cytotoxicity were in the range of 5 IM. So the in vivo drug concentrations required for anticancer effects were difficult to achieve using the oral route, and it was incompatible with the in vivo animal models. This severely obstructed the application of LOV as an independent anticancer drug. As an exciting finding, LOV was found to remarkably increase the antineoplastic effect of various chemotherapeutic drugs and reduce their side effects. Studies found that the combination of DOX and LOV has several advantages. First, the combination therapy produced synergistic effects and enhanced antitumor effects. Then, by impairing the glycosylation of P-glycoprotein (P-gp), LOV could improve the multidrug resistance of DOX. Finally, LOV could reduce DOX-induced cardiac, liver, and kidney toxicities. Considering the different physicochemical and pharmacokinetic properties of drugs such as solubility, half-life, etc., a simple independent administration could not achieve the desired effect. Therefore a codelivery drug delivery system was needed to solve these problems. Studies have shown that liposomes were effective carriers of LOV and DOX. Thus liposomes were selected as the drug delivery system. The results showed that the liposomes had a uniform particle size and good dispersion. The morphology of the liposomes showed that DOX-LOV-Lips existed as homogeneous spheres with an average diameter of 150 nm, which was similar to the dynamic light scattering (DLS) measurement. The particle size of the liposomes was conducive to the EPR

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effect (Wang et al., 2015). The changes of particle size and entrapment efficiency were used for assessing the stability of the liposomes. Over 30 days, there were no noticeable changes in the particle size and entrapment efficiency of the liposomes, suggesting that the liposomes were stable under storage conditions of 4 C. For further studies, the drug release characteristics of the liposomes were studied via dialysis method (Shahin et al., 2013). Investigations indicated that the cumulative release rates of DOX in a pH 7.4 phosphate-buffered saline (PBS) buffer solution were 43.7% and 40.1% respectively. The cumulative release rates of DOX in a pH 5.5 PBS buffer solution were 63% and 65.5% respectively. The results showed that the release rate and the cumulative release amount of DOX had a certain growth with decreases in pH. This may be due to certain reasons, namely: 1. This may be due to the high solubility of DOX at low pH. 2. Another reason could be that the acidic media destroyed the stability of the liposomes. Moreover, compared to DOX-Lips (liposomes), the coloaded liposomes had a similar release behavior to DOX at the same pH, which indicated that LOV did not affect the release of DOX. In vivo imagers, sometimes called preclinical imaging systems, are imaging systems that look deep into the tissues of living subjects. The benefits of this type of system are that it gives the most complete picture of the biological effects of a treatment or disease progression and the animal is kept alive, allowing for future analysis on the same subject. In order to prove whether liposomes could target tumor sites, an in vivo imaging system was applied to liposomes. The liposomes gradually aggregated at tumor sites over time. The fluorescence intensity reached the maximum at 8 h, then the intensity of the 1,10 -dioctadecyl-3,3,3,30 -tetramethylindotricarbocyanine iodide (DiR) signal began to decrease gradually. There was still a small amount of distribution in the tumor at 24 h in the DiR-Lips group, while there was almost no fluorescence in the DiR group. In addition, the results showed that the fluorescence intensity of the DiR-Lips group was higher than that of the DiR group at any given time point. The fluorescence of the isolated tissues also displayed the same outcomes. This might be attributed to the function of the EPR of liposomes. All the results indicated that liposomes could target and enrich in tumor tissues and prolong the duration of the action of drugs in tumor tissue sites.

5.5.1 Anticancer activity Considering the toxicity and side effects caused by most cancer drugs, the systemic toxicity of liposomes was evaluated by investigating the weight changes in mice. The inference results showed that significant weight loss was observed in the doxorubicin-solution (DOX-Sol) group, while the body weight of the liposomes group increased slightly. This phenomenon could be due to the EPR effect of the liposomes (Golombek et al., 2018; Zhao et al., 2017), which reduced the systemic toxicity of DOX to a certain extent. The survival time analysis showed the same results. The coloaded drug
liposomes significantly prolonged the survival time of mice compared to the other groups. Tumor growth profiles showed that all of the drug formulations efficiently inhibited tumor growth to different degrees compared to the saline group.

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The inhibition of tumor growth of DOX-Sol, DOX-Lips, and DOX-LOV-Lips were 30.4%, 46.2%, and 68.3% respectively. Compared to single-drug loaded liposomes, the coloaded liposomes obviously enhanced the antitumor effect of DOX. This phenomenon might be attributed to the targeting delivery of the liposomes to the tumor site as well as the synergistic effect of DOX and LOV.

5.5.2 Histological analysis To further evaluate the antitumor effect and toxicity of the liposomes, hematoxylin and eosin (H&E) staining was used. Cardio toxicity has been reported to be a significant adverse effect of DOX. The myocardial fibers of the coadministered group were impacted and arranged tightly. This indicated that there was negligible pathological damage in the heart. However, the DOX-Sol group showed apparent myocardial damages and necrosis. The myocardial fibers were disorderly arranged, and inflammatory infiltration was discovered in the myocardial cells. These results demonstrated that LOV could effectively protect heart cells from damage due to the inhibition of Rac1 signaling and oxygen radical
induced injury. From the liver tissue sections, local punctate or focal necrosis was seen in the DOXSol and DOX-Lips groups. However, it was not seen in the coloaded liposomes group, which indicated that the liver damages caused by DOX were weakened by the hepatoprotective effect of LOV. Renal sections showed glomerular hyperemia, partial necrosis of renal tubular epithelium, and no nucleus was found in the local area in the DOX-Sol group. On the other hand, these phenomena were not observed in the DOX-LOV-Lips group. The reason could be that LOV effectively suppressed the activities of glomerular proteolytic. In addition, no significant toxicity to the spleen and lungs was observed in all of the groups. An analysis of tumor tissues was performed to evaluate the extent of the inhibition of tumor cells. In the saline group, the tumor cells were densely arranged and the structures were clear. The sections from the groups treated with DOX-LOV-Lips were less cellular compared to the single drug group, which illustrated that the proliferation of tumor cells had been halted effectively in the DOX-LOV-Lips treated group. All the results indicated that the coloaded liposomes had great biocompatibility, excellent anticancer effects, and less toxicity. These phenomena might be credited to the synergy between LOV and DOX. According to the in vivo results, DOX-LOV-liposomes could efficiently inhibit the growth of tumors and reduce pathological damages to the main tissues compared with the single drug group. In conclusion, DOX-LOV-liposomes might be a promising method of treating liver cancer (Wang et al., 2019).

5.6 Gold nanoparticles Common oxidation states of gold include 11 (Au[I] or aurorus compounds) and 13 (Au[III] or auric compounds). Gold nanoparticles (GNPs), however, exist in a nonoxidized state (Au[0]). GNPs are not new; in the 19th century, Michael Faraday published the first scientific paper on GNP synthesis, describing the production of colloidal gold by the reduction of aurochloric acid by phosphorus. In the late 20th century, techniques such

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as transmission electron microscopy (TEM) and atomic force microscopy (AFM) enabled the direct imaging of GNPs, and the control of properties such as size and surface coating was refined. Common methods of GNP production include citrate reduction of Au[III] derivatives such as aurochloric acid (HAuCl4) in water to Au(0) and the Brust
Schiffrin method, which uses two-phase synthesis and stabilization by thiols. Numerous medicinal plants have shown the potential to produce stable gold nanoparticles within a few seconds. Microorganisms are also equally capable of adsorbing gold atoms and accumulating gold nanoparticles by secreting large amounts of enzymes, which are involved in the enzymatic reduction of gold ions (Singh et al., 2015; Singh et al., 2016). These biologically synthesized gold nanoparticles have become an attractive and potential option to explore as a tool for biosensors, immunoassays, targeted drug delivery, photoimaging, photothermal therapy (PTT), and photodynamic therapy (PDT). In the past few years, there has been an explosion in GNP research, with a rapid increase in GNP publications in diverse fields including imaging, bioengineering, and molecular biology. It is probable that this relates to a similar increase in the broader field of nanotechnology, increased governmental awareness and funding, and rapid progress in chemical synthesis and molecular biology. GNPs exhibit unique physicochemical properties, including surface plasmon resonance (SPR) and the ability to bind amine and thiol groups, allowing for surface modification and use in biomedical applications. Nanoparticle functionalization is the subject of intense research at present, with rapid progress being made in the development of biocompatible, multifunctional particles for use in cancer diagnosis and therapy. For example, multifunctional hybrid micellar nanoparticle-containing metal nanoparticles for simultaneous imaging and therapy of cancer, near- infrared fluorescent quantum dots for biomedical imaging, PEG to improve systemic circulation time and decrease immunogenicity, the F3 peptide to bind to tumor cells expressing nucleolins or endothelial cells, and doxorubicin as a therapeutic payload has recently been developed. Efficacy has been demonstrated both in vitro and in vivo in a mouse model implanted with human breast cancer cells. There has been considerable debate about the mode of entry of GNPs into cells, with the most likely mechanism being nonspecific receptor-mediated endocytosis (RME). In vivo, even in the absence of functionalization, nanoparticles passively accumulate at tumor sites that have leaky, immature vasculature with wider fenestrations than normal mature blood vessels. This is known as the EPR effect. Difficulties in utilizing the EPR effect for tumor drug delivery exist because of the heterogeneity of tumor vasculature, particularly at the center of poorly differentiated cancers as well as particle detection and uptake by the RES. PEGylation is the most common method of reducing RES uptake, producing a hydrated barrier causing steric hindrance to the attachment of phagocytes. The EPR effect combined with longer circulation times, often achieved by PEGylation, can increase the concentrations of drugs in tumors by between 10- and 100-fold compared to the use of free drugs. Further tumor targeting can be achieved by actively binding tumor-specific recognition molecules such as epidermal growth factor (EGF), transferrin, folic acid, or monoclonal antibodies to nanoparticles. Toxicity studies of GNPs have been conflicting, with interactions between GNPs and tissue at the cellular, intracellular, and molecular levels remaining poorly understood. While some studies have shown no cellular toxicity, other

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in vitro and in vivo studies have demonstrated cellular reactive oxygen species production, mitochondrial toxicity, cytokine release, apoptosis, and necrosis (Shukla et al., 2005).

5.6.1 Gold nanoparticle thermal therapy PTT, a minimally invasive local treatment, has attracted much attention in the past few years because of its remote controllability, easy applicability, and low systemic toxicity and side effects. PTT utilizes heat generated from photothermal agents under nearinfrared (NIR, λ 5 700 2 1100 nm) light irradiation, where the absorption of tissues is quite limited, to cause irreversible cellular damage and subsequent tumor destruction because cancer cells are more heat-sensitive than normal cells. In PTT, photothermal agents are delivered to tumors either intravenously or intratumorally. The introduced photothermal agents can finally ablate a tumor through the raised localized temperature at the tumor site, which depends on absorbing and converting the penetrated NIR laser into heat. For efficient photothermal therapies for cancer treatment, researchers have widely explored various photothermal agents, including a variety of metallic nanostructures (such as Au-, silver (Ag-), and copper (Cu)-based nanoparticles), carbon nanomaterials (such as graphene and carbon nanotubes), transition metal chalcogenides, conjugated polymers, and small organic dyes. Among these, Au-based nanoparticles have been regarded as the most prominent candidates for biomedical applications owing to their merits such as precise control over their size and shape, facile surface functionalization, good biocompatibility, tunable localized surface plasmon resonance (LSPR), and high photothermal conversion efficiency. In addition to these properties, gold nanocages (AuNCs) bear a unique hollow and porous structure, and, thus, have become a new promising platform for biomedical applications. However, there still remain challenges in realizing their functions successfully in complex biological systems. Hyaluronic acid (HA), a hydrophilic and linear negatively charged polysaccharide, is an extracellular matrix component that has been widely used as a superior biomaterial in the medical field as it is nonimmunogenic, ubiquitous, biocompatible, biodegradable, and easily modified with other functional groups. High molecular weight (MW) HA can be specifically degraded by intracellular hyaluronidases (Hyals) to produce lower MW fragments and oligosaccharides, therefore, it has been widely applied in controlled-release drug delivery systems. Moreover, HA can bind with cluster determinant 44 receptor, which is overexpressed in various malignant cancers, and several other receptors on the surfaces of cells, including Toll-like receptors 2 and 4, the receptor for hyaluronan-mediated motility, and the HA receptor for endocytosis (HARE). Among these, HARE is expressed in the sinusoidal endothelial cells of the lymph nodes, liver, and spleen. On the other hand, the half-life of intravenously administered HA is no more than 10 min because HA can be cleared rapidly in humans and a variety of animal species. However, a prerequisite of any targeted delivery system is a long circulation period of nanoparticles in the blood, which is favorable for the selective accumulation of nanoparticles in tumor sites. To conquer this limit, PEG is commonly conjugated onto nanoparticles. The PEG on the surface of the nanoparticles can improve the stability of the nanoparticles in the blood and effectively reduce RES uptake by preventing protein adsorption, which can increase the circulation time in the blood. Higher specificity

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and better targeting efficiency can be achieved through the modification of homing peptides. Homing peptides are considered to be the most promising targeting agents for human tumors owing to their several merits, including their relatively small MWs, ease of synthesis, low immunogenicity, good biocompatibility, and biodegradable characteristics in vivo. It has been reported that A54 peptide (sequence AGKGTPSLETTP) is the most specific and effective targeting agent against the BEL-7402 human hepatoma carcinoma cell line via cell surface marker mediated endocytosis. Huang et al. expanded a novel tumor cell
specific targeted AuNC-based drug delivery system (DOX-loaded, HA-grafted, and A54 peptide-targeted PEGylated AuNCs, abbreviated as DHTPAuNCs) and then investigated its therapeutic effects for the first time (Fig. 5.6). This system consists of a DOX-loaded AuNC core surrounded by an HA shell, and functional groups on the surface of the DHTPAuNCs, including a hydrophilic polymer (PEG) and a promising targeting ligand (A54 peptide). The DHTPAuNCs can bind specifically with BEL-7402 cells, and then the coated HA polymer can be degraded in lysosomes, leading to an instantaneous release of encapsulated anticancer drugs into

FIGURE 5.6 Schematic representation of (A) the preparation of DHTPAuNCs and (B) hypothetical subcellular drug release behaviors and cellular uptake pathways. AuNCs, gold nanocages; DAuNC, DOX-loaded AuNC; DHAuNC, DOX-loaded and HA-grafted AuNC; DHTPAuNCs, DOX-loaded, HA-grafted, and A54 peptide-targeted PEGylated AuNCs; DOX, doxorubicin; HA, hyaluronic acid; NIR, near-infrared irradiation.

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the tumor when activated by Hyal in the presence of an NIR laser and acidic pH. In addition, the nanoparticles can selectively accumulate in tumor sites as the PEG prolonged their circulation time and the A54 peptide enhanced their targeting ability. The results demonstrated that DHTPAuNCs showed a synergistic effect in vitro and in vivo. This can be utilized as a powerful and promising photothermal-chemotherapy agent for the treatment of HCC (Huang et al., 2017).

5.6.2 Mechanism First AuNCs were prepared through a galvanic replacement reaction between tetrachloroauric acid (HAuCl4) and Ag nanocubes (AgNCs) and then the AuNCs were characterized by TEM. In the second step, DOX was loaded into the AuNCs (212.84 6 1.25 mV) to form DOX-loaded AuNC (DAuNC) nanoparticles (22.15 6 0.87 mV). In addition, the hydrodynamic diameter slightly increased from 98.23 6 1.25 (AuNCs) to 99.34 6 1.91 nm (DAuNCs) after the formation of the DAuNCs. In the third step, Huang et al., synthesized and grafted HA-cys (HA 100 kDa) onto the surface of the AuNCs to prevent the premature release of the drugs. The unbound HA was removed by continuous dialysis. The average number of HA molecules bound to a single AuNC molecule was ca. 70, which could be determined by hexadecyltrimethylammonium bromide turbidimetric method as reported before. The conjugation of HA dramatically reduced the surface potential to 221.71 6 1.83 mV and increased the viscosity and stability of the particles. In addition, the hydrodynamic diameter changed to 117.87 6 3.17 nm after the conjugation of HA onto the DAuNCs, which was confirmed by the red shift in the LSPR band. The LSPR peak of the DAuNCs appeared at 773 nm and that of the DOX-loaded and HA-grafted AuNCs (DHAuNCs) shifted to 798 nm. As for application of AuNCs in vivo, it is critical to make the systemically administered nanoparticles to remain in blood circulation for a long period to achieve an effective concentration throughout tumors. The preparation of functionalized AuNCs by means of surface modification with PEG derivatives and liver cancer cell specific ligand (A54 peptide) was for active tumor targeting to enhance their preferable accumulation. PEG has been widely used for improved blood circulation to increase the chance of accumulation in tumors. First, ortho pyridyl disulfide (OPSS)-PEG-A54 was synthesized by the formation of an amide bond between the
NH2 group of the A54 peptide and the
COOH group of OPSS-PEGsuccinimidyl valerate (SVA) and this was characterized by 1-hydrogen nuclear magnetic resonance (1H-NMR) (Fig. 5.7). As seen from the top section of Fig. 5.7, the typical signal of
(CH2 CH2O)n on OPSSPEG-SVA can be observed at δ 3.58 ppm. The peaks at δ 7.25, 7.75, and 8.30 ppm correspond to the protons at the pyridine ring. The peak at δ 2.80 ppm is from the two
CH2 on the succinimide part. The
CH3 of A54 can be observed at δ 0.75
0.81 ppm (the middle section). From the 1H-NMR data of OPSS-PEG-A54 (the bottom section), the typical signals of
(CH2 CH2O)n and the pyridine ring on OPSS-PEG-SVA at δ 3.58 ppm, δ 7.25, 7.75, and 8.30 ppm and A54 peptide at δ 0.75
0.81 ppm can be seen. The peak at δ 2.80 ppm was missing, indicating that the succinimide part on OPSS-PEG-SVA was replaced by A54 peptide. All these results demonstrated that the OPSS-PEG-A54 was successfully obtained. Subsequently, the mixture of OPSS-PEG-SVA and OPSS-PEG-A54 (the molar ratio of

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FIGURE 5.7 1H-NMR spectra of OPSS-PEG-SVA, A54 peptide, and OPSS-PEG-A54 in D2O. OPSS, ortho pyridyl disulfide; PEG, poly(ethylene glycol); SVA, succinimidyl valerate.

OPSS-PEG and OPSS-PEG-A54 was 10:1) was grafted onto the surface of DHAuNCs through the thiol
disulfide exchange between the thiol group of the cysteine conjugated with HA on the surface of DHAuNCs and the disulfide of the PEG derivatives. The release of 2-pyridinethione could be used to monitor the course of the reaction at 343 nm. There were B800 PEG chains on each AuNC. Compared with DHAuNCs, the LSPR peak of DOXloaded, HA-grafted, A54 peptide-targeted PEGylated AuNCs (DHTPAuNCs) red shifted to 810 nm, indicating a successful conjugation. To evaluate the potential application of

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FIGURE 5.8 Photothermal conversion and the release profile of DHTPAuNCs. Notes: (A and B) Temperature changes of DHTPAuNC suspensions (AuNCs concentration at 109, 1010, and 1011 particles/mL) after 15 min of 808 nm laser irradiation at 1.25 W/cm2 (n 5 3), ***P , .005, significant difference in comparison with ultrapure water group. (C) Release profiles of DOX from DHTPAuNCs in acetate buffer (pH 5.5) and in the phosphatebuffered saline buffer (pH 7.4) with or without NIR laser irradiation. (D) Release profiles of DOX from DHTPAuNCs in pH 4.5 acetate buffer with and without Hyal (150 U/mL) or NIR laser irradiation. AuNCs, Gold nanocages; DHTPAuNCs, DOX-loaded, HA-grafted, and A54 peptide-targeted PEGylated AuNCs; DOX, doxorubicin; Hyal, hyaluronidase; NIR, near-infrared irradiation.

DHTPAuNCs as a photothermal conversion agent for cancer therapy, DHTPAuNC aqueous suspensions at various concentrations (109, 1010, and 1011 particles/mL) and ultrapure water (control sample) were exposed to NIR laser irradiation. The laser heating curves of the DHTPAuNCs demonstrated that the temperature of DHTPAuNCs aqueous solution could be raised from 25 C to 49.5 C (109 particles/mL), 57.0 C (1010 particles/mL), and 62 C (1011 particles/mL) after NIR irradiation (Fig. 5.8B). In comparison, the temperature of the ultrapure water only increased by 6.5 C. The strong LSPR of the DHTPAuNCs in the NIR region led to excellent photothermal properties, which was beneficial for the PTT effect in vitro and in vivo. Moreover, the elevated temperature may accelerate the release of the

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encapsulated drugs. In addition, the HA polymer grafted onto the surface of DHTPAuNCs could be degraded in the absence of the intracellular enzyme Hyal, which could also be advantageous for drug release. The changes in the hydrodynamic diameter and zeta potential of DHTPAuNCs and unmodified AuNCs in the presence of Hyal in a pH 4.5 acetate buffer show that the hydrodynamic diameter of DHTPAuNCs apparently decreased from 131.01 6 3.78 to 101.23 6 1.82 nm, which was close to that of unmodified AuNCs, and the zeta potential of DHTPAuNCs decreased slightly from 28.32 6 2.64 to 27.23 6 2.82 mV; however, no significant changes were found in the hydrodynamic diameter and zeta potential of unmodified AuNCs. This destruction can be attributed the HA on the surfaces of DHTPAuNCs in the presence of Hyal. Further evaluation showed that acidic pH and NIR laser irradiation could facilitate the release of the encapsulated drug. The amount of encapsulated DOX in the DHTPAuNCs was quantitated to be 1.0 mg DOX/16.3 mg AuNCs as previously calculated. As shown in Fig. 5.8C, within 12 h, in a PBS buffer (pH 7.4), the DHTPAuNCs showed almost no drug release. Even under NIR laser irradiation or in an acidic environment (pH 5.5), only a negligible drug release from the DHTPAuNCs was measured. These results demonstrated that DHTPAuNCs had a good encapsulation ability and were highly stable in the acidic tumor microenvironment (pH 5.5) and normal physiological conditions (pH 7.4) even with NIR laser irradiation. On the other hand, the results showed that the presence of Hyal had a significant effect on the drug release behavior at pH 4.5 (Fig. 5.8D). In comparison, an obvious burst release of DOX was assessed. This was attributed to the detachment and fragmentation of the HA on the surface of the DHTPAuNCs in the presence of Hyal. On this basis, with NIR laser irradiation, the release of DOX was dramatically enhanced, which demonstrated the exceptional photothermal conversion efficacy of DHTPAuNCs. When the DHTPAuNCs were irradiated with an NIR laser, the temperature of the solution was elevated, and the viscosity of the solution was reduced, which facilitated the release of DOX from the DHTPAuNCs. It has been demonstrated that the elevated temperature after NIR irradiation could accelerate the drug release. To sum up, only when HA was degraded by Hyal, such a result could be generated, were the encapsulated drugs released from the DHTPAuNCs and the release of DOX could be accelerated by the acidic pH and NIR. According to the result, it was assumed that this system is stable and can prevent any premature leakage after the particles are internalized, making it possible to achieve controlled drug release, which would reduce unwanted adverse side effects and significantly improve the therapeutic efficacy in vitro and in vivo. It is noteworthy that A54 peptide was reported as one of the most effective and specific peptides against liver cancer cells, especially the human HCC cell line BEL-7402, given that gold nanoparticles could lead to a significant fluorescence quenching of DOX. In other investigations, it was determined that the uptake of non-drug-loaded AuNCs were treated for BEL-7402 cells with HPAuNCs or HTPAuNCs (AuNC concentration of 0.625 3 1010 particles/mL) for different times (1, 2, and 4 h). The results of the cellular uptake assay showed that the cells treated with HTPAuNCs exhibited a stronger fluorescence intensity than those treated with HPAuNCs, indicating that the smart delivery system could efficiently enhance the cellular uptake of AuNCs. In addition, the amount of HTPAuNCs that was taken up by cells was 2.919 6 0.111 ng/106 cells after incubation for 10 h, which is 1.5-fold higher than that of the HPAuNCs (1.528 6 0.059 ng/106 cells). This result confirmed that the HTPAuNCs were more internalized to BEL-7402 cells than the HPAuNCs. The specific endocytosis mediated by A54 peptide enhanced the cellular uptake of HTPAuNCs.

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MTT assay was used to detect the inhibition rate of cancer cells according to these steps: 1. The cytotoxicity of the vehicles at various concentrations of AuNCs was assayed. In this experiment, unmodified AuNCs, HAuNCs, and HTPAuNCs were called vehicles. In BEL-7402 and L02 cells, the AuNCs did not have significant toxicity (data were not shown). 2. The anticancer effect of the combined PTT and chemotherapy against BEL-7402 cells at various concentrations of DOX was quantified. The cells were treated with free DOX, DHAuNCs, HTPAuNCs, and DHTPAuNCs at various concentrations (AuNCs concentration of 0.625, 1.25, 2.5, and 5.0 3 1010 particles/mL, 1 mg DOX/16.3 mg AuNCs). In the groups without NIR irradiation, the cell inhibition rate of DHTPAuNCs was 48.18% 6 2.16%, higher than that of DHPAuNCs (39.68% 6 1.86%) and similar to that of free DOX (52.01% 6 1.13%) with an AuNCs concentration of 2.5 3 1010 particles/mL. This result further confirmed the targeting ability. The graph results show that the cancer cells irradiated by NIR without the presence of AuNCs exhibited a high cell viability compared with the control group, which demonstrated that only NIR laser irradiation did not affect the growth of the cancer cells. However, the cells cultured with HTPAuNCs (AuNCs at a concentration of 2.5 3 1010 particles/mL), upon NIR laser irradiation, showed a cell mortality rate of 30.49% 6 2.91%, which was attributed to the localized heat generated by the HTPAuNCs. Meanwhile, when the cells were incubated with DHTPAuNCs (AuNCs at a concentration of 2.5 3 1010 particles/mL), upon NIR laser irradiation, the cell inhibition rate significantly increased to 77.63% 6 1.63%, which was much higher than that of sole PTT and single chemotherapy. The experiment results proved that more drugs could be delivered into tumor cells using DHTPAuNCs, and this novel delivery system could show synergistic effects of photothermal-chemotherapy in vitro.

5.6.3 Antitumor effect in vivo To probe whether the DHTPAuNCs could significantly reclaim their antitumor effect in vivo, the tumor growth inhibition ability of the AuNC-based nanocomposites with or without NIR laser irradiation was compared in BEL-7402 tumor-bearing nude mice (B150 mm3). Meanwhile, free DOX was used as a positive control and normal saline (NS) was applied as a negative control. An adequate concentration of nanocomposites localized within the target tumor, which are treated as exogenous energy absorbers that convert laser energy into heat, is a prerequisite for PTT. First, the photothermal conversion efficiency of the AuNC-based nanocomposites in vivo was evaluated by the temperature changes of the tumor site. Localized heating was observed in the tumor regions of the mice, which were treated with the AuNCs-based nanocomposites and NIR irradiation. The temperature in the tumor region increased rapidly from about 36.2 C
40.0 C, 45.0 C, and 49.0 C (HTPAuNCs group) because of the exceptional photothermal conversion efficacy of AuNCs selectively accumulated in the tumor region. However, the temperature in the tumor site of the NS group remained under 40.0 C after NIR laser irradiation for 10 min. It has been reported that cancer cells, with lower heat tolerance, could be

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killed by a temperature over 43 C. Hence, DHTPAuNCs could be applied as photothermal agents for cancer therapy. In other investigations, it was determined that the uptake of nondrug-loaded AuNCs were treated for BEL-7402 cells with HPAuNCs or HTPAuNCs (AuNC concentration of 0.625 3 1010 particles/mL) for different times (1, 2, and 4 h). Subsequently, the changes in the relative tumor volume (RTV, V/V0) were applied to assess the antitumor effect of DHTPAuNCs-mediated photothermal-chemotherapy in vivo. After five treatments, the control groups (NS, NS 1 NIR group, and HTPAuNCs group) resulted in RTVs of 368% 6 22%, 365% 6 45%, and 359% 6 29% respectively. The DHTPAuNCs group showed an RTV of 214% 6 39%, which is slightly higher than that of free DOX (291% 6 29%) because of its targeting ability. The DHPAuNCs group with the EPR effect also showed a similar RTV of 262% 6 29%. Meanwhile, the HTPAuNCs 1 NIR group achieved an RTV of 305% 6 25%, suggesting that single chemotherapy or sole PTT cannot achieve a desirable inhibition of tumor growth. The mice treated with DHTPAuNCs 1 NIR showed an RTV of 125% 6 33%, because of their synergistic manner. So, the antitumor effect in vivo could be dramatically improved by photothermal-chemotherapy, which was consistent with the results obtained in vitro. In all groups, no body weight loss was observed. This result further proved that functionalized AuNCs had good biocompatibility. Representative images of the tumors harvested from the mice after treatments confirmed the enhanced therapeutic effect mediated by synergistic therapy. In addition, histopathological studies were also performed on tumors. The morphology form of tumor tissue in the NS 1 NIR and HTPAuNCs groups was mainly similar to that of the NS group, and all of them had no obvious damage, which indicated that it would not cause cellular damage only with NIR laser irradiation, and the non-drug-loaded carrier was almost nontoxic to cells. Compared with the DOX group, both the DHPAuNCs and DHTPAuNCs groups caused more tumor cell apoptosis. The reason was that the carrier of nanomaterials could passively target the tumor site, and increased the accumulation of the drug in the tumor tissue. The most cell death was observed in the DHTPAuNCs 1 NIR group, which indicated that the photothermal-chemotherapy exerted a better antitumor effect than the single chemotherapy and the sole photothermal therapy respectively. For the NS group, TNF-α 5 26.56 6 0.09 and for the HTPAuNCs group, TNF-α 5 26.59 6 0.09.

5.7 Toxicity To further test the toxicity of the nanocomposites, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were selected as the most representative indicators to understand the impact of carrier materials on the liver. A large number of toxins enter the liver and the product of the metabolism of liver cells can be transported to the kidney through a long circulation system, and of these, 80% of renal blood flow will get to the renal cortex. Tumor necrosis factor-α (TNF-α) is a kind of important cytokines produced by activated mononuclear macrophages in the process of acute liver necrosis, which is the early reaction of liver damage. A large number of clinical and experimental researches have shown that the liver of patients with liver damage produce a lot of TNF-α, and the occurrence and development of hepatitis, liver cirrhosis, and liver cancer were closely related with TNF-α. Animal experimental results demonstrated that the content of TNF-α

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in the HTPAuNCs group had no significant increase compared with the NS group (for the NS group, TNF-α 5 26.56 6 0.09, and for the HTPAuNCs group, TNF-α 5 26.59 6 0.09). In addition, the dysfunction of the kidney will make the concentration of renal tubular solution increased and the renal tubular epithelial cells damaged. So the concentrations of urea and creatinine (CREA) are the most common and economic indicators used to detect kidney injury. In fact, these results showed that this drug carrier HTPAuNCs did not cause an obvious inflammatory reaction, liver toxicity, and kidney toxicity within the treatment period which were consistent with the experimental results in vitro.

5.8 Conclusion Over the past 30 years, considerable progress has been made in the preparation of wellcharacterized nanoparticle formulations loaded with a variety of anticancer agents (Alle´mann, Gurny, & Doelker, 1993). Nanoparticles may be especially helpful for the delivery of large and complex molecules like proteins or even nucleic acids and genes, for the treatment of infections and inflammations, and especially for the treatment of liver tumors. In summary, in this chapter, the coloaded liposomes of DOX and LOV were discussed for drug delivery and cancer treatment. This study indicated that DOX-LOV-Lips exhibited a stronger anticancer effect and produced less toxicity than single drug
loaded liposomes. In addition, experimental results for A54 peptide-targeted, HA-grafted, PEGylated AuNCs (DHTPAuNCs) showed that the intracellular enzyme, Hyal, could trigger DOX release from DHTPAuNCs, while NIR laser and an acidic pH could accelerate this process. The cellular inhibition rate of the integrated therapy mediated by the DHTPAuNCs was the highest among all of the groups (77.63% 6 1.63%). Synergistic treatment using chemotherapy and PTT remarkably delayed tumor growth with an RTV of 125% 6 33%. Also, in this chapter, we have explained a liver cancer-specific targeting drug delivery system based on DOXloaded, A54 peptide-targeted, HA-grafted PEGylated AuNCs (DHTPAuNCs) for cancer therapy. The results showed that the intracellular enzyme Hyal could trigger DOX release from DHTPAuNC, while NIR laser and acidic pH could accelerate this process. The cellular inhibition rate of integrated therapy mediated by the DHTPAuNCs was the highest among all of the groups (77.63% 6 1.63%). In comparison, tumor-specific delivery of siRNA has great potential for successful targeted cancer therapy. The shift of drug biodistribution toward tumor tissues not only improves therapeutic efficacy, but also reduces unwanted side effects when properly formulated. Although improvements are being pursued for individual nanovectors, it is critical to integrate multiple features so that new delivery systems will be empowered to negotiate through multiple biological barriers.

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C H A P T E R

6 Nanoparticles and pancreas cancer Akanksha Malaiya, Dolly Jain and Awesh K. Yadav Drug Delivery and Nanotechnology Laboratories, Department of Pharmaceutics, Bhagyoday Tirth Pharmacy College, Sagar, India

6.1 Introduction Patients with pancreatic cancer (PC) often present with nonspecific symptoms such as abdominal pain and weight loss, which can delay diagnosis. But at the advanced-stage of disease in most patients, even if they are diagnosed after the onset of symptoms (Chu et al., 2017). Over the past two decades, targeted therapy and immunotherapy are significantly used in the treatment of many cancer. In 2002, the US Food and Drug Administration (FDA) approved Imatinib mesylate (Gleevec, Novartis Pharma, New Jersey, USA) for frontline therapy in patients with chronic myeloid leukemia (CML). It is a first-generation tyrosine kinase inhibitor (TKI) which is effective and sustainable. On the other hand, progress in the treatment of PC has been disappointingly slow. PC is disreputably aggressive and occasionally treated, and these factors inhibit research efforts. Pancreatic tumors are immune-quiescent, and single-agent immunotherapies have failed to show a significant clinical response (Satyananda et al., 2019). Breakthroughs in nanotechnology are providing vast prospects for diagnosis, imaging, and drug delivery to PC for its treatment (McCarroll et al., 2014). PC has a poor prognosis, which can usually be attributed mainly to its late-stage diagnoses. More than 80% of the cases presented have already reached metastasis or a locally advanced condition (Zhang et al., 2016).

6.2 Physiology of pancreatic cancer PC is raised by the development of neoplasia. A cancer cell reaches the bloodstream, and then multiplication of the cancer cell occurs. Cancer cells deplete rapidly and typically settle when near to a capillary. After this, they cross the blood vessel wall and attach to new tissues, organs, or bone with secondary cancer. The conversion of healthy cells to cancer cells is extremely improbable as it is especially difficult for cells that are always about

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to die before reaching their destination. However, only one is ejected to avoid the congestion of cancer cells. Near the lymphatic system, PC cells locate, along with tissue targets, multiple organs and many blood vessels; therefore, they are still likely to be regenerated from their area of origin even with the successful treatment of PC. Pancreatic adenocarcinoma consists of dense solid tumors. Noncancerous fibroblast cells, cancer cells, and an extracellular matrix exist within the tumor microenvironment. The permeation of drugs in these solid tumors is limited, leading to drug treatments being ineffective. In the case of these dense PC tumors, there is no Enhanced Permeability and Retention Effect (EPR) accumulation of nanotechnologies. Furthermore, chemotherapy does not distinguish between cancerous and fibroblast cells. Even the administration of potent drugs will not eradicate PC cells and they continue to proliferate PC cells and the tumor will develop even if they penetrate through dense tumor stroma and nontarget cells will be killed. Consequently, an active targeting approach is necessary to deliver drugs to particular disease cells inside this complex microenvironment. Adhesion molecules, including integrins, other adhesion molecules, antigens, and proteases that are upregulated on the surface of PC cells., act as potential targets for the active transports of anticancer bioactives. In the process of attachment of fibrous extracellular PC, cells involve the molecules that are expressed by tissues to the stroma. Therefore disrupting of the microenvironment is required for the targeting of these sites for effective treatment (Manzur et al., 2017). Currently, the pancreatic tumor microenvironment paying great attention by physicians and surgeons for given medical advice to pancreatic cancer patients. Fibrotic stroma connected with PC contain numerous types of cells associated with cancer including fibroblasts (CAFs), inflammatory cells, blood vessels, and nerve cells. The stroma contains a variety of extracellular matrix components. These are activated with pancreatic CAF to produce hyaluronic acid (HA), fibronectin, collagen, and laminin (Fig. 6.1) (Neoptolemos et al., 2018).

6.3 Current scenario and epidemiology of pancreatic cancer PC is the fourth or fifth largest cause of the death worldwide and more than 2 lakhs people die every year (Michaud, 2004). The population of the world in 2020 can be assumed to be 7.5 billion, of which, 12 million people die due to this dreaded cancer. Pancreatic adenocarcinoma is a type of exocrine cancer that constitutes more than 90% of all cases of PC causing death. In western countries, the occurrence of PC may reach the second position by 2030. Von Hoff et al. (2013) reported the survival rate of PC patients. The survival was found to be 8 month after the administration of when gemcitabine (GEM) with albumin-bound Paclitaxel (PTX), while in the case of GEM alone, it was found to be 6.7 months. The most common reason for PC is diabetes, drinking alcohol, obesity as well as smoking as one of the biggest factors (Ilic & Ilic, 2016). Different types of chemotherapeutic agents and their combinations are largely used in the treatment of PC, but these produce high toxicity, tetragenocity, neurotoxicity, low cellular uptake, autotoxicity, low half-life, etc., as investigated in clinical trials, phases II and III (Lowenfels & Maisonneuve, 2004).

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FIGURE 6.1 The microenvironment of pancreatic cancer.

6.4 Treatment of pancreatic cancer Treatment and clinical management in PC are often determined by the clinical stage of the disease and are generally focused on the question of pathology. Patients who have infectious diseases are eligible for surgery and, thus, greatly improve their chances of survival and recovery. Chemotherapy, radiation, and surgery are some common treatment methods of PC. The methods used as well as the order in which they are administered, often depend on the clinical condition of the disease (Reynolds & Folloder, 2014). Modern chemotherapeutic drugs do not considerably distinguish between normal cells and cancerous cells, which limit the maximum tolerable dose of drugs (Sinha et al., 2006). Nanotechnology has utilized in drug delivery, opening up new podiums in medicine. Some of the smart drug-delivery vehicle and nanotherapeutics have reached the clinical stage. (Bertrand et al., 2014; Rebelo 2017). It is likely to amend the physiochemical properties of nanocarriers, that is, surface properties, shape, and size, which give controlled and site-specific drug delivery and improve their stability and solubility. These properties are necessary for oncology. Furthermore, it’s possible to encapsulate many drugs in a single nanoparticle, which gives synergistic effects to encourage therapeutic efficacy, thus, preventing the risk of resistance. Malignant pancreas neoplasm is mainly classified as ductal, acinar, or neuroendocrine based on the cellular differentiation of neoplastic cells combined with macroscopic tumor appearance. Combined neoplastic cells such as ductal, acinar, or

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neuroendocrine are malignant pancreas neoplasms classified primarily on the basis of cellular differentiation with macroscopic tumor appearance. The early symptoms of PC are often very ambiguous. They may precede the diagnosis by years and go unrecognized. However, a number of screening tests such as blood markers (DUPAN-2, CA19-9, CA-50, SPAN-1) have been studied to assist such as cell-surface-associated mucin, heat shock proteins, or carcinoembryonic antigen. (Rebelo & Reis, 2018). In addition to standard chemotherapy, combination therapy, surgical treatment, radiotherapy or neonatal chemotherapy, and immunotherapy are used in the treatment of PC. Although, it has been observed that cancer chemotherapy is one of the best approaches to eradicate cancer and the success of chemotherapy mainly depends on the selection of the optimum carrier system (Table 6.3).

6.5 Mechanism of nanoparticle uptake in pancreatic cancer Due to the dynamic structure of the plasma membrane, it separates the chemically distinct intracellular milieu from the extracellular environment by regulating the exit and entry of large and small molecules. Several studies have reported the elucidation of the cellular uptake mechanism of nanoparticles (NPs) through the plasma membrane in living cells. These mechanisms are generally based on the solubility, size, and shape of the nanoparticle. Different endocytic pathways such as endocytosis, exocytosis, etc., are responsible for the entry of NPs into the cells. The process of endocytosis was first described by Christian de Duve in 1963. It is an energy-dependent process where materials are internalized by cells from their surrounding environment and inhibited by adenosine triphosphate (ATP) depleted the environment. (Bertrand et al., 2014). This process is divided into three categories, namely (1) phagocytosis, (2) pinocytosis, and (3) receptor-mediated endocytosis. The phagocytosis process is also known as cell engulfment, and the uptake of NPs with a size of more than 500 nm in diameter occurs here. This process involves cells such as macrophages, dendritic cells, neutrophils, etc. These particles bind to specific plasma membrane receptors and form endocytic vesicles ( . 250 nm in diameter) called phagosomes, and fuse with lysosomes known as phagolysosomes (Jansen et al., 2018). Gupta et al. (2015) reported that micelles permit the encapsulation of lipophilic drugs. Biodegradable polymers were used in the formation of the micelles and they tended to release in the acidic environment of lysosome and endosomes. Thus nanoemulsions and micelles made from paclitaxel-loaded poly (ethylene oxide)-co-poly(D, L-lactide) (PTX-PEG-PLDA) showed less hematological toxicity and made attractive carriers as compared to a formulation of poly(ethylene oxide)-co-poly(Llactide) (PTX-PEG-PLLA) for the treatment of PC following endocytosis. Through signal cascades or growth factors, the process of macropinocytosis is induced, which stimulates the endocytic mechanism. Clathrin-mediated endocytosis is induced when extracellular receptors and ligands interact with each other and enter into cells. Inside the endosomal or lysosomal vesicle, the NPs are trapped. So, the degradation of the sequestered cargo material occurs by lysosomal enzymes. Caveolae-mediated endocytosis is the second major trafficking pathway and plays a vital role in the uptake of NPs and biomolecules. Caveolae are spherical or flask-shaped invaginations of the plasma membrane, and are highly rich in lipids. Caveolae share the high-cholesterol and sphingolipid concentrations found in adipocytes and endothelial cells. in the caveolae mediated enocytosis, NPs enter the cell due to

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the protein called as caveolin (CAV1, CAV2, and CAV3) and the formation of caveolae occurs. (Oh & Park, 2014).

6.6 Receptor for targeting pancreatic cancer Chemotherapeutic treatment of cancer is often limited due to various types of side effects and the fact that it affects tumor cells as well as normal cells. Thus drug delivery in the treatment of cancer is a challenge, so newer approaches such as targeted drug delivery are not only supplements to conventional chemotherapy and radiotherapy, but they also avoid the destruction of normal cells. To achieve the goal of successful treatment, PCspecific ligands or surface receptors have been developed that selectively deliver drugs within tumor cells. Several receptors and antibodies are used to target PC, including epidermal growth factor receptor (EGFR), HER2, folate receptor (FR), transferrin receptors (TR), death receptor, urokinase plasminogen activator receptor (UPAR), CA125, IGF-1, ERBB2, CD133, CD44, and interleukins (IL) (Bardeesy & DePinho, 2002).

6.6.1 Epidermal growth factor receptor Receptors such as EGFR (ErbB1), HER2 (Arya, Vandana, Acharya, & Sahoo, 2011) (ErbB2), HER3 (Erb3), and HER4 (ErbB4) are from transmembrane glycoprotein
containing family with a molecular weight of 170 kd (Galvez-Contreras, Quin˜ones-Hinojosa, & Gonzalez-Perez, 2013). Epidermal growth factor receptor (EGFR) are present in normal cells and are responsible for various functions like cell adhesion, organ development, cell proliferation, etc., but in the case of PC, EGFR overexpression causes tumor angiogenesis, cancer cell proliferation, apoptosis, etc. (Oliveira-Cunha 2011). Anticancer drugs carrying Epidermal Growth Factor (EGF) can bind to EGFR, thus facilitating the treatment of PC. EGFR has been targeted by monoclonal antibodies such as cetuximab in combination with drugs such as GEM, erlotinib with bevacizumab, docetaxel, bortezomib, etc., as investigated in preclinical and clinical trials (Huang & Buchsbaum, 2009). Yang et al. (2019) studied that tumor activity in PC was decreased by inhibiting the activation of the IL6/STAT3 signaling pathway. The combination of rhein and EGFR inhibitor showed great antitumor activity on PC cell lines such as BxPC-3, Patu8988T, AsPC-1, and PANC-1. Yet no clinically approved agent is available to inhibit the STAT3 inhibitor. Thus a combination of agents might be promising to inhibit STAT3 signaling. Caspase 3 assay showed enhanced apoptosis as compared to when a combination of both (rhein and erlotinib) was used.

6.6.2 CD44 receptor Different types of cluster differentiation (CD) receptors are present in tumor microenvironments such as CD14, CD22, CD36, CD44, and CD133. Among these, CD44 is widely used to target cancer (Malaiya & Yadav, 2018). CD44 occurs in various isoforms due to its flexible exon splicing and posttranscriptional modification. CD44 comprises a binding site for HA close to the N-terminal, and the binding of HA is the beginning phase for the functioning of the CD44 receptor. CD44 surface receptors take part in many cellular

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mechanisms like growth, differentiation, and motility and also play an important role in the immigration and addition of cancer cells to the matrix in a cellular environment, thus, enhancing the aggregation of cells and tumor growth (Prajapati et al., 2019a). Kesharwani, (2015a) developed 3,4-difluorobenzyl curcumin (CDF)
loaded HA-conjugated nanomicelles of styrene-maleic acid (HA-SMA). The developed formulation showed potent anticancer activity with sustained-release action. The cellular uptake of HA-SMA nanomicelles was found to be increased due to CD44 receptor
mediated endocytosis. The cell viability was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The developed formulation (HA-SMA-CDF) showed significant cell killing activity compared to the drug at an equivalent drug concentration. Quite similar results were observed for the formulation on both AsPC-1 and Mia PaCa-2 cell lines.

6.6.3 Folate receptor FR presents in normal cells and is found in the form of FRα, FRβ, and FRγ. Folic acid prevents DNA from changing and is also responsible for cell growth, metabolism, the synthesis of nucleic acid, etc. Generally, its deficiency causes anemia. The number of FR is greater in PC as paralleled to normal cells and it is used as a targeting ligand with anticancer drugs. When folic acid is conjugated with an anticancer drug (5-fluorouracil, doxorubicin, cisplatin, GEM, vincristine, PTX, methotrexate, etc.,) and NPs are used as a delivery vehicle, this system acts as an ideal carrier in the treatment of PC as well as another carcinomas such as lung, breast, ovarian, colon, renal, mesothelioma, etc. (Chen et al., 2013). Zhou et al. (2013) studied that folate-chitosan-gemcitabine NPs used for the treatment of pancreatic carcinoma. FR expression was different in cell lines Capan1, L3.6pl, BxPC-3, MIA PaCa-2, SW1990, and COLO357 (contained the highest amount of FR). This study found that cell growth inhibited by PEG-FA-GEM-chitosan was greater as compared to PEG-GEM-chitosan NPs and reduced the toxicity of GEM along with improving the prognosis of PC in patients.

6.6.4 Transferrin receptor Transferrin receptor (Tfr) is present in the form of glycoprotein in normal cells and is responsible for transferring iron-bound protein, which possesses various types of functions such as DNA synthesis, metabolic process as well as the transfer of oxygen. Transferrin protein binds with iron from the Tfr through receptor-mediated endocytosis. Tfr is overexpressed in pancreatic adenocarcinoma. According to Daniels et al. (2012), Tfr is used in the targeted drug delivery of chemotherapeutics for the inhibition of PC cells. Mesoporous silica NPs (MSNs) were loaded with camptothecin (CPT). The results showed that cell death was induced by a decrease amount of CPT in the Tfr-MSN system as compared to the nontargeted MSNs on PC lines such as PANC-1 cells (Ferris et al., 2011).

6.6.5 Vascular endothelial growth factor Vascular endothelial growth factor (VEGF) is a potent glycoprotein. Its receptor is expressed on endothelial cells as well as PC cells. The family of the VEGF receptor

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includes various members like VEGFR-1 (FLT-1), VEGFR-2, and VEGFR-3 (FLT-4); and VEGFR-1 and VEGFR-2 are mostly found in endothelial cells, while VEGF-3 is expressed in lymphatic and tumor cells. VEGFRs are express in tumors cells, that is, PC, prostate cancer, breast cancer, etc. Thus VEGF increases the growth of cells in tumors with VEGFRs through an endothelial cell-independent pathway. It also stimulates downstream signaling pathways and vascular permeability, playing wide role in tumor angiogenesis. VEGF inhibitors (AEE788, PTK-787, CP-547, etc.) are also available, which reduce tumor growth by inhibiting the VEGF pathway (Lee et al., 2015).

6.7 Characterization techniques NPs are produced by different methods. NPs are characterized to determine their properties, quantity, and quality, which are of great importance in PC treatment. To investigate the shape, size, diameter, dispersion, purity, surface modification, stability, etc., various spectroscopic methods such as diffraction, thermal, and separation techniques are discussed in Tables 6.1 and 6.2 (Chinnaiyanet al., 2019; Ding et al., 2011).

6.8 Nanocarrier systems in the treatment of pancreatic cancer Progress in the clinical use of nanotechnology for the treatment of PC may open new avenues. Numerous nanoparticle
drug combined aggregates are in various stages of clinical trials (Rebelo & Reis, 2018). Nanocarriers are defined as colloidal drug-delivery systems containing submicron sizes in the nanometer range. Nanocarriers can be characterized by drug bioactivity, enhanced drug stability and solubility, and site-specific delivery of drugs as well as high surface area. The various physicochemical properties of NPs can be modified by optimizing their composition, morphology, particle size, and surface properties like charge, coating, attachment of targeting moieties, and functional groups. The main aim of using NPs in drug delivery is to cure various illnesses and enhance the efficacy with lesser undesirable side effects (Kasa et al., 2019). These nanoformulations include microemulsions, dendrimers, carbon nanotubes, micelles, quantum dots (QDs), liposomes, polymeric NPs, small interfering ribonucleic acid (siRNA) NPs, nanospheres, nanocapsules, and solid lipid NPs (Fig. 6.2). In xenograft models of human PC established in athymic mice, the parentral administration of curcumin-loaded polymeric NPs (NanoCurc) markedly inhibited primary tumor growth. While, the NanoCurc in combination with GEM enhanced the inhibition of tumor growth. Moreover, combination completely abolished systemic metastases in orthotopic PC xenograft models. (Bisht et al., 2011).

6.8.1 Nanoparticles Nanoparticle (NPs) are particles comprised of therapeutic moieties, for instance, drugs molecule, proteins, peptide and nucleic acids. The NPs are assembled using different kinds of material such as polymers, lipids and metals (Davis et al., 2010). NPs can be used as nanomedicine due to their stability in the physiological environment and they increase drug stability,

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TABLE 6.1 Characterization techniques of a drug-loaded delivery system for the treatment of pancreatic cancer. S. no

Properties

Characterization technique

References

1

Surface topology, internal structure, diameter, number of layers, and intershell spacing

Atomic force microscopy

Arya et al. (2018); Kesharwani et al. (2015b)

2

Internal structure, diameter, number of layers

Transmission electron microscopy

Thipe et al. (2019); Kesharwani et al. (2015b)

3

Aggregation, diameter, and length

Scanning electron microscopy

Jamil et al. (2019)

4

Crystal structure, impurities, and interlayer spacing

X-ray diffraction

Massey et al. (2019)

5

Position, width, the relative intensity of bands purity

Raman spectroscopy

Carmicheal et al. (2019); Lu et al. (2019)

6

Optical and electronic properties

Photoluminescence spectroscopy

Zhou et al. (2019)

8

Chemical structure, functionalization

X-ray photoelectron spectroscopy

Lei et al. (2017)

9

Evaluates thermal stability and purity of CNT systems

Thermal gravimetric analysis

Xing et al. (2019)

10

Purity measurement, length, and diameter distribution

UV, Vis

Thipe et al. (2019)

11

Impurities and functional group

IR, and FTIR spectroscopy

Massey et al. (2019)

12

Dispersion capacity, size, and chirality, cell physiology

Fluorescence spectroscopy

Zhou et al. (2013)

13

Purification and separation of size

Gas chromatography Navarrete et al. (2014)

14

Tumor targeting and transfection efficiency

Confocal microscopy Wan et al. (2019)

15

Cell cycle distribution

Flow cytometry

Wan et al. (2019)

reduce toxicity, have a high therapeutic efficacy, and deliver drugs at the target site when anchored with a ligand (Fig. 6.3). Due to the EPR, NPs with suitable size could escape the tumor blood capillaries composed underdeveloped, leaky endothelium and be retained in the tumor tissues for days due to the lack of lymphatic drainage. It is one of the approach for targeting PC (Jain., 2010). In some cases, NPs can cause cell damage due to the nonspecific cellular targeting and from the lymphatic and circulatory systems, NPs may distribute to organs, such as kidneys from where partial or total clearance may occur (Buzea et al., 2007). A number of clinical trials of NPs in combination with chemotherapeutic agents have been conducted for the treatment of various cancers (colon cancer, lung cancer, gastric cancer, colorectal cancer, PC, etc.). Nanocarriers are promising approaches, but may cause toxicity due to their size, nonphysiological surface chemistry, surface charge, etc. (Fillion, 2018). Nanomedicine formulations can target tumor cells through protein, sugar molecules, specific ligands, peptide, antibodies, nucleic

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TABLE 6.2 Patent technology in pancreatic cancer (past ten years). Patent no

Remarks

References

US20190321492A1 This study suggested that contrast agents (dithiolane-modified Gd-111) functionalized onto gold nanoparticle surfaces by forming gold
thiol bond. This method used in vivo imaging of pancreatic tissue

Meade et al. (2019)

US20170209387A1 The higher concentration of glutaminase inhibitors formulated with nanoparticles (sub-100 nm) delivered higher drug exposure due to higher permeability and retention effect within the tumor

Hanes et al. (2017)

US20170202965A1 Cerium oxide nanoparticles with a combination of radiation therapy used to deliver gemcitabine. MTT assay was performed on human pancreatic cancer cell lines (L3.6PL)

Baker (2017)

US20190255087A1 According to the invention, amorphous calcium phosphosilicate Adair et al. (2017) nanoparticles were encapsulated with 5-fluoro-20 deoxyuridine monophosphate to enhance their cytotoxic effects on BxPC-1 and PANC-1 cancer cells US20150050356A1 According to this study, nanoparticles combined with albumin protein and rapamycin were used in the prevention of cancer

Desai et al. (2015)

US20130045240A1 Combination therapy of nanoparticles comprising paclitaxel and albumin protein as well as a hedgehog inhibitor allowed for the inhibition of a hedgehog signaling pathway

Tao et al. (2013)

US20120219508

Acetylated carboxymethylcellulose covalently linked to Poly(ethylene glycol) and a hydrophobic drug. This system dissolves the hydrophobic drug in an aqueous environment and balanced the hydrophilic and hydrophobic elements

Li et al. (2012)

US20120040915

Peptide and nanoparticle conjugates used in the treatment of diseases and Mukhopadhyay disorders mediated by GIPC (GAIP interacting protein C-terminal), also et al. (2012) known as Synectin. PC/synectin and cell cytotoxicity studies were performed on MIA PaCa-2, PANC-1, and AsPC-1 cancer cells

WO2011057216

Calcium phosphosilicate nanoparticles are stable at physiological pH and used as a diagnostic as well as a therapeutic agent in the treatment of pancreatic cancer

Adair et al. (2011)

WO2011057146

Magnetic nanoparticles with an iron oxide core were used in diagnostic imaging

Flynn (2011)

acids, etc., as well various polymers, which are responsible for effective treatment (Table 6.3). GEM-loaded chitosan (C) NPs were prepared using the ionic gelation method for the treatment of PC. The amine groups present at the surface of gemcitabine, loaded chitosan NPs (Gem-CSNPs) were covalently couple with the carboxylic groups of the anti-HER2. The efficacy of NPs on PANC-1 and MIA PaCa-2 PC cell lines studied. The targeted NPs showed better antiproliferative activity leading to apoptosis compared to unconjugated GEM loaded NPs and free GEM due to higher cellular binding with subsequent uptake and extended intracellular retention (Arya et al., 2011). Massey et al. (2019) developed next-generation poly-L-lysine coated poly (lactic-co-glycolic acid) NPs (PPNPs) loaded with PTX. The outcomes revealed better inhibitory effect of NPs formulation on AsPC-1, MIA PaCa-2, and PANC-1 cellscompared to to free PTX.

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FIGURE 6.2 Nanocarriersin pancreatic cancer.

FIGURE 6.3 Multifunctional nanoparticles for targeted drug delivery.

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All controlled mice showed metastasis in organs such as lungs, lymph nodes, and liver. The histopathology, ex vivo imaging and in vivo data confirmed that the PPNPs potentially reduced the growth and the metastasis in chemo-native orthotopic and chemo-exposes xenograft mouse models, the FDA in 2003 has approved PTX loaded albumin NPs under the trade name Abraxane for the treatment of metastatic PC. FDA approved in 2013, albumin nanoparticle loaded with PTX known as Abraxane used in the treatment of metastatic PC. Clinical trial (Phase III) study revealed that the Abraxane in combination with GEM shows enhanced antitumor activity compared to the use of Abraxane alone (Frese et al., 2012; Von Hoff et al., 2011). Arya (2018) fabricated curcumin-loaded poly(D-, L-lactide-co-glycolide) (PLGA) NPs. Polyethylene glycol (PEG) was used as a surface coating, which enhanced the blood circulation time and chitosan due to its biocompatibility, nontoxicity, mucoadhesive, and biodegradable nature. PLGA NPs are efficient delivery vehicles owing to their ability to increase the loading capacity of drugs and their controlled release rate, etc. Curcumin NPs (CNPs) showed a higher cellular uptake, 7.5-fold in MIA PaCa-2 and 6.7-fold in PANC-1 as compared to free curcumin. The CNPs showed low IC50 values in both PC cell lines as compared to natural curcumin, which showed a higher cytotoxic effect over 72 h. The CNPs showed a higher toxicity and proapoptotic activity compared to free curcumin. Thipe et al. (2019) developed gold NPs conjugated with resveratrol (Res-AuNPs). The surface of the NPs was encapsulated with gum arabic (GA) and a cell line study was performed on PANC-1, PC-3, and MDA-MB-231 cancer cells. A threefold increase in the resveratrol corona on Res-AuNPs showed superior anti-cancer effects due to the high resveratrol corona around the AuNPs surface. In the Indian Ayurvedic system, gold was used in combination with resveratrol and other phytochemicals called Swarna Bhasma. Thus Res-AuNPs may be considered as modern Ayurvedic medicine in the treatment of cancers.

6.8.2 Liposomes Liposomes were first developed by Alec Bangham in 1961 (Bangham et al., 1965). These spherical and bilayer phospholipid vesicles have the potential to act as carriers to encapsulate both lipophilic and hydrophilic drugs, and they increase the therapeutic index of many drugs. These are biocompatible and biodegradable, making liposomes idle candidates for the therapeutic delivery of anticancer drugs. The efficiency of liposomes can be modulated by coating them with various polymers. For active targeting, several targeting moieties are used for the surface modification of liposomes; for instance, antibiotics, glycoproteins, polymers, etc. Most of them are immunogenic and cause difficulties in conjugation (Bulbake et al., 2017). A number of methods are used to formulate liposomes, including ethanol injection, freeze-drying, and reverse-phase evaporation, etc. Boulikas (2009) studied Lipoplatin, a liposomal cisplatin (CST) encapsulated in liposome, and found that it produces various advantages like long term circulation and high encapsulation efficiency. It was also capable of penetrating cell membranes in a 200-fold higher concentration in tumors as compared to CST. Lipoplatin reduced the side effects of cisplatin such as renal toxicity, ototoxicity, peripheral neuropathy, and myelotoxicity, etc. Lipoplatin has also been used with GEM in the treatment of PC (Stathopoulos 2006). Yang et al. (2018) studied antibody fragment (Af)
conjugated liposomes loaded with PTX and GEM, and found that they exhibited a controlled release effect. Due to the maleimide-thiol chemistry in the conjugation process of Af on the liposome, an enhanced cellular uptake was

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TABLE 6.3 Nanoparticle-based drug-delivery systems for pancreatic cancer therapy. Name of nanosystem Micelles

Nanoparticles

Drug

Polymer

References

3,4-Difluorobenzylidene curcumin (CDF)

Styrene-maleic acid

Kesharwani et al. (2015b)

Oxaliplatin

PEG-b-poly(glutamic acid)

Ahn et al. (2015)

Gemcitabine, doxorubicin HCL, 5-FU and paclitaxel

Poly(vinyl pyrrolidone-b-poly caprolactone) and poly(vinyl pyrrolidone-b-poly(dioxanone-co-methyl dioxanone))

Veeren et al. (2017)

Bisnaphthalimidopropyl- Poly(allylamine)-g-cholesterol diaaminooctane

Hoskins et al. (2010)

Curcumin

Poly(styrene-alt-maleic anhydride)

Li, (2016)

GEM-hydrochloride

Poly(ethylene glycol)

Kesharwani et al. (2015)

GEM

Polyglycerol-co-polycaprolactone

Ray et al. (2019)

Squalenoyl-gemcitabine

Poly(ethylene glycol)

Ozturk, et al. (2017)

Ultrasoundresponsive nanoemulsion

Paclitaxel

Poly(ethylene oxide)-co-poly(L-lactide)

Rapoport et al. (2009)

Magnetic iron oxide nanoparticles

Doxorubicin

Dextran

Arachchige et al. (2017)

Gemcitabine

Poly(ethylene glycol)

Trabulo et al. (2017)

Polymeric micelles

Platinum drug

Methoxy-PEG-b-poly(glutamic acid) (PEG-b-P(Glu)), Maleimide-PEG-b-P(Glu)

Ahn et al. (2015)

pH-responsive nanoparticles

Gemcitabine

PEG-b-poly(carbonate)

Ray et al. (2019)

Liposome

Gemcitabine and cisplatin

([Poly(diethylene glycol) methacrylate-co-poly (oligoethylene glycol)methacrylate]-b-poly(2ethylhexyl)methacrylate)

Emamzadeh et al.(2019)

Nanogel

Cisplatin, gemcitabine

PEG-b-poly(methacrylic acid)

Soni et al. (2019)

Carbon nanotubes

Paclitaxel

Polyethylene glycol

Andreoli et al. (2014)

Nanospheres

Gemcitabine

Poly(lactide-co-glycolide)

Jaidev et al. (2015)

Dendrimer

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157

observed as compared to the nontargeted liposome. Okamoto et al. (2019) reported the novel treatment of PC by forming PTX-loaded bovine serum albumin (PTX
BSA) liposomes, which showed cytotoxicity against AsPC-1 cells and statistics analyses of variance (two-way ANOVA) followed Bonferroni analysis.

6.8.3 Carbon nanotubes Carbon nanotubes (CNTs) are highly capable carriers for drug delivery to PC cells due to their illustrious properties such as high aspect ratio, superior drug loading potential, nonimmunogenicity, and availability of various functional groups in contrast to other nanocarriers. The surface of CNTs can be easily modified by chemical treatment for the conjugation of a wide variety of targeting ligands. These functional groups can be conquered on the surface of CNTs by various functionalization techniques (covalent or noncovalent). Functionalization augments dispersibility, circulation time, permeability, and reduces toxicities (Prajapati 2019b). Yang et al. (2011) developed magnetic functionalized CNTs for the lymphatic targeting of GEM. In this study, the human PC cell lines BxPC-3 and SW1990 were used. The in vivo and in vitro effects of GEM-entrapped magnetic multiwalled carbon nanotubes (mMWNTsGEM) and GEM-loaded magnetic-activated carbon particles (mACs-GEm) were compared. The mMWNTs-GEM and mACs-GEM exhibited noticeable antitumor efficacies. mMWNTsGEM was found to exhibit better outcomes than mACs-GEM. The mMWNTs formulation exhibited enhanced efficacy in the lymph nodes and aptitude to cross cell membranes as compared to the mACs. Bhattacharya et al. (2019) developed biosensors of single-walled carbon nanotubes (SWCNTs) by wrapping them with DNA for the real-time monitoring of GEM in pancreatic ductal adenocarcinoma. The developed DNA-SWCNT biosensor showed a 50% reduction of Raman intensity after treatment with GEM. The biosensor significantly altered hydrogen peroxide (H2O2) in tumors and dynamically reduced H2O2.

6.8.4 Dendrimer The word dendrimer is obtained from the Greek words, “dendron” meaning “tree or branch” and “meros” meaning “part.” Dendrimers have been widely explored in biomedical applications due to their well-defined shape and size (Singh, 2016). Generally, dendrimers are spherical in shape and highly branced that have a well-defined homogenous and chemical structure and defined as mono-dispersive, compact, and globular structures, 3D and highly branched polymers, a variety of surface functional group for drug conjugation and inner cavities for entrapment of drugs and consists of a monomer unit with a high degree of branching; hence are known as 21st century polymers (Jain & Jain, 2014). In 1978, Fritz Vogtle and coworkers introduced dendrimer chemistry, and Tomalia et al. (1985) synthesized the first family of dendrimers carrying a drug. Dendrimers can be used by loading drugs within the dendritic structure, either as drug carriers or by interacting with drugs in their terminal functional groups via electrostatic or covalent bonds (Nanjwade et al., 2009). A covalent bond is formed between the drug and exterior surface of the dendrimer. The outer surfaces of dendrimers are mentioned as potential sites for interactions with drugs (Daraee et al., 2016). The structural design of dendrimers may depend on the number of drug molecules involved in the dendrimers. The formation of a compound on the surface of

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dendrimers with a large number of dendrimers increases the loading capacity (Kesharwani et al., 2014). With the increasing generation of dendrimers on the surface of dendrimers, the number of clusters present also increases. Ozturk (2017) studied the efficacy of GEM-loaded PEGylated Polyamidoamine (PAMAM) dendrimers for PC treatment. The developed complex was effectually taken up by Flt-1-expressing PC cells. This resulted in an improved cytotoxicity of GEM and revealed a noteworthy anticancer efficacy when compared with GEM given alone. Li et al. (2019) developed dendrimers for PC targeting; the outcomes revealed that changes in the generation of dendrimers noticeably affected the antitumor efficacy. G3-PAMAM exhibited a diminished particle holding in tumor tissue, while G7-PAMAM was less penetrating due to its large size and strong interaction with the cells. G5-PAMAM displayed a sensible cell internalization and tumor holding capacity.

6.8.5 Micelles Micelles are amphiphilic nanocarriers that are effective in delivering drugs for targeting. Loading with hydrophobic drugs makes the hydrophobic core of micelles more suitable for targeting, which increases their half-life and bioavailability (Cho, 2015). Micelles are selfassembled nanosize colloidal carrier and generally prepared by combination of watersoluble polymers with phospholipids or with long-chain fatty acids and other surfactants. The structure of micelles have hydrophobic core which is its great advantage to encapsulate hydrophobic or amphiphilic drug molecules for their site specific delivery and protects them from external environment. Furthermore, the diameter of a micelle is usually less than 100 nm, which limits their uptake by the Reticuloendothelial system (RES) system. Furthermore, their hydrophilic surface ejects a micelle with immediate detection, and consequently, prolongs their circulation time. Initially, a reduced burst release is observed, which is due to drug adsorption on the surface of the micelle. No signs of inflammation, cyst formation, or macrophage accumulation were observed when Hyaluronic Acid Distearoyl Phosphatidylethanolamine (HA DSPE) micelles were used as compared to sterile water, and biosynthesis was shown with cartilage tissue. A longer retention time of the micellar formulation in the knee joint was observed by in vivo real-time imaging analysis (Saadat et al., 2014). Cabral et al. (2013) reported that polymeric micelles loaded with 1,2-diaminocyclohexane-platinum (II) having a diameter of 30 nm could simply accumulate in poorly permeable pancreatic tumors and developed fully suppressed tumors without any ligand-mediated delivery. In addition, 50 nm micelles showed reduced antitumor activity, while micelles did not show any antitumor effects at sizes of 70 nm and 100 nm. However, the accumulation and efficacy of larger micelles were enhanced and a transformation growth factor-β (TGF-β) inhibitor was used to increase the permeability of tumors (Khare 2014).

6.8.6 Nanogel Nanogels are crosslinked hydrophilic polymeric nanoparticle which is typically coated with a (small) hydrogel of polymer, giving a core-shell type of structure (Samanta et al., 2019). Nanogels have arisen as capable drug-carrying agents to reach cancer cells as they can easily be made and sewn. In fact, they have the ability to clinically collapse of a

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159

diverse nature within a simple mechanism. Nanogel preparation may promote the encapsulation of bioactive molecules and make valuable nanocarrier for therapeutic benefit. In addition, they have the capacity to carry large amounts of drugs, making them attractive for in vivo applications. 3D HA hydrogels can be developed by spatially controlled light exposure. HA-based hydrogels are focused on drug-delivery objectives due to their unique properties such as being biodegradable, biocompatible, nontoxic, and nonimmunogenic (Wei et al., 2013). Ma et al. (2019) developed DNA-like poly-GEM self-assembled nanogels by the synthesis of the solid phase, which not only undergoes quick intracellular degradation to produce active derivatives of GEM, but through molecular recognition, they can also self-assemble into nanogels. Soni et al. (2019) reported an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) anchored polymeric nanogels for targeted delivery of cisplatin for the treatment of pancreatic ductal adenocarcinoma (PDAC) developed a nanogel and studied about combined simultaneous treatment with GEM and targeted significantly attenuated tumor growth with no detectable acute toxicity.

6.8.7 Quantum dots QDs are nanosized semiconductor crystals that exhibited electronics properties. Precisely, they show strong fluorescence, which is quite different from conventional fluorescent tags castoff in medicine and other biostudies and it is not simply quenched. QDs are extremely tunable and valuable for tissue imaging and exhibit near-infrared ( . 650 nm) emission (Alarfaj 2018). Furthermore, QDs can be used in various solutions or tissues, and individuals with only wavelengths can be excited and simultaneously. Consequently, QDs are envisioned for use as theranostics, that another area of use of QDs in the medical field. Yong et al. (2009) worked on PC imaging using indium phosphate
zinc sulfide QDs. Anti-Claudin4 was used to functionalize the surface of the QDs and used for site-specific targeting. Claudin4 is known to be overexpressed in both primary and metastatic pancreatic tumors. The QDs were incubated with MIA PaCa-2 and PANC1 cells and their viability was determined over 48 h. Up to 100 mg/mL, the QDs were not shown to cause any significant decrease in viability over the study duration. Cellular uptake was observed using confocal microscopy. Those cells treated with the QDs showed excellent uptake with bright signals compared to their unlabeled (no anti-Claudin4) counterparts. The targetability, functionalization, and simple synthesis process of the QDs indicated their potential as a therapeutic and diagnostic tool for PC (Wei et al., 2013). Bharali (2009) reported the cytotoxic effects of tetraiodothyroacetic-conjugated pegylated QDs on human PC cells. The conjugate was synthesized with amino-functionalized pegylated QDs and epoxy-activated tetraiodothyroacetic acid that showed successful targeting to PC cells through integrin receptors and demonstrated an antiproliferative effect. Various other researchers have also reported the likely importance of QD drug-delivery systems for PC.

6.9 Conclusion Pancreatic carcinoma is aggressive and is usually diagnosed at the later stages. The conventional methods for the treatment of PC are not efficient, while novel targeted drug

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delivery using nanocarriers provide effective treatment with reduced dose and toxicity of chemotherapeutic agents. They can be used not only for drug delivery and gene therapy, but also for diagnostic imaging. The biocompatibility, stability, and biodegradation of NPs depend on their size, concentration, and the material used. Surface engineered nanocarriers provide the opportunity to deliver therapeutic compounds to target sites and reduce toxicity. An investigation suggested that NPs produce local cytotoxicity in vivo, but it did not show any dangerous effect on neighboring and other cells. Unfortunately, NPs remain within the body for a long period and accumulate side effects. Toxicities related issues of NPs can be diminished by the use of new safe material and methods for the fabrication of NPs. Indeed, NPs are a promising material in biomedical approaches. NPs may prove to be effective nanocarriers with improved biocompatibility and safety in the treatment of PC.

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C H A P T E R

7 The role of nanoparticles in the treatment of gastric cancer Kuldeep Rajpoot and Sunil K. Jain Institute of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur, India

7.1 Introduction Cancer was first exposed in 1500 BCE. Since then, various approaches have been introduced and utilized to fight it, but still, no significant success has been attained (Sudhakar, 2009). In context of gastric cancer (GC), it is ranked as the fourth most frequently occurring type of cancer, and also proves to be a leading cause of mortality, predominantly in East Asia (Leake et al., 2012). Numerous factors (Fig. 7.1) that are linked are responsible for this deadly cancer. Moreover, GC may be host linked, environment related, or from bacterial sources. A few ethnic groups might be highly prone to it compared to other groups (Piazuelo & Correa, 2013). Further, GC is a kind of localized-tumor with locoregional metastasis, which is a most important negative prognostic factor (Imano et al., 2012). It is difficult to cure GC as most patients are only diagnosed at advanced stages. In clinical practice, apart from early diagnosis, it is also important to diagnose a cancer at diverse stages and to ensure proper planning of surgical resection. However, techniques for diagnosis as well as available approaches for the treatment of GC are inadequate. Nevertheless, surgery has been regarded as one of the most recognized methods to treat GC to date. In this context, further innovative approaches are required to deal with GC (Orditura et al., 2014). The diagnosis of GC includes (1) tumors imaging (i.e., regular systemic as well as locoregional imaging) in GC, (2) the detection of tumors in the primary stage using the endoscopy method or GC associated biomarkers, and (3) the detection of circulating tumor cells (CTCs) of GC. The exceptional physicochemical aspects of nanomedicine have made it a vital candidate in theranostics applications. The incorporation of nanotechnology in medical applications is termed as nanomedicine. Moreover, illnesses in the stomach have been treated via many novel drug carrier systems such as microspheres (Jain, Patel, Rajpoot, & Jain, 2019; Patrey, Rajpoot, Jain, & Jain, 2016), microbeads (Jain, Kumar, Kumar, Pandey, & Rajpoot, 2016; Jain, Prajapati,

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FIGURE 7.1 Various factors responsible for the occurrence of gastric cancer.

Rajpoot, & Kumar, 2016), and nanoparticles (NPs); among these, NPs have gained the most interest owing to their nanosize. Further, they are widely employed in imaging, detection, and the treatment of diverse diseases (Somwanshi et al., 2013). NPs incorporating bioactive agents provide many benefits as theranostics in cancer due to the unique material properties that appear at the nanoscale. NPs can be employed not only in imaging, but also as a therapeutic agent in the diverse kinds of cancer (e.g., GC). In addition, in the management of GC, these NPs can overcome several side effects associated with chemotherapy and, therefore, may elevate the efficiency of the treatment (Li, Liu, & Gao, 2017). A number of drug-loaded NPs have been used in the treatment of GC, including liposomal doxorubicin (DOX) formulation (i.e., Doxil) (Espelin, Leonard, Geretti, Wickham, & Hendriks, 2016), pegylated liposomal-DOX (Cascinu et al., 2011), liposomal paclitaxel (Chen, Chen, et al., 2014; Xu et al., 2013), and albumin-bound paclitaxel (Abraxane) (Sasaki et al., 2014), etc. Further, the use of NPs is handy as it could lessen the adverse effects and enhance the efficiency of treatments (Li, Liu, & Gao, 2017). These nanodrugs promote the efficacy and reduce the side effects of the chemotherapeutics they load and increase the effectiveness of GC treatment. Moreover, theranostic NPs, which are multifunctional nanosystems designed by virtue of their integrating diagnostic and therapeutic capabilities into a single NP, have attracted intensive attention (Chen, Ehlerding, & Cai, 2014).

7.2 Nanoparticles in the imaging of gastric cancer NPs have been applied in the early diagnosis of GC, locoregional imaging, and in the detection of CTCs, etc. (Wang, 2011). Moreover, NPs play a prospective role in the

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diagnosis of cancer (Baetke, Lammers, & Kiessling, 2015; Ho, 2015). The applications of NPs in the imaging of GC have been presented in Table 7.1.

7.2.1 Nanoparticles in systemic imaging Although the successful development of safe and effective NP-based imaging modalities for in vivo and targeted GC imaging remains a big challenge, some studies have made progress in this direction. The development of cancer nanomedicine has forged new pathways for the enhanced imaging of cancers using new types of nanomaterials. A variety of NPs have emerged as promising strategies for cancer diagnosis owing to their nanoscale sizes, high agent loadings, tailorable surface properties, controllable release patterns, and enhanced permeability and retention effect (Mirkin, Meade, Petrosko, & Stegh, 2015). As to the imaging of GC, the modalities for whole-body scanning include computed tomography (CT), MRI, positron emission tomography (PET), single-photon emission CT, and PET-CT. However, current imaging contrasts and tracers suffer from nonspecific distribution throughout the body, rapid clearance, poor pharmacokinetics, and undesirable side effects (Li et al., 2013; Mirkin et al., 2015). The NPs used as CT/MRI contrasts are generally inorganic NPs, among which, the most extensively studied include superparamagnetic NPs (Bakhtiary et al., 2016). Superparamagnetic iron oxides (SPIOs) as MRI contrast agents are the first to have been clinically approved, namely ferumoxides (Feridex in the United States and Endorem in Europe) and ferucarbotran (Resovist). Although both Feridex and Resovist are approved specifically for MRI of the liver, magnetic NPs (MNPs) are still the most frequently used in the imaging of GCs. BRCAA1 monoclonal antibody (mAb)
conjugated fluorescent MNPs were reported by Wang et al. for the in vivo targeted imaging of GC (Wang, Ruan, et al., 2011). The NPs could target in vivo GC tissues loaded in mice and could be used to detect GC tissues by fluorescent imaging and MRI. Wang et al. reported SPIO NPs coated with SiO2 as core
shell NPs (Wang, Qu, et al., 2015). The NPs were labeled with near infrared fluorescence (NIRF) dye and anti-CD146 mAb (Liu, Ji, et al., 2012) for MRI/NIRF. The MKN45 xenograft tumor model used could be clearly identified as early as 30 min post injection. Trastuzumab (Herceptin) is a humanized mAb targeted to the extracellular domain of HER-2, a tyrosine kinase receptor. Trastuzumab is approved by the Food and Drug Administration (FDA) for the treatment of HER2-overexpressing metastatic GC (Kataoka et al., 2016; Kulhari, Pooja, Rompicharla, Sistla, & Adams, 2015). Several trastuzumab-conjugated superparamagnetic NPs have been reported for imaging purposes (Kulhari et al., 2015) such as liposome-coated fluorescent MNPs (Jang et al., 2014), and dextran iron oxide NPs (Chen et al., 2009). Although these NPs were used in breast cancer, these systems can also theoretically be applied to HER2-overexpressing GCs (De Carli, Rocha, Antunes, & Fagundes, 2015; Rajagopal, Niveditha, Sahadev, Nagappa, & Rajendra, 2015). Apart from superparamagnetic NPs, there have been limited reports about other inorganic NPs in GC imaging. Cheng et al. synthesized GRP78 binding peptide (GRP78BP)-guided 111In-labeled polymeric micelles (Cheng et al., 2013). In vivo studies were conducted using murine xenograft of GC, results showed higher radioactive intensity

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TABLE 7.1 The applications of nanoparticles in the imaging of gastric cancer. Types of nanoparticles

Imaging approach

Type of study

References

SPIOs NPs

MRI/PAI

PDT

Yang, Lin, et al. (2018)

QDs

FI

In vitro study using MGC80-3 cell line

Zhang, Sun, Zhang, Yang, and Si (2013)

SPIOs NPs

MRI

Passive targeting

Tatsumi et al. (2006)

Pegylated liposome-ICG

Multispectral optoacoustic tomography MRI

Theranostic study using DOX

Lozano, Al-Ahmady, Beziere, Ntziachristos, and Kostarelos (2015)

Nano dense-Si NPs

Imaging agent

In vivo/in vitro study

Wang, Qu, et al. (2015)

Fluorescent MNPs

MRI/NIR-FI

BRCAA1 Mab

Wang, Ruan, et al. (2011)

Bismuth NPs

MRI/CT/PAI triple-modal imaging

PTT

Wu et al. (2018)

Human H-ferritin NPs

FI

In vivo human gastric tumorbearing mice

Du et al. (2018)

Nanocolloid ICG

NIR fluorescence imaging

Passive targeting

Tummers et al. (2016)

ICG-loaded lactosome

NIR-FI

PDT

Tsujimoto et al. (2015); Tsujimoto et al. (2014)

Au/Ag-coated MWCNTs

Sensitizing agent

In vivo study

Zhang, Gao, et al. (2014)

Pegylated pure metallic bismuth nanocrystals

CT

PTT

Li, Liu, Hu, et al. (2017)

PEG-coated SPIOs NPs

MRI

miRNA-16

Sun et al. (2014)

MNPs

FI

In vivo study

Ruan et al. (2012)

Liposome-coated fluorescent MNPs

MRI

Trastuzumab

Jang et al. (2014)

Liposomal ICG

NIR fluorescence imaging

Passive targeting

Hoshino et al. (2015)

Coating of Si/Au nanorod on MWCNTs

Imaging agent

In vivo study

Wang, Bao, et al. (2014)

AuNPs

MRI

Gadolinium chelate Gd(III)-DO3A-SH contrast agent

Chauhan et al. (2019)

SPIOs

Imaging agent

In vivo study

Tokuhara et al. (2008) (Continued)

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TABLE 7.1 (Continued) Types of nanoparticles

Imaging approach

PLGA NPs

Type of study

References

MRI

Anticancer agents (possibly)

Mariano, Alberti, Cutrin, Geninatti Crich, and Aime (2014)

Graphene oxide/SPIOs NPs

MRI

In vitro/in vivo study using DOX

Gonzalez-Rodriguez, Campbell, and Naumov (2019)

QDs

Imaging agent

In situ study

Hu et al. (2014)

111

In-labeled polymeric micelles

single-photon emission CT

GRP78

Cheng et al. (2013)

Gelatinase-responsive NPs

CT/MRI (possibly)

Anticancer agents (possibly)

Cui, Li, et al. (2014); Cui, Liu, et al. (2014); Liu, Li, et al. (2012); Liu et al. (2013); Wang, Wu, et al. (2014); Wu, Li, et al. (2015)

Ferric ions tuned Cu22XSe NPs

Photoacoustic imaging/MRI

PTT

Zhang, Huang, et al. (2018)

Dextran iron oxide NPs

MRI

Trastuzumab

Chen et al. (2009)

Pegylated upconversion NPs

Upconversion luminescence imaging

MGb2 antibody

Wang, Abbineni, Clevenger, Mao, and Xu (2011)

Photosensitizerconjugated MNPs

MRI

PDT

Huang et al. (2011); Huang et al. (2012)

Pegylated liposome-ICG

Multispectral optoacoustic tomography

MUC-1 mAb

Lozano et al. (2015)

F127-folate coated SPIOs MRI NPs

Contrast agent

Vu-Quang et al. (2019)

PEG-g-PEI-SPIOs NPs

MRI

CD44v6 siRNA

Chen et al. (2012, 2013)

Silica capped gold nanoclusters

CT

Folic acid

Zhou et al. (2013)

SPIOs NPs

MRI

In vitro/in vivo study using DOX

Vu-Quang et al. (2019)

pH-sensitive MNPs with MRI folate receptor-targeting

Theranostic study using DOX

Ma et al. (2015)

SiO2-coated SPIOs NPs

Anti-CD146 mAb

Wang, Qu, et al. (2015)

MRI/NIR-FI

AuNPs, Gold nanoparticles; CT, computed tomography; DOX, doxorubicin; FI, fluorescence imaging; g, grafted; ICG, indocyanine green; mAb, monoclonal antibody; MNPs, magnetic nanoparticles; MRI, magnetic resonance imaging; MWCNTs, multiwalled carbon nanotubes; NIR, near infrared; NPs, nanoparticles; PAI, photoacoustic imaging; PDT, photodynamic therapy; PEG, polyethylene glycol; PEI, polyethylenimine; PLGA, polylactic-co-glycolic acid; PTT, photothermal therapy; QDs, quantum dots; SPIOs, superparamagnetic iron oxide; siRNA, small interfering RNA.

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for GRP78BP-directed 111In-labeled micelles in the tumor tissues after analysis over 111 In-labeled micelles. Moreover, GRP78 has been demonstrated as a potential probing target for nuclear imaging for GC.

7.2.2 Other ways of imaging 7.2.2.1 Nanoparticles in locoregional imaging Pretreatment knowledge of lymph node status and the diagnosis of peritoneal dissemination are extremely helpful for planning treatment (Qiao et al., 2015). However, to date, few imaging modalities have been proven to be capable in breast cancer, GC, lung cancer, etc. Unlike other cancers, GC is a comparatively “localized” disease with lymphatic and peritoneal metastasis as independent prognostic factors (Jian-Hui et al., 2016; Kang, Meng, Yu, Ma, & Li, 2015). A new kind of molecular imaging probe based on pegylated upconversion NPs with highly sensitive detection of lymphatic metastasis in GC was also reported (Qiao et al., 2015). Ferumoxtran-10 (Combidex) is a SPIOs-nanoparticulate lymphotropic contrast agent for MRI. It has exhibited efficacy for the detection of metastatic lymph nodes in various cancers. Tatsumi et al. investigated the efficacy of ferumoxtran-10enhanced MRI for the diagnosis of metastases to lymph nodes in GC. The parameters for predictive accuracy were superior to those evaluated by CT or ultrasound. Nodes in the retroperitoneal and para-aortic regions were more readily identified and diagnosed on the MR images than those in the perigastric region (Tatsumi et al., 2006). In another study, Tummers et al. studied imaging using an indocyanine green (ICG)
absorbed nanocolloid in 22 patients suffering from GC. In 21 of the 22 patients, at least 1 lymph node was detected by NIR-fluorescence imaging (FI). In 8 of the 21 patients, tumor-positive lymph nodes were found. The overall accuracy of the technique was 90%. Moreover, in 8 of the 21 patients, lymph nodes outside the standard resection plans were identified, which contained malignant cells in 2 of the patients; which is quite meaningful for the surgical resection of GC (Tummers et al., 2016). Upconversion NPs usually display a satisfactory signal to noise ratio and improved detection sensitivity when used in imaging (Wang, Abbineni, et al., 2011). Upconversion means the process of converting near-infrared radiations into visible light via nonlinear optical processes. Further, in in vivo studies in a mouse model of human GC, the primary tumor and adjacent lymphatic metastasis site were clearly differentiated. Moreover, lymphatic metastases smaller than 1 mm were successfully detected. So, this NP may provide a highly effective approach for regional GC diagnosis. Image-guided surgery (IGS) is often in real time, so it is extremely useful for surgical planning for GC. IGS is a relatively new modality for cancer imaging aimed at the identification of tumors and regional metastases during surgical resection (Hill & Mohs, 2016). ICG, which is an FDA-approved, strongly photoabsorbent/ fluorescent probe has already shown prospective in the IGS of GC. The incorporation of fluorescent NPs will likely provide a higher signal to background ratio and reduce false-positive rates through active targeting (Hill & Mohs, 2016). Several types of fluorescent NPs have been reported such as hyaluronic acid (HA)-derived ICG NPs (Hill et al., 2015), SPIOphospholipid-polyethylene glycol (PEG)-ICG (Ma, Tong, Bao, Gao, & Dai, 2013), liposomeembedded ICG (Lozano et al., 2015), nanocolloid-ICG (Tummers et al., 2016), etc.

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There are also reports about the imaging of the peritoneal dissemination of GC using NPs, for instance, lactosome, which is an NP composed of poly(L-lactic acid)-based epsipeptide (Hara et al., 2013). Moreover, there are also ICG-pegylated liposome-ICG (Lozano et al., 2015) and ICG-lactosomes (Tsujimoto et al., 2015) that were reported to be used in the imaging of the peritoneal dissemination of GC for theranostic purposes. Hoshino et al. used LP-ICG-C18, a synthesized ICG liposomal derivative, to evaluate the peritoneal metastases of GC on nude mice. It was reported that this kind of NIR-fluorescing liposomal probe can effectively target peritoneal disseminated tumors and can easily be detected by an NIR imaging system (Hoshino et al., 2015). NPs were also used in the field of ultrasound. Moreover, fast and low-cost organ-specific examinations can be excellently performed by ultrasound (Baetke et al., 2015). Fan et al. reported nanobubbles that were used as an ultrasound contrast agent. The nanobubbles exhibited a superior contrast imaging effect over the commercialized SonoVue microbubbles on GC xenografts. Further studies showed that the nanobubbles were able to pass through the gaps between the endothelial cells in the tumor vascular system to enter the tissue space. These findings could provide morphological evidence for the extravascular ultrasound imaging of tumors and, thus, warrant further studies (Fan et al., 2013). 7.2.2.2 Nanoparticles in theranostics The word “theranostics” refers to the simultaneous integration of diagnosis and therapy (Chen, Ehlerding, et al., 2014). NPs are good alternatives to realize a theranostic function due to their particular properties (Muthu, Leong, Mei, & Feng, 2014). There are generally two categories of theranostic NPs, namely (1) the NPs themselves can be detected by imaging modalities such as AuNPs, MNPs, and other inorganic NPs (Gobbo, Sjaastad, Radomski, Volkov, & Prina-Mello, 2015; Lima-Tenorio, Pineda, Ahmad, Fessi, & Elaissari, 2015) and (2) the targeted codelivery of diagnostic and therapeutic agents by NPs. To date, a number of NP-based theranostic modalities have been reported in the simultaneous diagnosis and treatment of GC. Although the advancement of NP-based theranostics for GC is encouraging, the clinical application of these systems is limited because of toxicity concerns. Some researchers are trying to use nanomaterials that have been approved for clinical application to realize the theranostic purpose such as polycaprolactone (PCL) (Iqbal et al., 2015), liposomes (Lozano et al., 2015), polylactic-co-glycolic acid (PLGA) (Mariano et al., 2014), etc. Chen et al. reported PEG-grafted polyethylenimine (PEI)-SPIOs NPs (PEG-g-PEI-SPIONs) as an MRI-visible vector for small interfering RNA (siRNA) targeting in GC (Chen et al., 2013). The siRNA was targeted to human CD44v6 (siCD44v6, which is a protein marker mostly employed for determining the metastatic nature of cells in GC) after loading in PEG-g-PEI-SPIONs. However, studies have suggested that PEG-g-PEI-SPIONs downregulated the expression of CD44v6 in gastric carcinoma cell line SGC-7901 (in vitro) and it also knocked down the transporting as well as invasive capabilities of the SGC-7901 cells. In addition, PEG-g-PEISPIONs were reported to be a highly efficient contrast agent for MRI scanning (in vivo). In a study, Lozano et al. reported a targeted pegylated liposome-ICG using the anti-MUC1 mAb as a targeting ligand (Lozano et al., 2015). Compared to nontargeted liposome-ICG formulations, the targeted liposome-ICG showed rapid and early accumulation mainly in the periphery of the tumor, suggesting binding to the available MUC-1 receptors. Then they

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encapsulated DOX in the targeted liposome. The engineering of DOX-loaded targeted ICG liposome systems presents a novel platform for combined tumor-specific therapy and diagnosis, although the antitumor potential of this system has not yet been reported. Elsewhere, Mariano et al. encapsulated an amphiphilic Gd (III) complex in PLGA NPs to yield an innovative, highly sensitive MRI contrast substance for imaging the directed delivery of a drug (Mariano et al., 2014). However, the great stability as well as sensitivity of PLGA NPs was reported, which permitted their uptake and accumulation (in vivo) in the murine melanoma xenograft. Once a drug is entrapped along with a contrast agent, PLGA NPs could be used as an efficient theranostic agent for MRI purposes. Due to the overexpression of gelatinases in GC tissues (Burlaka, Ganusevich, Gafurov, Lukin, & Sidorik, 2016), NPs have proven to accumulate in GC tissues more efficiently (Liu et al., 2013). In a group of studies, Liu et al. successfully synthesized PEG
PCL NPs containing gelatinase-sensitive peptide (Li et al., 2013; Liu et al., 2013). Moreover, NPs are the preferable platform for the codelivery of different hydrophilic/hydrophobic agents, including nucleic acids (Cui, Liu, et al., 2014), chemotherapeutics (Cui, Li, et al., 2014; Wu, Li, et al., 2015), and small molecules of anti-GC activities such as tetradrine (Li et al., 2009), 5-aza-2o% -deoxycytidine (Wu, Li, et al., 2015), salinomycin (Wang, Wu, et al., 2014), etc.

7.3 Nanoparticles in the detection of tumors 7.3.1 Nanoparticles in the early detection of gastric cancer via endoscopy Apart from occult blood tests of stools, endoscopy is the most important and effective diagnostic method, especially for the detection of early GC. To enhance the sensitivity of endoscopy, Zavaleta et al. reported a noncontact, fiber optic, which is usually constructed as a Raman spectroscopy device, having a promising ability to offer multiplexed handy data during endoscopy (Zavaleta et al., 2013). Moreover, this device has been widely exploited for surface-enhanced Raman scattering (SERS) NPs as an ideal molecular imaging contrast agent. Although, traditional white-light endoscopy may provide merely structural evidence deprived of the biochemical data of the gastrointestinal tract (Zavaleta et al., 2013). A certain subgroup of cells (e.g., cancer cells) could be identified using SERS, which are usually AuNPs. They are capable of amplifying the efficiency of Raman scattering, that is, the inelastic scattering of a photon upon interaction with matter. When conjugated to tumor-targeting ligands, NPs will target tumor biomarkers and can be detected by a Raman spectroscopy device (Zavaleta et al., 2013). However, Wang et al. prepared and studied SERS NPs against anti-epidermal growth factor receptor-mAb (anti-EGFR-mAb) as well as anti-human epidermal growth factor receptor-2mAb (anti-HER2-mAb). They investigated the effect of NPs using rat esophagus. Further, the results revealed an improved effect against tumor cells overexpressing both EGFR and HER2 by confirming with flow cytometry as well as immunohistochemistry (Wang, Kang, Khan, Bao, & Liu, 2015; Wang, Khan, et al., 2014). Unambiguously, this technique is based on one or more molecules that express on the surface of cancer cells with high specificity. For GC, such molecules include carcinoembryonic antigen (CEA), cancer-related antigen 19-9 (CA19-9), cancer-related antigen 72-4 (CA72-4), HER2, EGFR,

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etc. Although none of these markers are of 100% sensitivity and specificity, the combination of routine optical endoscopy and SERS NPs will probably provide a more sensitive way for early GC detection.

7.3.2 Nanoparticles in the detection of gastric cancer using biomarkers The detection of GC-related biomarkers is also an important part of early diagnosis. Due to their particular properties, the use of certain types of NPs may increase the sensitivity of a biosensor and generate higher accuracy, speed, and precision (Perfezou, Turner, & Merkoci, 2012). Further, the advances in nanostructured-based biosensors with great analytical capability are constantly increasing (Ravalli & Marrazza, 2015). However, NPs can be applied in electrical/electrochemical-based nanosensors (Afreen, Muthoosamy, Manickam, & Hashim, 2015; Hayat, Catanante, & Marty, 2014), optical-based nanosensors (Salvati, Stellacci, & Krol, 2015; Vilela, Gonzalez, & Escarpa, 2012), magnetism-based nanosensors (Muluneh & Issadore, 2014; Shao et al., 2015), and fluorescence-based nanosensors (Huang et al., 2014). Among the NPs used in nanosensors, QDs, gold, as well as MNPs-based biosensors are the most commonly used (Nie, Liu, Ma, & Xiao, 2014; Ravalli & Marrazza, 2015; Viswambari Devi, Doble, & Verma, 2015). These NPs have been reported to be used in nanosensors for the detection of CA724 (Wu, Guo, et al., 2015), CA125 (Ravalli & Marrazza 2015), HER2 (Chun et al., 2013), and CEA (Shu, Wen, Xiong, Zhang, & Wang, 2013). Some other nanostructures have also been applied in this area together with NPs. Jokerst et al. integrated semiconductor NP-QDs into a modular, microfluidic biosensor for the multiplexed quantitation of CEA, CA125, and HER-2/Neu (Jokerst et al., 2009). As to their study, the application of QD probes as a miniaturized biosensor led to a 30-fold improvement in the signal compared to that of fluorophores. Moreover, this also decreased the detection limit via approximately 2-fold as compared to enzyme-linked immunosorbent assay (ELISA). As these NP-enhanced nanosensors are of greater sensitivity and accuracy, they may also be used to the exploration of new biomarkers for the early detection of GC (Cainap et al., 2015).

7.3.3 Nanoparticles in the detection of circulating tumor cells in gastric cancer CTCs are cancer cells that break away from either a primary tumor or a metastatic site and circulate in the peripheral blood as the cellular origin of metastasis (Lin et al., 2014). It is also vital for the real-time diagnosis and treatment planning/evaluation of patients, which has been defined as “liquid biopsy.” However, due to their rarity and heterogeneity, it still remains a big challenge to develop a CTC detection method with clinically significant specificity and sensitivity, even with the commercialization of some devices such as CellSearch (Olmos et al., 2009) (however, CellSearch has not been approved to be used in GC). CTCs in blood have been widely investigated as a potential biomarker for the diagnosis, prognosis, and molecular testing of metastatic GC (Myung, Tam, Park, Cha, & Hong, 2016; Wang, Wei, Zou, Qian, & Liu, 2015). With advances in nanotechnology, a series of new nanomaterials have been reported to be promising in enhancing the detection of CTCs (Myung et al., 2016) such as nanofibers (Hou et al., 2013), nano-roughened

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structures (Yoon, Kozminsky, & Nagrath, 2014), NanoVelcro Chips (Lin et al., 2014), NPs (Myung et al., 2016), and microfluidic chips (Yoon et al., 2014). A series of NPs, including QDs (Lee et al., 2013), gold NPs (AuNPs) (Galanzha et al., 2009), TiO2 NPs (He et al., 2013), and MNPs (Xu et al., 2011), have been reported. The NPs used for the detection and/or isolation of CTCs are usually composed of ligands (such as antibodies, aptamers, etc.,) that bind specifically to a known biomarker for CTCs; NPs that can be detected by a specified signal or can be captured out of the blood (Lee et al., 2013). These NPs were capable of detecting CTCs in the blood; moreover, some of these NPs could detect and isolate CTCs simultaneously (Song et al., 2011). Although all the mentioned studies reported NPs that detect or isolate CTCs ex vivo, there have been a few studies aimed at detecting CTCs in vivo. In a study by Galanzha et al., the combined use of MNPs and gold-plated carbon nanotubes detected CTCs in the blood vessels of tumorbearing mice (Galanzha et al., 2009). However, studies of CTC detection and isolation by NPs mostly concentrate on prostate cancer (Song et al., 2011), lung cancer (Zhang, Liu, et al., 2019), breast cancer (Galanzha et al., 2009), and colon cancer (Burz et al., 2018; Wang et al., 2019). Reports on the detection of gastric CTCs by NPs are observed comparatively less. He et al. reported the isolation of CTCs from the peripheral blood samples of GC patients with a biocompatible nanofilm composed of TiO2 NPs (He et al., 2013). Furthermore, 50% of the captured cells could be detached from the substrate and were expected to potentially be used for clinical use. Besides, there has emerged some NPs that can detect special markers of GC or GC stem cells such as HER2 (Jang et al., 2014), CD146 (Wang, Qu, et al., 2015), CD44 (Chen et al., 2013), CD133 (Chen et al., 2015), etc. These NPs are expected to be potential candidates for gastric CTC detection.

7.4 Nanoparticle-based therapy of gastric cancer Nanotechnology helps to target tumors individually via either active or passive mechanisms. Surface-modified NPs loaded with anticancer drugs have been employed specifically to target cancer cells (Rajpoot, 2019; Rajpoot & Jain, 2019, 2018) and destroy them without altering or hampering the surrounding noncancerous tissues (Gmeiner & Ghosh, 2015). Moreover, NPs have also been utilized in the treatment of GC by employing not only innovative techniques but also altering the prevailing approaches of treatment of cancer. Diverse forms of NPs have been utilized as single entities or in combination to manage GC (Fig. 7.2). Table 7.2 shows a few important examples of NPs. Although, some NPs has emerged that can detect the special markers of GC or GC stem cells such as HER2 (Jang et al., 2014), CD146 (Wang, Qu, et al., 2015), CD44 (Chen et al., 2013), CD133 (Chen et al., 2015), etc. These NPs are expected to be potential candidates for gastric CTC detection.

7.4.1 Chitosan nanoparticles Chitosan NPs have been extensively studied owing to their salient properties such as safety, biocompatibility, and bioavailability in the management of cancer. Elsewhere,

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FIGURE 7.2 Schematic illustration of various types of Nanoparticles used in the treatment of Gastric Cancer. AgNPs, Silver nanoparticles; AuNPs, gold nanoparticles; CNTs, carbon nanotubes; NPs, nanoparticles.

Qi et al. examined the potential of chitosan NPs against MGC803 (i.e., a GC cell line) for their proliferation effect. In his regard, they utilized chitosan NPs with a positive charge on the surface. After study, NPs produced not only a cytotoxic response, but also induced the death of the cells (Qi, Xu, Li, Jiang, & Han, 2005). In another study, a novel peptide (GX1) was exploited to construct multifunctional vascular-targeting docetaxel (DCT)incorporated NPs. Further, the NPs used N-deoxycholic acid glycol chitosan (DGC) and a GX1-PEG-deoxycholic acid (GPD) conjugate as a carrier and targeting ligand respectively. The GX1-DGC-DCT presented a greater cytotoxicity effect against not only cocultured GC cells, but also human umbilical vein endothelial cells (HUVEC) as compared to free DCT. Further, GX1 proficiently improved the cellular uptake of NPs via the HUVEC cells (Zhang, Xing, et al., 2019).

7.4.2 Polymeric nanoparticles The use of some biodegradable polymers that are safe can help in decreasing the side effects that are usually associated with NPs incorporating anticancer drugs, that is, the incorporation of hyaluronan drug into platinum NPs (Liu et al., 2015). PEG
PCL NPs have been developed after loading DCT. Further, these were attached using mAb as a ligand. A cellular uptake analysis showed that these antibody-conjugated NPs achieved a significantly higher cellular uptake. The DCT-PEG-PCL-mAb NPs induced cell apoptosis

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TABLE 7.2 List of some nanoparticles employed in gastric cancer. Name of nanoparticles

Active agents

Exosomes

HGF siRNA In vivo study

Zhang, Wang, et al. (2018)

PLGA NPs

Anticancer study

In vivo/in vitro study

Sadat Tabatabaei Mirakabad et al. (2014)

PD-L1 monoclonal antibody- DCT conjugated NPs

Cellular uptake, cytotoxic, and apoptosis study

Xu et al. (2019)

PLGA NPs

DCT/ LY294002

In vivo GC and xenograft mouse model study

Cai et al. (2019)

Immunoliposomes

Drug carrier In vivo study

Peer et al. (2007)

β-Casein micelles

Paclitaxel

Maya Bar-Zeev, Yehuda, and Yoav (2018)

AuNPs

Theranostics In vivo/in vitro study

Singh, Harris-Birtill, Markar, Hanna, and Elson (2015)

Silica NPs

Ce6

Yang, Teng, Fu, and Zhang (2019)

Dendrimer

Drug carrier In vivo/in vitro study

Peer et al. (2007)

PMMA-AA/ZnO NPs

Curcumin

In vitro MTT assay and AGS GC cell lines study

Dhivya, Ranjani, Rajendhran, Mayandi, and Annaraj (2018)

Chitosan NPs

DCT

In vivo study against inhibition of tumor growth in SGC791 cell-bearing mice

Zhang, Xing, et al. (2019)

PEG
PCL NPs

Gambogic acid

In vitro cytotoxicity study

Zhang, Zou, et al. (2018)

Immuno-PEG liposomes

Drug carrier Clinical trial (Phase 1)

Peer et al. (2007)

Polydopamine-PLA-TPGS NPs

Barbaloin

In vitro and in vivo study

Wang, Yang, Chen, and Wei (2018)

HA-coated NPs

Plasmid METase/5FU

In vivo tumor growth inhibition study

Yang, Zhang, and Xin (2018)

HA-tailored polyamidoamine dendrimer G5-loaded AuNPs

METase gene

Tumor growth inhibition study

Li, Zhang, and Xin (2018)

Type of study

In vitro cytotoxic activity

Tumor-targeted PDT of GC

References

AuNPs, Gold nanoparticles; Ce6, chlorins e6; DCT, docetaxel; 5-FU, 5-fluorouracil; GC, gastric cancer; HA, hyaluronic acid; HGF, hepatocyte growth factor; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NPs, nanoparticles; PCL, polycaprolactone; PDT, photodynamic therapy; PEG, polyethylene glycol; PLA, polylactic acid; PLGA, polylactic-co-glycolic acid; PMMA-AA, poly(methyl methacrylate-co-acrylic acid); siRNA, small interfering RNA; TPGS, tocopheryl polyethylene glycol succinate.

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and enhanced arrest of G2/M cell-cycle (a decisive point in a cell’s life cycle) in cancer cells, indicating the inhibition of microtubule synthesis (Xu et al., 2019). Wu et al. investigated polymer-based NPs to treat GC. In this context, a PEG-tailored polyethyleneimine copolymer was utilized to administer siRNA to diminish the functioning of CDD4 cells, which are generally responsible for the development of GC. Moreover, gene therapy, for instance, siRNA, has been regarded as a promising tool to manage cancer. Further, this innovative copolymer assists to maintain the effect of siRNA and confirm the safety of this approach (Wu et al., 2010). In another study, gambogic acid (GA)-loaded NPs (GA-NPs) were synthesized by employing PEG and PCL as polymer and then they were administered peritumorally to assess their antitumor effect. Further, a cytotoxicity study showed that the GA-NPs efficiently prevented the propagation of GC cells. However, an in vivo antitumor study following the peritumoral injection of GA-NPs revealed greater antitumor action over that of free GA (Zhang, Zou, et al., 2018). Zhang et al. synthesized ursolic acid
incorporated NPs using a methoxy-PEG-PCL copolymer, and then they examined these NPs against GC cells. Moreover, they reported an augmented apoptosis effect against GC cells (Zhang, Li, et al., 2013). Further, barbaloin-incorporated formulations were synthesized using different components such as polydopamine, polylactide, and D-ɑ-tocopheryl polyethylene glycol succinate. Moreover, they attached galactosamine to NPs for attaining a targeting effect against GC cells. These NPs exhibited a significant decrease in the viability of cells in GC (Wang et al., 2018). Clinically DCT is an effective chemotherapeutic molecule utilized in radiotherapy for the treatment of diverse cancers. Nevertheless, DCT exhibits low applicability owing to its nonspecific spreading in tissues, which increases numerous adverse effects. Moreover, Cui et al. conducted an investigation using DCT-entrapped gelatinase stimuli PEG-Pep-PCL NPs in GC cell lines to combat several issues associated with it and revealed that it improved the radiosensitivity of DCT (Cui, Li, et al., 2014). In addition, HA-modified polyamidoamine dendrimer generation-5 (G5)-loaded gold NPs was developed for efficient delivery of methioninase gene to impedes growth of GC by targeting CD44 1 cells. (Li et al., 2018).

7.4.3 Silver nanoparticles The cytotoxicity of biological and commercial NPs was investigated in AGS (GC cells) as well as normal fibroblast cells (L-929) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Increased apoptosis was observed in the cells treated with biological silver NPs (AgNPs) compared to untreated GC cell lines (P , .001) (Mousavi, Tafvizi, & Zaker Bostanabad, 2018). In another study, combinations of neem and AgNPs have been used for in vitro investigation against GC cells. Further, neem exhibited not only anticancer activity, but also an antibacterial effect. In contrast, AgNPs were employed to target the GC cells. The results suggested an enhanced effect of AgNPs. Additionally, the findings revealed these to be safe, and they also assist to combat the drawbacks of several other existing cancer treatment methods (Sironmani, 2016). Green biosynthesized AgNPs incorporating D. pleiantha rhizome exhibited a dose-dependent cytotoxic potential against human GC cell lines and revealed a half-inhibitory concentration (IC50) of 7.14 μM (Karuppaiya, Satheeshkumar, & Tsay, 2019).

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7.4.4 Gold nanoparticles In a study, Herceptin and oxaliplatin were loaded on the surface of AuNPs of iron pentacarbonyl, oleic acid, and oleylamine, and then they were coated with PEG. The findings suggested that oxaliplatin-Au-Fe3O4-herceptin is a promising multifunctional platform for simultaneous magnetic traceable and HER2 targeted chemotherapy for GC (Liu et al., 2018). Zhou et al. reported folic acid
conjugated silica-capped gold nanoclusters for GC imaging. This kind of nanoprobe exhibited good biocompatibility, and could actively target not only folate (1) MGC-803 cells but also in vivo GC tissues with 5 mm in diameter in nude mice models. Further, excellent results were obtained after red-emitting fluorescence imaging and CT imaging study. For the nuclear imaging of GC, there have been some attempts to enhance the effectiveness of nuclear imaging by NPs. Further, the enhanced expression of the cellular membrane-bound glucose-regulated protein 78 (GRP78) has been regarded as one of the most important biomarkers in GC (Zhou et al., 2013).

7.4.5 Magnetic nanoparticles MNPs are excellent candidates to treat GC. They may enhance the aptitude of other cancer therapies. In this regard, Yoshida et al. investigated MNPs incorporating the chemothermal agent DCT to attain an enhanced thermal effect via subcutaneous delivery in mice bearing GC cells to increase the efficacy (Jiang & Chan, 2012). Ma et al. synthesized magnetic-polymer NPs with folate receptors and pH-sensitive multifunctionalities to achieve a targeting effect. Further, these NPs were loaded with DOX for the treatment of advanced GC. The better efficacy of the NPs compared to that of free DOX was confirmed by in vitro and in vivo studies (Ma et al., 2015). Moreover, the accumulation of the NPs at the tumor site was detected by MRI. However, a high intake of super magnetic NPs can lead to the accumulation of iron in a specific organ to which it is delivered. This produces toxic effects and leads to DNA damage as well (Sharma, Madhunapantula, & Robertson, 2012). In another research work, Sun et al. used MNPs to deliver microRNA-16, with the purpose of reversing drug resistance to chemotherapy in a mouse GC model (Sun et al., 2014). The MNPs used in this study were PEG-coated Fe3O4 NPs. Apart from in vivo imaging, the NPs significantly suppressed SGC7901 (adriamycin resistant) tumor growth, probably through increasing the sensitivity of SGC7901/ADR cells to adriamycin.

7.4.6 Carbon nanotubes Yao et al. utilized single-walled carbon nanotubes (SWCNTs) as a promising carrier system for confirming the targeting effect. Further, they employed salinomycin as a drug to achieve an anticancer response. Further, HA was utilized as a promising targeting agent to treat stem cells of GC. They reported positive results and confirmed that the formulations diminished the transport and invasion of stem cells in GC (Yao, Zhang, Sun, & Liu, 2014). NPs synthesized using graphene oxide also showed potential applications, especially in treating cancer. Graphene oxide NPs facilitated with femtosecond laser has also been developed to prepare microbubble of water, which are then employed to treat GC efficiently (in vitro) (Li et al., 2014). In another study, Zhang et al. prepared nanodiamond

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incorporating a polymer that may have the potential to enhance the oral uptake of sorafenib to improve its efficiency in preventing the metastasis of GC (Zhang, Niu, et al., 2014).

7.4.7 Photodynamic therapy Photosensitive NPs were synthesized by entrapping an ICG derivative (i.e., ICGincorporated lactosome; ICGm). In this study, Tsujimoto et al. determined the existence of the metastatic lymph nodes in the mice that were treated with ICGm; however, they were not detected in the mice that were treated with ICG. Moreover, a photodynamic therapy (PDT) study revealed that ICGm encouraged not only apoptosis, but also inhibited the development of metastatic lymph nodes. In addition, a study was also carried out on peritoneal disseminated xenografts of human GC using nude mice. The PDT not only decreased the size of the disseminated nodules, but also significantly enhanced weight loss along with the survival rate in mice treated with ICGm (Tsujimoto et al., 2015). PDT has been widely recognized as a promising way to cure cancer. However, the limited tumor homing property of the currently available drug delivery systems is a bottleneck in the delivery of photodynamic agents. In a study, a research group prepared silica NPs and then they were coated with membrane of GC cells (i.e., SGC7901 cells). Further, the experimental results suggested that these formulations could specifically target homogenous SGC7901 cells both in vitro and in vivo. Moreover, in vivo results demonstrated a better anticancer outcome compared to undecorated silica NPs and chlorin e6 (Ce6) (Yang et al., 2019). Further, Huang et al. reported photosensitizer-conjugated MNPs for simultaneous in vivo GC imaging as well as therapy. The NPs, which were 20 nm in size, were covalently attached to Ce6 at the surface of the MNPs. After investigation, these NPs showed potential against PDT, and simultaneously, the MNPs presented a targeting ability due to their magnetically directed drug delivery and exhibited their application for MRI. The NPs were observed to be appropriate for concurrent delivery using PDT and in vivo MRI of nude mice loaded with GC (Huang et al., 2012).

7.4.8 Miscellaneous The effect of TiO2 NPs was studied on the apoptosis induction and invasion of GC cell line MKN-45. The viability and proliferation of cancer cells in the presence of various forms of TiOzA2 NPs were reduced (P # .05). Increased cell invasion was seen in the PEGamorph TiO2 group compared to the control group (Nasr et al., 2018). Further, Xiao et al. employed cerium oxide
based NPs and utilized a thermal decomposition technique. After investigation using GC cell lines, a dose-independent inhibitory response against the transportation of GC was revealed via in vivo and in vitro studies. Though, the study revealed a response at high doses of cerium oxide NPs (Xiao et al., 2016).

7.5 Conclusion GC is regarded as a fearsome disease owing not only to the high morbidity, but also due to large mortality rate. To overcome these hurdles, innovative nanocarriers that have

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a significantly high potential to treat GC are required. In this regard, nanomedicine has shown its potential in treating GC specifically. Importantly, the diagnosis of GC depends on the use of some specific markers/ligands that are overexpressed on the cells in GC; hence, these markers/ligands are usually attached to NPs and exploited for targeted theragnostic purposes. These nanosystems have not only shown their potential for detecting GC in the early stages, but they have also exhibited their capability in different areas such as local imaging, IGS, and the treatment of GC. Moreover, NPs exhibit some restrictions, for instance, most researches on NPs are limited to preclinical or in vitro investigations; therefore, the safety of most synthesized NPs is still unclear. Eventually more in-depth study will be required to unlock the ample potential of NPs and to discover new innovative approaches in the laboratory to attain significant results for treating GC and then transfer them effectively to clinical trials, which will finally result in large scale production.

Disclosure statement Authors declare no conflict of interest.

Abbreviations 5-FU AgNPs anti-EGFR-mAb AuNPs Ce6 CEA CNTs CT CTCs DCT DGC DOX ELISA FDA FI g G5 GA GC HA HGF HUVEC IC50 ICG ICGm IGS mAb MNPs

5-Fluorouracil Silver NPs Anti-epidermal growth factor receptor-mAb Gold NPs Chlorin e6 Carcinoembryonic antigen Carbon nanotubes Computed tomography Circulating tumor cells Docetaxel N-deoxycholic acid glycol chitosan Doxorubicin Enzyme-linked immunosorbent assay Food and Drug Administration Fluorescence imaging Grafted generation-5 Gambogic acid Gastric cancer Hyaluronic acid Hepatocyte growth factor Human umbilical vein endothelial cells Half-inhibitory concentration Indocyanine green ICG-incorporated lactosome Image-guided surgery Monoclonal antibody Magnetic nanoparticles

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References

MRI MTT MWCNTs NIRF NPs PAI PCL PDT PEG PEI PET PLA PLGA PMMA-AA PTT QDs SERS siRNA SPIOs SWCNTs TPGS

181

Magnetic resonance imaging 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Multiwalled carbon nanotubes Near-infrared fluorescence Nanoparticles Photoacoustic imaging Polycaprolactone Photodynamic therapy Polyethylene glycol Polyethylenimine Positron Emission tomography Polylactic acid Polylactic-co-glycolic acid Poly(methyl methacrylate-co-acrylic) acid Photothermal therapy Quantum dots Surface-enhanced Raman scattering Small interfering RNA Superparamagnetic iron oxide Single-walled CNTs Tocopheryl polyethylene glycol succinate

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C H A P T E R

8 Nanoparticles and colon cancer Priya Shrivastava1, Rajeev Sharma2, Laxmikant Gautam1, Sonal Vyas3 and Suresh P. Vyas1 1

Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, India 2Formulation Scientist, Pharmaceutical Company, Chandigarh, Punjab, India 3Bundelkhand Medical College & Hospital, Sagar, India

8.1 Introduction Cancer is a state that involves uncontrolled cell division with the ability to invade or spread to adjacent tissues. When genetic alterations interfere with the orderly process of cell division, it indicates cancer. Cells start to proliferate abnormally. Such cancer cells may develop into a mass known as a tumor. Tumors are mainly of two types, namely malignant and benign. A tumor is called malignant when it grows and spreads to other parts of the body, while a tumor is said to be benign when it can grow, but will not spread. There are over 100 types of cancer, including breast cancer, myeloma, leukemia, lymphoma, lung cancer, prostate cancer, and colon cancer. Among them, the third most widely diagnosed cancer worldwide is colon cancer (Araghi et al., 2019). There are about 1.36 million cases worldwide, which account for it being the fourth leading cause of cancer-related deaths. There has been a high incidence rate of colon cancer in the west, including Australia, Europe, and North America, etc. It is relatively uncommon in Africa, Asia, and Central and South America (May & Anandasabapathy, 2019). Colon cancer
related signs and symptoms include diarrhea, nausea, changes in the bowel habits, reduced quantity of stools, bloating, abdominal cramps, weight loss, and loss of appetite. It develops when malignant tumors arise in the colon, which is the last section of the digestive tract and is almost 5 ft. long. The colon participates in producing and absorbing vitamins, absorbing water and electrolytes, and forming and propelling feces toward the rectum for elimination. It also acts as a storage site for fecal materials prior to defecation (Renzi, Lyratzopoulos, Hamilton, & Rachet, 2019). Colon cancer development takes place over a period of time. The process generally starts as a “polyp” in the interior lining of the colon. Polyps are usually noncancerous growths, but some of them can turn into cancer. There are two common forms of polyps in the colon. These include (1) hyperplastic and Nano Drug Delivery Strategies for the Treatment of Cancers DOI: https://doi.org/10.1016/B978-0-12-819793-6.00009-6

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inflammatory polyps, which typically are not at a risk of developing into cancer, and (2) adenomas or adenomatous polyps, which, if left alone, could develop into colon cancer. Tumor cell growth begins in the wall of the colon and then extends to the surrounding vessels of blood and lymph. Then the cells enter into the nearby lymph nodes and metastasize to remote organs (Huang & McGee, 2019). Colon cancer has been associated with numerous lifestyle factors, including a sedentary lifestyle, a low-fiber and/or high fat diet, heavy alcohol consumption, smoking, obesity, etc. People with type 2 diabetes or insulin resistance and chronic inflammatory diseases such as ulcerative colitis and Crohn’s disease are at greater risk of developing colon cancer. Inflammatory bowel disease is responsible for 2% of colon cancer cases every year. DNA mutations can also cause colon cancer. These mutations can lead to oncogenes being turned on or tumor suppressor genes being turned off, which results in cells growing out of control. Some of these mutations are transmitted to the generations and hence inherited on in a family. These mutations are termed as inherited gene mutations. These mutations result in hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome), which is responsible for about 3% of all cases of colon cancer in which 1% of the cases have a strong association with Gardner syndrome and familial adenomatous polyposis (FAP) (Antelo et al., 2019). Nearly all colon cancer
related deaths are associated with metastasis. Colon cancers can be averted by lifestyle changes, which include regular exercise, maintaining normal body mass index (BMI), high consumption of fruits and grains, etc. Several analytical tests can be used to detect colon cancer. These tests can be divided into two main categories. (1) Stool-based tests: These tests screen the stool for possible signs of colon cancer or polyps. The guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and stool DNA test are examples of screening tests that fall under stool-based tests. (2) Visual (structural) tests: These tests screen the structure inside the colon and rectum for any abnormal areas that might be cancer or polyps. Colonoscopy, computed tomography (CT) colonography, and flexible sigmoidoscopy are examples of screening tests that fall under visual tests. A fecal occult blood test (Hemoccult FOBT) and analysis of urinary volatile organic compounds can also diagnose colon cancer. Common markers such as carcinoembryonic antigen (CEA) and cancer antigen (CA 19-9) can be used to diagnose colon cancer. The degree of cancer metastasis can be assessed by a CT scan. Colon cancer is generally confirmed by colonoscopy depending on where the lesion is found. It is a safe procedure in which biopsied samples are taken and examined for histopathological changes, including cell types and grades (Burt, 2000). Usually, a tumor lesion has an abnormal tubular structure with several lumens and reduced stroma. Sometimes mucus is secreted by tumors. In colon cancer cells, to confirm the presence of specific antigens, immunostaining can be used. Surgery is often the main therapy for colon cancers found in the early stages. The type of surgery depends on the stage and extent of the colon cancer as well as on the type of tumor. During a colonoscopy, usually in stage 0 and some early stage I tumors (early colon cancers), nearly all polyps can be removed. For a polypectomy, the procedure involves the removal of small polyps from the inner lining of the colon. A part of the colon can be removed by local excision. The whole colon is removed in a total colectomy (Birkett et al., 2019; West et al., 2008). Even after surgery, cancer may not be completely cured. For removal, radiation therapy, chemotherapy, etc., can be used in such cases to reduce the

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progression of colon cancer. High-energy X-rays are used to kill tumor cells in radiation therapy (Lightner, Spinelli, McKenna, Hallemeier, & Fleshner, 2019). Radiation therapy is often associated with side effects, including irritation of the skin, nausea, hair loss, tiredness, and sexual dysfunction. Radiation therapy is also usually given in combination with chemotherapy. Chemotherapeutic bioactives have the potential to directly kill tumor cells and help make radiation therapy more effective in killing tumor cells. Chemotherapy is another treatment option where anticancer bioactives could be used to prevent or slow down the growth of dividing cancer cells. Several bioactives, which include capecitabine, oxaliplatin, 5-fluorouracil (5-FU), and irinotecan can be used to treat colon cancers. However, chemotherapy is often associated with side effects, which include nausea, vomiting, bone marrow depression, alopecia, loss of appetite, and mouth sores. To overcome these limitations, several nanoparticulate carrier systems have been designed for optimal size and surface characteristics to improve the biodistribution of bioactives and to increase their circulation time in the blood stream (You et al., 2016). This chapter is devoted to the development and advancement in the field of nanoparticle-mediated colon cancer treatment.

8.2 Molecular biology of colon cancer Colon cancer occurs as a result of the gradual accumulation of epigenetic and genetic alterations that facilitate the transformation of normal colonic epithelial cells to colon cancer cells. This cycle of colon carcinogenesis, which has been termed as the polyp
carcinoma sequence, typically occurs over 10
15 years and includes concurrent histological and molecular alterations. The resulting consequence of these epigenetic and genetic alterations on the molecular biology of tumor cells in which they occur is the acquisition of key biological factors that are fundamental to the malignant phenotype. From the study of colon cancer genetics at the molecular level, it has become clear that colon cancer progression involves a multistage process. The molecular biology of colon cancer reveals that it is caused due to genomic instability that results because of the loss of DNA repair ability of cells. Therefore, it leads to genetic or epigenetic mutations. In this aspect of genomic instability, genetic or epigenetic mutations occur and coordinate with each other to facilitate the initiation and progression of colon cancer (Nguyen & Duong, 2018).

8.2.1 Adenoma
carcinoma sequence The progression of adenocarcinoma from normal epithelial cells usually follows a gradual progression of histological alterations and associated epigenetic and genetic alterations. Such epigenetic changes and genetic mutations provide a growth benefit to these mutant cells. This results in the clonal expansion of these mutated cells. This cycle leads to the progression of adenomas to adenocarcinomas through the sequential acquisition of epigenetic and genetic alterations resulting in clonal heterogeneity. Until now, only adenomatous polyps are known to be capable of malignant transformations. Nevertheless, only a subset of adenomas progress into cancer, and progression probably occurs over years or decades (Ewing, Hurley, Josephides, & Millar, 2014). Colon cancer appears to involve and proceed through a unique pathway i.e., responsible for mitosis and referred to as “hyperplastic polyp-serrated adenoma-adenocarcinoma pathway” (Fig. 8.1). Nano Drug Delivery Strategies for the Treatment of Cancers

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FIGURE 8.1 First step in colon carcinogenesis: The adenoma
carcinoma sequence.

8.2.2 Genetic mutations Since 1990, there has been much progress in determining the mechanisms involved in colon cancer at the molecular level, when Fearon and Vogelstein proposed their genetic model for colon cancer. A development from normal mucosal cells to adenoma cells to malignant cells was supported by the demonstration of aggregating mutations in the genes of APC, K-RAS, P53, and DCC. All of which are considered to be important, but are not successfully accounted for in all the cancers of the colon. The first known lesion in the development of colon cancer is the (ACF). The true neoplastic potential of this lesion is still undetermined. But, among these lesions, some of them may appear to progress and develop into adenocarcinoma. Mutations in the APC gene are often carried by dysplastic aberrant crypt foci and tend to have the highest potential for colon cancer progression. Therefore mutations in APC, resulting in the Wingless/Wnt signaling pathway being overactivated, tend to trigger the development of tumors in the colon. Subsequent mutations in the other genes also play a role in the development of tumors and the subsequent development of other malignant characteristics such as tissue invasiveness and the ability to metastasize (Roper & Hung, 2013).

8.2.3 Biomarkers A cancer biomarker or molecule refers to a process or substance that indicates the existence of a tumor/cancer in the body. It may be a tumor-secreted molecule or a specific reaction in the body to the presence of cancer. Ideally these biomarkers can be analyzed in biofluids like blood or serum. They are important for the early diagnosis of colon cancer

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for its therapy and for patients’ outcome. These biomarkers can be categorized into three groups, namely diagnostic, predictive, and prognostic (Peluso et al., 2017). 8.2.3.1 Diagnostic biomarkers These biomarkers allow for early diagnosis of colon cancer. 8.2.3.1.1 Genomic instability: an evolving hallmark of colon cancer

Most colon cancers are characterized by genomic instability. This is the result of genomic alterations during cell division. Damage to multiple genes that control cell division and tumor suppressors results in the development of cancer. It is well known that several mechanisms closely monitor genomic integrity, that is, the mitotic checkpoint, DNA damage checkpoint, and DNA repair machinery, and failure to control any of these mechanisms often leads to genomic instability, which predisposes cells to malignant transformations. Maintaining genomic stability is crucial for cell integrity in order to prevent errors from endogenous genotoxic stress such as reactive oxygen species (ROS) from cellular metabolism, DNA replication, and exogenous carcinogens, for example, ultraviolet radiation, ionizing radiation, or DNA damaging chemicals. Loss of this genomic stability promotes the acquirement of multiple mutations that drive the progression of colon cancer (Markowitz & Bertagnolli, 2009). There are a variety of examples of genomic instability, including chromosomal instability, microsatellite instability (MSI), aberrant DNA methylation, and DNA repair defects (Fig. 8.2). A wide genomic study on gene mutations in colon cancers has reported acquired somatic mutations in several hundred genes. Table 8.1 highlights several essential genes involved in the tumorigenesis of colon cancer. (a) Chromosomal instability Chromosomal instability (CIN) is often associated with genetic variation due to either an altered chromosome structure or number. Chromosomal mutations are commonly used to examine genetic heterogeneity in tumors. Structural aberrations or variations in the chromosome copy number are observed in up to 85% of colon cancers. Loss of tumor suppressor gene activity together with APC, whose normal function is to combat tumorigenesis, has been involved in the progression of CIN.

FIGURE 8.2 Schematic representation of genetic instability: An evolving hallmark for colon carcinogenesis.

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TABLE 8.1 Several essential genes involved in the tumorigenesis of colon cancer. Gene

Location on chromosomes

Mutation type

Function of gene product

Oncogenes BRAF

7q34

Point mutations (most frequent V600E)

Cell proliferation and survival

K-RAS

12p21

Point mutation (codons 12 and 13 of exon 2)

Cell proliferation and survival

MYC

8q24

Gene amplification

Cell proliferation and survival

EGFR

7p21

Gene amplification

Cell proliferation and survival

MLH1 (associated with microsatellite instability)

3p22.2

Germline mutation

Cell proliferation and survival

APC regulates spindle microtubules, and is needed during mitosis to detect misaligned chromosomes. The importance of this role in conserving mitotic fidelity is focused by the CIN observed in colon cancer carrying APC mutations, for example, FAP, an autosomal dominant condition, in which hundreds to thousands of adenomatous colonic polyps develop. FAP is also characterized by a loss of function of the APC gene (Fig. 8.4). Germline mutation in the APC gene results in a nonfunctional truncated protein, leading to the accumulation of β-catenin and the uncontrolled expression of multiple genes that facilitate colon tumorigenesis (Pritchard & Grady, 2011). (b) Microsatellite instability Microsatellites are referred to as short tandem repeats (STRs) (mononucleotide/dinucleotide). These are short (1
6 base pairs) repeating stretches of DNA scattered throughout the entire genome. They account for about 3% of the human genome. They are vulnerable to transcription errors during replication due to their repetitive nature. Microsatellites are prone to high mutation rates. As they possess a normal karyotype, microsatellite unstable tumors are different from CIN. The tumorigenesis process in MSI involves the inactivation of genes responsible for DNA mismatch repair (MMR) through somatic mutation or aberrant methylation. MSI is a hyper-mutable phenotype and rare molecular mutation. It is the result of a defective DNA MMR system (Fig. 8.4). Patients with MSI exhibit a high frequency of replication errors, particularly in repetitive DNA sequences, mainly due to the slippage of the DNA polymerase. The inability to repair strand slippage within nucleotides repeats changes the size of the microsatellites and this can be attributed to a loss of gene function. This is particularly important if the microsatellite lies within the coding region of the gene as it may result in altered gene function or a change in gene expression (Kastrinos & Syngal, 2011). The presence of MSI is noted in gastric, sporadic colon, sporadic endometrial, and the majority of other cancers. Around 15%
20% of colon cancers exhibit MSI. The presence of alternate-sized repetitive DNA sequences that are not present in the corresponding germline DNA is also referred to as MSI. MSI in the genome also leads to the development of Lynch syndrome. Germline mutations in MMR genes result in Lynch syndrome progression (Berretta et al., 2017). It carries

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a lifetime risk of colon cancer of nearly 80%. Mutations resulting in the loss of function in four genes involved in MMR have been reported, namely MLH1, MSH2 (accounting for the majority of colon cancer cases), MSH6, and PMS2. Lynch syndrome is a commonly inherited colon cancer syndrome accounting for 2%
3% of all cases. The progression of adenoma cells to carcinoma sequence (malignant cells) is seen relative to sporadic colon cancer. The risk of developing extra-colonic malignancies is also increased in affected individuals, particularly in endometrial and ovarian cancers. Lynch syndrome is an autosomal dominant colon cancer disorder. Individuals affected with Lynch syndrome carry a germline mutation in a single copy of an MMR gene. This alone is not adequate to account for the reported elevated risk of colon cancer, which only occurs when somatic mutations affect the remaining wild-type parental allele. In the EPCAM gene, germline deletion alterations have currently been recognized as a novel cause of Lynch syndrome. The mechanism involved is the disruption of the 30 end of the EPCAM gene, resulting in the epigenetic silencing of the adjacent MSH2 MMR gene. Patients with Lynch syndrome are correctly identified as clinically relevant because it allows for targeted colon cancer monitoring for the index cases and family members. The germline mutation analysis of the four DNA MMR genes involved in the pathogenesis of Lynch syndrome might make a definitive molecular diagnosis. This efficient approach involves the assessment of the loss of MMR gene products by immunochemistry, and for MSI, using polymerase chain reactions. 8.2.3.1.2 Insulin-like growth factor binding protein 2

Insulin-like growth factor binding protein 2 (IGFBP2) is a protein that controls the binding between IGF and IGF-1. Their levels are increased due to the overexpression of corresponding mRNA in colon cancer. The levels of IGFBP2 in plasma and serum are significantly higher in colon cancer and in advanced tumors relative to those at an early stage (Liou et al., 2010). 8.2.3.1.3 Pyruvate kinase M2

Pyruvate kinase M2 (PKM2), which is generally upregulated in colon cancer, is a glycolytic enzyme. It plays an essential role in the reprogramming of the metabolism, cell cycle progression, and gene transcription. It can be found even in normal colic cells. In colon cancer cells, its level is higher. Mutated PKM2 might be detected in stools using the ELISA technique. Nevertheless, its role as a diagnostic marker must be further studied (Dhar et al., 2013). 8.2.3.1.4 Telomerase

Telomeres, repetitive (TTAGGG) DNA
protein complexes at the chromosomal end, are essential for the survival of tumor cells. They are controlled by an enzyme called telomerase in a variety of tumors. Telomerase is a large ribonucleoprotein complex accountable for the progressive synthesis of the repetitive telomeric DNA sequence (TTAGGG) at the 30 ends of linear chromosomes. It everts the loss of a DNA from each round of replication. Studies have reported that telomerase is involved in the maintenance of telomere length, gene expression and regulation, cell proliferation, WNT/β-catenin signaling, NF-kB signaling, cell adhesion and cell migration, MYC-driven oncogenesis,

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apoptosis, and epithelial mesenchymal transition. All of these telomerase processes are thought to make a significant contribution to the oncogenesis cycle (Pinol-Felis et al., 2017). 8.2.3.2 Predictive biomarkers These biomarkers are useful in predicting a patient’s response to therapy and, therefore, patients can be chosen to undergo a particular treatment/therapy on the basis of a likely positive response. They might even be used to identify the correct dose of bioactives and to avoid their toxicity (Taylor, 2019). 8.2.3.2.1 B-Raf proto-oncogene serine/threonine kinase (BRAF)

BRAF is frequently mutated in colon cancer. The BRAF mutation is observed in advanced colon cancer (Fig. 8.4). The BRAF protooncogene consists of 18 exons and is located on chromosome 7 (q34). It encodes for the BRAF protein kinase. The most common is BRAF V600E mutation which leads to a point mutation resulting in a substitution of glutamic acid by valine, as a consequence, it activates mitogen-activated protein kinases (MAPK) signaling pathway. Conventionally, it has been identified by PCR analysis, although, immune histochemistry has been approved for its research (Galuppini et al., 2017). 8.2.3.2.2 Kirstein rat sarcoma

K-RAS, that is, Kirstein rat sarcoma, belongs to the RAS family of genes and presents one of the most marked protooncogenes in colon carcinogenesis (Fig. 8.4). The genes from the RAS family encode proteins that are highly conserved and are involved in the signal transduction pathway. The RAS protein triggers various downstream signaling pathways such as PI3K and mitogen-activated protein kinase (MAPK) pathways which control various cellular functions including cell proliferation, differentiation, survival, motility, and intracellular trafficking. KRAS is investigated as one of the crucial downstream constituents of the epidermal growth factor receptor (EGFR) signaling pathway. Thus, a mutation in the K-RAS gene may activate EGFR signaling pathway resulting in uncontrolled cell proliferation and growth. K-RAS mutations are observed in 37%
41% of colon carcinomas and appears to be relatively early in the development and progression of colon carcinoma. The vast majority of K-RAS mutations affect codon 12, a subset affects codon 13, and rare mutations affect codon 61. K-RAS mutations are involved in the development of colon adenoma, but are certainly not necessary for adenoma initiation (Won et al., 2017). K-RAS mutations seem to follow APC mutations and are associated with advanced adenomatous lesions. This model is illustrated by the finding that small adenomas with APC mutations carry K-RAS mutations in approximately 20% of tumors, while about 50% of the more advanced adenomas have K-RAS mutations. Therefore mutations in the K-RAS gene tend to initiate the development of colon cancer early in the adenoma
carcinoma sequence by mediating adenoma growth. K-RAS mutations are commonly found in aberrant crypt foci, which are flat-colonic epithelial lesions with altered glandular structures, but in which there is usually no dysplasia. A significant fraction of hyperplastic polyps (lesions) also have K-RAS mutations. These lesions are minimally likely to progress into carcinomas. Despite observations that K-RAS mutations are present with negligible malignant potential

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in some colon cancer lesions (e.g., aberrant crypt foci, hyperplastic polyps), mutant K-RAS alleles, when present, seem to play a major role in driving the behavior of advanced colon cancer cells. Reports using genetic disruption approaches in advanced colon cancer cells to target mutant K-RAS alleles have shown that the inactivation of mutant K-RAS function abolished the tumorigenic growth properties of the cells in both in vitro and in vivo studies (Karapetis et al., 2008). 8.2.3.2.3 Ezrin

Ezrin, belonging to the ezrin-radixin-moesin (ERM) family, is a cytoskeletal protein that plays a crucial role in metastasis, invasion, and cell motility. Elevated cytoplasmic expression of ezrin is often associated with an increased aggressiveness of colon cancer and, therefore, with a poor prognosis. This might be a target for colon cancer therapy (Bulut et al., 2012). 8.2.3.2.4 DNA base excision repair genes

DNA repair mechanisms such as MMR or base excision repair (BER) affect tumor characteristics and prognosis. They also determine chemotherapeutic response. Defective MMR leads to chemoresistance in colon cancer. The BER gene, that is, the MYH gene is responsible for repairing DNA damaged by ROS. Excision repair cross-completing-1 (ERCC1) belongs to the family of genes that arrest DNA damage by nucleotide excision and repair (Kastrinos & Syngal, 2011). 8.2.3.2.5 PTEN

The phosphatase and tensin homolog protein (PTEN) is a tumor suppressor gene whose inactivation triggers the deregulation of the phosphoinositide-3-kinase pathway. PTEN loss has been linked to aggressive colon cancer. It is a predictive factor for cancers with wild-type K-RAS and is treated with anti-epidermal growth factor receptor (EGFR) therapy (Razis et al., 2014). 8.2.3.3 Prognostic biomarkers These aid in estimating the natural course of the disease. They are molecules that are involved in several processes such as angiogenesis, cellular proliferation, invasion, differentiation, and metastasis (Feng et al., 2019). 8.2.3.3.1 Adenomatous polyposis coli

The gene adenomatous polyposis coli (APC) encodes a protein that carries multiple functional domains that conciliate oligomerization as well as binding to a variety of intracellular proteins, including β-catenin, γ-catenin, glycogen synthase kinase (GSK)-3β, axin, tubulin, EB1, and hDLG. A germline mutation in APC leads to FAP or one of its variants, Gardner syndrome, attenuated FAP, Turcot syndrome, or flat adenoma syndrome. Moreover, studies have revealed that APC is mutated in up to 70% of all sporadic colon adenocarcinomas. It is a high mutation frequency unique to colon cancers. Such mutations are present at the early stages of the development and progression of colon cancer and precede other changes found during the development of colon cancer (Fig. 8.4).

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FIGURE 8.3 Schematic representation of Wingless signaling pathway: Proposed model for colon carcinogenesis initiation.

One of the main tumor-promoting consequences of these mutations results in the overactivation of the Wingless/Wnt signaling pathway (Fig. 8.3) with subsequent gene expression that facilitates cell growth. APC mutations distort the association of APC with β-catenin. This results in excessive amounts of β-catenin and the overactivation of the Wnt signaling pathway. As a result, genes that promote tumor formation are transcribed. The Wnt signaling pathway is overactivated since GSK-3β forms a complex with APC, β-catenin, and axin, and phosphorylates these proteins. The phosphorylation of β-catenin is intended for ubiquitin-mediated proteasomal degradation. Truncating APC mutations stop this mechanism from occurring and allow the amount of cytoplasmic β-catenin to increase, which can then translocate to the nucleus and interact with other transcription factors (Chen et al., 2013; Clarke, 2005). 8.2.3.3.2 Tumor protein-53

Tumor protein-53 (P53) was originally identified as a protein forming a stable complex with the SV40T antigen. It was initially suspected to be an oncogene. P53 has been shown to be a transcription factor with tumor suppressor activity in subsequent studies. It is located at chromosome 17p13.1, and is mutated in 50% of primary human tumors, including tumors of the gastrointestinal tract (GIT). P53 is currently considered a transcription factor. It is involved in the maintenance of genomic stability by controlling the cell cycle in

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FIGURE 8.4 Role of predictive and prognostic biomarkers in colon carcinogenesis.

response to genotoxic stress and apoptosis. P53 mutations have not been observed in the initial stages of colon cancer, that is, colon adenomas. They appear in the late events in the colon adenoma
carcinoma sequence that can mediate the transition from adenoma to carcinoma (Fig. 8.4). In contrast, P53 mutations in conjunction with a loss of heterozygosity (LOH) of the wild-type allele was found to coincide with the presence of carcinoma in an adenoma, therefore, providing further evidence of its role in the transition to malignancy. The role of P53 in identifying DNA damage and inducing cell cycle arrest and DNA repair or apoptosis has led to P53 being called the “guardian of the genome.” Consequently, P53 usually acts as a tumor suppressor gene by inducing genes. This can cause cell cycle arrest or apoptosis and as well as angiogenesis inhibition through the induction of Thrombospondin-1 (TSP1). These functions can be blocked by mutant P53 by forming oligomers with wild-type TP53. This causes the DNA-binding specificity to be diminished. Table 8.2 highlights several essential genes involved in the suppression of tumors in colon cancer (Al-Sohaily, Biankin, Leong, Kohonen-Corish, & Warusavitarne, 2012; Li, Zhou, Chen, & Chng, 2015). 8.2.3.3.3 Deleted in colon cancer [loss of heterozygosity (18q)]

Since it was first identified in a colon cancer study, in 1990, DCC (deleted in colon cancer) has been a target in colon cancer. For many years, DCC has held a controversial position as a tumor suppressor gene. Newly, DCC has been described as a dependence factor. Several theories have been put forward that have revived the interest in the candidacy of DCC as a tumor suppressor gene. It might be a ligand-dependent suppressor gene that is frequently epigenetically silenced. One of the most common anomalies in advanced colon

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TABLE 8.2 Several essential genes involved in the suppression of tumors in colon cancer. Gene

Location on chromosomes Mutation type

Function of gene product

Tumor suppressor genes TP53

17q13

Point mutation (missense), allele loss

Apoptosis, autophagy induction, cell cycle arrest

APC

5q21

Point mutation, frameshift mutation, allele loss leading to truncated protein deletion

Wingless signaling pathway inhibition

SMAD4 18q21

Allele loss, nonsense, missense

Intracellular mediator of TGF-β pathway

PTEN

10q23

Nonsense, deletion

Inhibition of the phosphatidylinositol-3kinase pathway

BAX

19q13

Frameshift mutation

Apoptotic activator

DCC

18q21

Point mutation

Triggers tumor cell apoptosis, cell surface receptor for nectrin-1

cancer is the LOH of DCC in region 18q21 (Fig. 8.4). The elimination of DCC is not considered to be a major genetic change in the development of tumors, but one of many alterations that can facilitate existing tumor growth (Zauber, Sabbath-Solitare, Marotta, & Bishop, 2008). 8.2.3.3.4 SMAD4

SMAD4 is an oncosuppressor receptor that is located on chromosome 18q21. In advanced stage colon cancers, it is a frequent site for LOH. This receptor plays a crucial role in the TGF-β signaling pathway by controlling gene expression following the activation of TGF-β receptors. It is also associated with metastasis and tumor invasion (Fig. 8.4). SMAD4 is, therefore, a valuable prognostic biomarker (Alazzouzi et al., 2005). 8.2.3.3.5 Epidermal growth factor receptor

EGFR is identified as a crucial player in colon cancer initiation and progression. It is a 170 kDa transmembrane protein and is a member of the tyrosine kinase receptor family. This receptor plays a critical role in oncogenesis. This receptor is overexpressed in various tumors, including colon cancer. Two monoclonal antibodies (mAbs), that is, cetuximab and panitumumab are commonly used in the therapy of colon cancer exhibiting EGFR overexpression (Heinemann, Stintzing, Kirchner, Boeck, & Jung, 2009). 8.2.3.3.6 Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is an angiogenesis factor responsible for the angiogenesis of several solid malignancies, including colon cancer. VEGF mutations are often linked with a greater aggressiveness and poor prognosis in colon cancer (Falchook & Kurzrock, 2015).

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8.2.3.3.7 Aberrant DNA methylation

Aberrant DNA methylation is another gene-silencing mechanism in colon cancer. It may result in a loss of MMR function. Methylated cytosine is incorporated into the normal genome. It is commonly referred to as a fifth DNA base. It exists outside of exons mainly within CpG dinucleotides rich islands. Further, nearly half of the promoter sequence regions and CpG islands present wherein are not methylated in normal cells. Therefore, aberrant methylation which includes CpG islands rich motifs throughout the promoter sequence may lead to the silencing of the gene under reference. The gene is essentially involved in the expression of protein/enzymes i.e., involved in mismatch repair and editing of replicating genes. Thus, the mutations in such cells are allowed leading to different cell proliferation and growth-related consequences. There is aberrant methylation in the colon cancer genome within promoter-associated CpG islands, resulting in the silencing of gene expression. The hypermethylation of promoters encompassing CpG islands is commonly known as CpG island methylator phenotype (CIMP). This is seen in about 15% of colon cancers. Most of them demonstrate a loss of MLH1 expression, resulting in MMR deficiency and MSI (Ogino et al., 2006). 8.2.3.3.8 BAX

The BAX receptor belongs to the proapoptotic Bcl-2 protein family. The expression of the BAX receptor is a predictive and prognostic marker for colon cancer (Fig. 8.4). It plays a crucial role as a central mediator of the mitochondrial pathway for apoptosis. The loss of this proapoptotic Bcl-2 family protein confers drug resistance in human cancers. It also plays an important role in caspase-3 activation and induces thapsigargin (THG)-mediated apoptosis in HCT116 colon cancer cells as reported by Yamaguchi, Bhalla, and Wang (2003).

8.3 Conventional treatment options for colon cancer and their limitations There are several conventional methods for colon cancer treatment, which include surgical resection, radiation therapy, chemotherapy, immunotherapy, and targeted therapy. These treatments are either used alone, depending on the stage at which the disease is detected and diagnosed, or in combination (DeSantis et al., 2014).

8.3.1 Surgical resection The surgical removal of precancerous or cancerous tumors possesses the potential for the complete recovery of the patient. This might be a better and effective option for small, localized cancerous growths. During colonoscopy, the surgical removal of polyps is called polypectomy. Although recurrence is possible, surgery is the only way to treat radiation-resistant solid tumors as well as tumors resistant to chemotherapy (e.g., pancreatic carcinoma). Moreover, comprehensive geriatric assessment (CGA) may identify susceptible patients with significantly increased risk of severe postsurgical complications (Kristjansson et al., 2010).

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8.3.2 Radiation therapy Radiation therapy involves the use of high-energy X-rays to kill cancer cells. Radiation therapy, along with chemotherapy, is commonly used in adjuvant or neoadjuvant therapy for the treatment of rectal cancers, while chemotherapy is more common in the treatment of colon cancers (Marshall, 2008). However, radiation therapy is also associated with side effects. The possible side effects of radiation therapy for colon cancer include nausea, fatigue/tiredness, and skin irritation, which can range from redness to blistering and peeling, bladder irritation, problems with wound healing if radiation is given before surgery, scarring, fibrosis (stiffening), and adhesions that cause the tissues in the treated area to stick to each other.

8.3.3 Chemotherapy Chemotherapy is a major part of the treatment of colon cancer after surgery. It is a treatment that involves cancer killing bioactives used to destroy colon cancer cells. This is also the main method used in the treatment of cancer. It includes bioactives such as alkylating agents, plant alkaloids, antitumor antibiotics, enzymes, hormones, etc., which kill cancerous cells or inhibit tumor growth or cell division. However, there are no bioactives that can only kill malignant cells without killing normal tissues; often their side effects are dangerous. The treatment of malignant tumors or metastatic cancer is primarily based on chemotherapy, which is the method or process of administering a bioactive to destroy tumor cells by direct cytotoxicity, leading to tumor regression. Such chemotherapeutic bioactives interrupt cell division processes, including DNA replication and chromosome separation, and are not specific to tumor cells. Addressing all promptly dividing cells in the body, only a small portion of bioactives reach the target tissue (Cunningham, 2010). This creates a risk of damaging healthy tissues, particularly those tissues with a high replacement rate (e.g., immune cells and intestinal linings). Although, these cells typically repair themselves after the discontinuation of chemotherapy. FDA-approved bioactives for colon cancer treatment, which mostly consist of cytotoxic bioactives, are discussed in Table 8.3.

8.3.4 Targeted therapy Antibody Based Therapies: Conventional chemotherapy is nonselective. Chemotherapeutic agents interact with the cells and, therefore, they can destroy normal tissues. In the course of tumor development, tumor cells secrete growth factors that initiate neovascularization, which opens a more tumor-specific treatment pathway. For example, a proangiogenesis protein that is overexpressed in cancer cells is VEGF and it is one of the most common targets (Chu, 2012). The first FDA-approved monoclonal anti-VEGF bioactive, marketed as Avastin, was bevacizumab. It is used in conjunction with conventional chemotherapy for the treatment of metastatic colon cancer. It inhibits angiogenesis, which can decrease the growth of new blood vessels (Van Cutsem, Lambrechts, Prenen, Jain, & Carmeliet, 2010). Another potential target that is commonly expressed in colon cancer cells is EGFR. Panitumumab is a monoclonal antibody. It binds to the extracellular domain of EGFR and prevents its activation. Cetuximab is another monoclonal antibody that acts by

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TABLE 8.3 Chemotherapeutic/cytotoxic bioactives for colon cancer therapy. Name of bioactive/ category

Trade name

Mechanism of action

Structure

Routes of administration

Side effects

5-Fluorouracil Category: antimetabolite/ pyrimidine analogue

Adrucil, Acts as an inhibitor of Carac, Efudex, thymidylate synthase Efudix

Intravenous (infusion or bolus), topical

Myelosuppression, mucositis, diarrhea, skin toxicity

Irinotecan Category: camptothecin analogue

Camptosar

Topoisomerase I inhibition by the active metabolite SN38

Intravenous

Neutropenia, hepatic dysfunction

Celecoxib Category: nonsteroidal anti-inflammatory drug

Celebrex

Selective COX-2 inhibitor

Oral

Gastrointestinal toxicity, ulceration, perforation of stomach or intestine

Oxaliplatin Category: platinumcontaining alkylating agent

Eloxatin

DNA synthesis inhibitor in cells

Intravenous

Hepatic encephalopathy, gastrointestinal bleeding

Capecitabine Category: pyrimidine analogue

Xeloda

Nucleic acid synthesis inhibitor/thymidylate synthase inhibitor

Oral

Hepatotoxicity

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binding to EGFR. It arrests uncontrolled growth in cancers with EGFR mutations. Preclinical trials demonstrated that cetuximab is synergistic with small molecule chemotherapeutics, especially irinotecan (Karapetis et al., 2008). Panitumumab is generally used in combination with cetuximab to treat metastatic colon cancer. The use of chemotherapy with these targeted therapies has, therefore, resulted in a median survival period of over 2 years. The aim of targeted drug delivery is to concentrate anticancer bioactives in cancer tissue while decreasing the relative concentration of the bioactive used in the proximal tissue (Banerjee et al., 2017). Nanoparticles have received great attention due to their physicochemical characteristics, ability to conjugate or couple with interesting surface functional groups, biocompatibility, biodegradability, nontoxicity, and large surface and volume ratios. Nanometric materials such as biodegradable biopolymers, metal oxides, metals, and polymers have led to significant breakthroughs in the accomplishment of nanodrug formulations for targeted therapy. In targeted colon cancer therapy, nanobioconjugation plays a vital role. It involves the covalent coupling of cancer receptors, antibodies, targeting moieties, cytotoxic anticancer bioactives, and immunotoxins. Nanoparticulate systems can carry anticancer bioactives to tumor sites through active or passive targeting strategies, enhancing the effectiveness of bioactives and thereby reducing their side effects (Wang, Langer, & Farokhzad, 2012). Globally these carriers are recommended to detect cancer cells, specifically in order to treat the few side effects. They can readily be encapsulated with bioactives in conjugation/coupling with fluorescent-tagged cancer-specific markers.

8.3.5 Immunotherapy Immunotherapy is primarily based on the fact that the immune system can help fight against colon cancer. The immune system has a considerable effect on cancer, particularly as a suppressor of tumor initiation and progression. Moreover, it also affects the response to immunotherapy and conventional therapy (e.g., chemotherapy, radiotherapy, and targeted therapies). Nevertheless, tumors may have numerous mechanisms to escape immune surveillance. Hence different approaches may be followed to restore immune responses both as passive immunotherapy (adoptive cellular therapy and mAbs) and as an active immunotherapy (cytokines, immune checkpoint inhibitors, costimulatory pathways, and cancer vaccines) approaches (Mocellin & Nitti, 2008). The FDA has approved checkpoint inhibitors (pembrolizumab and nivolumab) for the treatment of metastatic colon cancer. The conventional therapy for colon cancer is associated with several limitations, which include toxic effects, lack of selectivity, nonspecific targeting, and the development of multidrug resistance (MDR). MDR is a threat in colon cancer therapy that can be significantly averted by nanoparticulate drug delivery systems. Nanoparticulate structures are rapidly evolving with the goal of overcoming the drawbacks associated with conventional therapies.

8.4 Nanoparticles: the modern trends in the treatment of colon cancer Nanoparticle- or nanotechnology-based drug delivery vehicles offer new possibilities for the early detection and effective treatment of colon cancer. Different nanoparticles

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FIGURE 8.5 Schematic representations of various nanoparticulate systems for targeted drug delivery to cancerous colon tissues.

have been developed and explored as drug delivery vehicles for diagnostic and therapeutic purposes. Such nanoparticles are linked with targeting moieties to achieve selective treatment and to reduce toxicity. Passive targeting relies on the enhanced permeability and retention effect of tumors and extravasation, while active targeting often requires binding to specific targeting moieties that are recognizable by colon cancer tissues such as folate, mAbs, VEGF, aptamers, and membrane penetrating peptides. Moreover, smart carriers have been gradually applied to nanotechnology-based drug delivery systems. These carrier systems are developed to respond to certain changes in the bioenvironment and release encapsulated bioactive contents on demand, therefore, achieving effective bioactive concentrations at tumor sites (He et al., 2019). Various nanodrug delivery carriers in pharmaceutical approaches for targeted drug delivery to cancerous colon tissues are discussed here (Fig. 8.5).

8.4.1 pH-responsive nanoparticles These nanoparticles possess an extracellular acidic environment and an altered pH gradient through their cell compartments. Nanoparticles that react to pH gradients are promising carriers for the delivery of bioactives to the colon. These pH-responsive nanoparticles are comprised of a corona and a core. One or both of these respond to the external pH in order to change their solubility/insolubility or change states. In order to facilitate cell targeting and internalization, nanoparticles with coronas that are either positive or become soluble to make their targeting groups available, which bind at the extracellular pH of

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tumors, have been developed. For the rapid release of bioactives into the extracellular fluid or cytosol, nanoparticles with cores that are soluble or alter their structures to release the carried bioactive(s) at the extracellular pH of tumors or lysosomal pH have also been tailored. These pH-responsive nanoparticles have therapeutic benefits over their conventional pH-insensitive counterparts (Shen, Tang, Radosz, Van Kirk, & Murdoch, 2008). Prajakta et al. (2009) developed pH-sensitive nanoparticles loaded with curcumin to target colon cancer. Eudragit S100 was used in the formulation to aid targeting as the polymer dissolves at colonic pH. This leads to selective colonic release of the entrapped bioactive. The HT-29 human colon adenocarcinoma cell line was selected for cytotoxicity assay (MTT). Both the nanoparticle formulation and curcumin were tested at equimolar concentrations. The results demonstrated that after 24 h of treatment, the nanoparticles inhibited 91.22% of the cells as compared to the 63.85% achieved by curcumin (100 μM). The improved therapeutic action might be due to increased cellular absorption, which is affected by size, and may result in a reduction of the overall dosage requirement (Prajakta et al., 2009). Ahmadi et al. (2019) designed pH-sensitive nanoparticles that are biodegradable by character for the codelivery of hydroxytyrosol (HT) and doxorubicin (DOX) in HT-29 colon cancer cells. Poly(lactide-co-glycolic acid-co-acrylic acid) (PLGA-co-PAA) was synthesized by radical acrylic acid (AA) telomerization in the presence of mercaptoethanol (ME). Subsequently resulting in the ring opening polymerization of lactide and glycolide in the presence PAA-OH as a chain transfer agent. The IC50 value of the hydroxytyrosoland doxorubicin-loaded nanoparticles measured was lower than the free ones over the same time at the same concentration. The HT- and DOX-loaded nanoparticles showed more cytotoxic effects than the free ones. The cellular uptake of the HT- and DOX-loaded nanoparticles was more than 94%. 40 , 6-diamidino-2-phenylindole (DAPI) staining and cell cycle analysis showed high apoptosis on HT-29 cells treated with the dual drug
loaded nanoparticles as compared to the single drug
loaded formulations and free drugs. Furthermore, the results demonstrated that the HT- and DOX-loaded nanoparticles inhibited gene expression more effectively than the single forms. These results supported that the dual drug therapy developed in this study could be effectively used for HT-29 colon cancer cell disruption (Ahmadi et al., 2019). These types of nanocarrier systems should be further explored in animal models and clinical trials.

8.4.2 Liposomes A liposome is a spherical-shaped vesicle composed of one or more bilayers of phospholipids and cholesterol with a particle size ranging from 30 nm to several micrometers. Such vesicular systems are advantageous due to their ability to encapsulate both hydrophilic and lipophilic bioactives. The inner aqueous part of liposomes is well covered by lipid bilayers and is capable of entrapping hydrophilic entities, whereas the hydrophobic region in the lipid bilayers intercalates hydrophobic entities. They mimic natural cell membranes. Due to their excellent entrapment efficiency, safety, and biocompatibility, they have long been investigated as drug carriers. Furthermore, by conjugating polymers and ligands, the surface of these nanocarriers can be easily modified to give vesicles special properties. In addition to this, site-specific delivery to solid tumors by targeting liposomes can promote a slow

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release of bioactives at tumor sites, therefore, increasing the bioactive concentration in the solid tumor relative to other tissues (Malam, Loizidou, & Seifalian, 2009). Xiong et al. (2017) developed mannosylated liposomes to improve the therapeutic effects of paclitaxel in colon cancer models. The mannosylated liposomes showed a higher CT26 (colon cancer cells) cell uptake and tumor inhibition rate, which could be due to their target effect to the mannose receptor (Xiong et al., 2017). Ektate, Munteanu, Ashar, Malayer, and Ranjan (2018) reported the use of ultrasound and Salmonella-laden temperature-sensitive liposomes (thermobots) for the treatment of colon cancer. They designed thermobots that actively transported membrane-linked lowtemperature-sensitive liposomes (LTSL) inside colon cancer cells. This triggers the release of doxorubicin. Simultaneously, the developed carrier system polarized macrophages to the M1 phenotype with high intensity focused ultrasound (HIFU) heating (42 C
42 C). Biocompatibility analysis demonstrated that the developed thermobots were highly capable in loading LTSL without affecting their viability. In vitro results demonstrated that the thermobots showed efficient intracellular targeting, high doxorubicin accumulation, and elevated expression of proinflammatory cytokine in C26 murine colon cancer cells. In vivo results showed that the combination of thermobots and HIFU heating (B30 min) resulted in the enhanced polarization of macrophages to the M1 phenotype and therapeutic efficacy in C26 murine colon cancer cells. An assessment of the data revealed that the thermobots and focused ultrasound treatments have the potential to improve colon cancer therapy (Ektate et al., 2018). Korani, Ghaffari, Attar, Mashreghi, & Jaafari (2019) designed and developed bortezomib-loaded nanoliposomal formulations and evaluated their anticancer efficacy in mice bearing C26 colon carcinoma cells. The IC50 values of the developed formulations against the C26 colon carcinoma cell line were compared with the free bortezomib. The IC50 values for the free drug and the liposomal formulation were observed to be 0.0072 6 0.00075 and 0.05 6 0.001 respectively against the C26 colon carcinoma cell line. An in vivo study revealed that the liposomal formulation effectively retarded the tumor growth and elevated the median survival time (MST) of the mice. Furthermore, the findings indicated that the developed liposomal formulation of bortezomib could significantly increase the therapeutic potential of bortezomib. This nanocarrier system can be considered as a promising drug delivery system in clinical settings (Korani et al., 2019).

8.4.3 Polymeric nanoparticles Polymeric nanoparticles are nanosized colloidal particles with a size range of 10 nm to 1 μm. They are solid in nature. These nanoparticulate systems have attracted considerable interest over the past few years owing to their small size and behavior. They possess a matrix structure consisting of synthetic or natural polymers that are biodegradable and biocompatible; in which bioactives can be entrapped or encapsulated, physically adsorbed on the surface, or chemically linked to the surface. Biodegradable polymers possess certain advantages since they are completely eliminated from the body by natural metabolic pathways. Natural polymers are generally biodegradable and biocompatible. However, their use is limited due to variations in their properties from batch to batch. Contrarily, synthetic

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polymers are well known for their controlled chemical compositions (Parveen & Sahoo, 2008). The most commonly used synthetic polymers are polyacrylates, polycaprolactones, polylactide, and polylactide-polyglycolide copolymers. Lactide-glycolide copolymer has been extensively explored. Alginate, albumin, and chitosan are the most widely explored among the various natural polymers. Polymeric nanoparticles can form two types of structures depending on the preparation method used, namely nanospheres or nanocapsules. Nanospheres are composed of a matrix system in which a bioactive can be uniformly dispersed, while in nanocapsules, the bioactive is embedded in a cavity and the cavity is surrounded by a polymeric membrane. The preparation methods of polymeric nanoparticles are classified under three techniques, namely (1) the preparation of nanoparticles from a preformed polymer dispersion, including nanoprecipitation, emulsification, solvent evaporation, dialysis, salting out, and supercritical fluid; (2) the polymerization of monomers, including emulsion, miniemulsion, microemulsion, controlled radical polymerization, and interfacial polymerization; and (3) the coacervation of hydrophilic polymers or ionic gelation. The advantages of polymeric nanoparticles include controlled bioactive release, the ability to combine both therapy and imaging (theranostics), protection, and the specific targeting of bioactives. Polymeric nanoparticles are recognized by their attractive properties such as their small size, biodegradability, long shelf life, water solubility, and stability during storage. These properties make them a promising candidate for the delivery of bioactives, proteins, DNA, or genes to specific targeted tissues or organs. These are, therefore, used in cancer therapy, vaccines, and gene therapy for crossing the blood brain barrier as well as in the diagnosis of diseases (Liechty & Peppas, 2012). 8.4.3.1 Nanocapsules Nanoencapsulation, a relatively new strategy, offers new possibilities in drug delivery. Nanocapsules are submicroscopic drug carrier systems. They are composed of an oily or aqueous core surrounded by a thin polymer membrane. They vary in size from 5 to 1000 nm, but usually they are between 100 and 500 nm. Nanocapsules have advantages as bioactive carriers. Bioactives are placed inside the core cavity, which provides protection against rapid degradation. The walls of nanocapsules are often made up of a biodegradable polymer. They are usually formed on the spherical interface of particles or droplets or by the selfassembly of amphiphilic polymer molecules. They can be synthesized by various methods, namely nanoprecipitation, emulsion diffusion, double emulsification, polymer coating, etc. (Huynh, Passirani, Saulnier, & Benoıˆt, 2009). From aqueous solutions, capsules are generated by the sequential deposition of polymer layers onto a sacrificial template. Interactions such as hydrogen bonding, electrostatic or covalent bonding, etc., can be used as the driving force for the assembly of a multilayer shell. The dissolution of the sacrificial template allows hollow capsules to be formed. Nanocapsules are analogous to vesicular drug delivery systems that contain bioactives within their cavity, which consists of a liquid core or polymer matrix surrounded by a polymeric membrane. The cavity contains the bioactive in liquid or solid form as a molecular dispersion. Such hollow nanocapsules possess the ability to encapsulate catalysts, dyes, bioactives, and biopolymers such as nucleic acids and proteins. In fact, they possess the ability to provide a shielding environment (protective covering) to peptides, hormones, proteins, enzymes, bioactives, and metabolites against chemical and biological degradation. They also manifest site specificity. This might

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improve the stability and bioavailability of bioactives. These carriers can also regulate cutaneous bioactive penetration/permeation and act as a physical sunscreen due to their ability to scatter light. The permeability of these capsules can be adjusted by altering the pH or by the incorporation of a temperature-sensitive, redox-sensitive, and/or pH-sensitive polymer. Additionally, the targeted delivery of proteins intracellularly enables the site-specific delivery of protein to treat tumor cells. Such smart polymeric nanocapsules, therefore, exhibit wideranging applications in the targeted drug delivery of intracellular degradable bioactives due to their versatile biological performance (Mora-Huertas, Fessi, & Elaissari, 2010). Tsakiris et al. (2019) developed nanocapsules for the treatment of colon cancer. The authors encapsulated six anticancer bioactives, that is, SN38, doxorubicin hydrochloride, oxaliplatin, 5-fluorouracil, irinotecan, and regorafinib within lipid nanocapsules. Their size was approximately 50 nm. In vitro studies revealed that the drug-loaded lipid nanocapsules were slightly less toxic than the free drug. Nevertheless, there was no significant difference between the IC50 values of the free and encapsulated drugs. Clonogenic assays demonstrated that SN38-loaded lipid nanocapsules were one of the most potent formulations against the CT26 murine colon cancer cell line. It was found to be cytotoxic at low concentrations. Hence this formulation was chosen for in vivo studies. In vivo experiments showed that a combination of SN38 lipid nanocapsules and regorafinib lipid nanocapsules decreased the development of CT26 murine colon cancer and improved the MST of Balb/C mice (Tsakiris et al., 2019). Oyarzun-Ampuero, Rivera-Rodrı´guez, Alonso, & Torres (2013) fabricated hyaluronan nanocapsules loaded with docetaxel for the treatment of colon cancer. Using a solvent displacement technique, the nanocapsules were prepared. The size of the nanocapsules was found to be B200 nm, and they had a spherical shape. A cell viability assay was performed in H460 lung cancer cell line to assess the efficacy of the docetaxel-loaded hyaluronan nanocapsules. Such cells were chosen because they overexpress CD44 receptors that have demonstrated to interact avidly with hyaluronic acid. The results of a cytotoxicity assay revealed that the docetaxel-loaded hyaluronan nanocapsules were more cytotoxic against H460 lung cancer cells than free docetaxel. The developed nanocarrier formulations were 3.6-times more efficient (P , .005) than the free drug in terms of the IC50 values. These novel nanocomposites are promising as intracellular drug delivery systems (Oyarzun-Ampuero et al., 2013). 8.4.3.2 Nanospheres Nanospheres have a structural polymeric matrix composite of spherical shape that varies in size between 10 and 200 nm in diameter. A bioactive is entrapped, dissolved, encapsulated, or attached to the polymeric matrix composite. The character of nanospheres can be crystalline or amorphous. Such nanocarriers are designed to protect bioactives from chemical and enzymatic degradation. In the polymeric matrix, the bioactive is distributed and dispersed uniformly. Nanospheres are mainly of two types, namely biodegradable nanospheres and nonbiodegradable nanospheres. Examples of biodegradable nanospheres include albumin nanospheres, gelatin nanospheres, polypropylene dextran nanospheres, modified-starch nanospheres, poly(lactic acid) (PLA), poly(D-, L-glycolide) (PLG), PLGA, and poly(cyanoacrylate) (PCA) nanospheres, whereas PLA is the only polymer that has been approved for use as a controlled release agent in the case of nonbiodegradable nanospheres. Furthermore, magnetic and immune nanospheres are have also been reported in

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the past few years. Nanospheres which contain and carry immune components including antibody or antigen offer enroute protection to the bioactive(s) while they are in circulation. Also, they may release the bioactive(s) slowly over a protracted period of time. Moreover, they may be further ameliorated to be target oriented (Lin et al., 2016, Pathak, Vaidya, & Pandey, 2019). The magnetic nanospheres contain magnetite (Fe3O4)/ferrite (Fe2O3) together with the drug. Thus, they exhibit magnetic responsiveness. Therefore, under the influence of the external magnetic field, they can be localized at a particular sight or organ within the body simultaneously the release of the drug could be modulated by application of the external magnetic field of varying strength” (Wen et al., 2014, Kim et al., 2014, Yang et al., 2017). Methods for the preparation of nanospheres include emulsification polymerization, solvent evaporation, solvent displacement technique, and phase inversion temperature methods. According to the latest reports, hollow gold nanospheres are of great interest owing to their excellent physical and chemical properties for the delivery of bioactives. The hollow structure enhances the loading of bioactives and functional materials making them advantageous in the field of drug delivery. Such nanocarriers are able to release the encapsulated bioactive in a slow and sustained manner. Bioactive release occurs through a diffusion mechanism. They can penetrate the cell gap and the tissues to reach the target organs. Additionally, the coupling of ligands to the surface of nanospheres facilitates site-specific targeting. A reduction in toxicity or nontoxicity makes them preferable for bioactive delivery (Garcı´a, Aloisio, Onnainty, & Ullio-Gamboa, 2018). Xu et al. (2019) developed targeted nanospheres loaded with bufalin for colon cancer treatment. In this study, bufalin-loaded CaP/1,2-bis(diphenylphosphino) ethanepolyethylene glycol (CaP/DPPE-PEG) nanospheres with covalently coupled epidermal growth factor (CaP/DPPE-PEG-EGF) were synthesized by a facile room temperature method and used as carriers for the delivery of bufalin for targeted antitumor therapy. Cell line studies were performed in HCT116 colon cancer cells. In vitro cellular uptake study results demonstrated that the developed nanocarrier formulation could be significantly internalized by the HCT116 colon cancer cells via receptor-mediated endocytosis using epidermal growth factor. Cytotoxicity assay results revealed that the bufalin-loaded nanospheres exhibited enhanced cytotoxicity as compared to bufalin alone in HCT116 cells. Animal studies demonstrated that the developed nanosphere formulation showed greater uptake in the liver and spleen because of the robust phagocytic activity of the reticuloendothelial system. It also presented significantly higher fluorescence as compared to the free bufalin in the tumors (Xu et al., 2019). Ayub et al. (2019) fabricated paclitaxelloaded self-assembled disulfide cross-linked sodium alginate derivatized nanoparticles for colon cancer. The encapsulation efficiency and cumulative percentage of drug release of the developed formulation were found to be 77.1% and 45.1% respectively. The nanocarrier formulation showed a pH-dependent swelling transition from pH 1 to 7 (102.2% increase). A cell viability assay was performed on HT-29 cells. The results demonstrated high viabilities (86.7%) upon treatment with the developed nanosphere formulation at 0.8 μg/mL concentration. More than 70% of the paclitaxel-loaded nanospheres were detected in the HT-29 cells. This showed successful internalization of the developed nanospheres in the cancer cells. Therefore this might be a promising and potential nanocarrier system for colon cancer targeted drug delivery (Ayub et al., 2019).

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8.4.4 Solid lipid nanoparticles Solid lipid nanoparticles (SLNs) are a new generation submicron size colloidal drug delivery systems that are solid at room and body temperatures. They are composed of surfactant-stabilized lipids. They incorporate the benefits of polymeric nanoparticles, emulsions, and liposomes, while decreasing some of their individual drawbacks. Usually, they contain a hydrophobic solid matrix core with a coating of phospholipid. The hydrophobic tail portion of the phospholipid is embedded in the core matrix. Because of this, the core is exclusively hydrophobic in nature and it is expected that SLNs have a higher entrapment efficiency for hydrophobic bioactives in the core as compared to conventional liposomes (Newton & Kaur, 2019). SLNs have been studied for several routes of administration, that is, oral, pulmonary, ocular, dermal, rectal, and parental. The best suitable route for the administration of SLNs is the intravenous route. They can be homogenously dispersed in aqueous and aqueous surfactant solutions. For the preparation of SLNs, solid lipids (e.g., waxes, steroids, purified triglycerides, and fatty acids), emulsifiers, and water are used. The methods used to prepare SLNs include hot homogenization, cold homogenization, solvent emulsification evaporation, and solvent emulsification diffusion. The advantages of SLNs include their easy scale-up, nontoxic character, stability against coalescence or aggregation, protection offered to the entrapped bioactive, prolonged release of bioactives from the matrix, biodegradability, and low production cost. Several studies have reported that when these nanoparticles were used as bioactive carrier systems for chemotherapeutics, especially for colon cancer and malignant melanoma, significant results can be obtained (Ekambaram, Sathali, & Priyanka, 2012). Shen et al. (2019) developed an oral drug delivery system based on SLNs coated with polysaccharide for targeting colon cancer. The SLNs coloaded with doxorubicin and superparamagnetic iron oxide nanoparticles (SPIONS) were developed by the emulsion method. The prepared nanoformulation was surface modified with folic acid (FA)/D-α-tocopheryl polyethylene glycol 1000 succinate, and octadecanol-modified dextran in a layer by layer manner. The hydrodynamic diameter of SLNs was observed to be 100 nm. The developed formulation was evaluated in terms of its cell uptake against mouse colon CT26 cancer cells. The prepared formulation showed a lower IC50 value as compared to free doxorubicin (58 μM) against CT26 cells. An in vivo antitumor efficacy study demonstrated the successful suppression of the primary colon tumors and peritoneal metastasis in terms of the ascites and tumor volume, size and number of tumor nodules, in addition to the absence of systemic side effects after oral administration of SLN therapy (Shen et al., 2019). Campos et al. (2019) designed and developed nimuslide-encapsulated SLNs. The release profile of the nimuslide-loaded SLNs revealed a sustained release pattern with 30% of the drug released within 24 h. The plain and nimuslide-loaded SLNs were observed to be nontoxic in the highest concentration (100 μg/mL) for up to 48 h against Caco-2 cells. The cell viability was found to be 80%. Thus far, these nanocarrier systems possess the potential for the effective therapy of colon cancer (Campos et al., 2019).

8.4.5 Metallic nanoparticles Metallic nanoparticles have currently become the subject of intense research work due to their exotic properties compared to bulk metals. Researchers have taken an interest in

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fabricating metallic nanoparticles such as gold, iron oxide, and silver nanoparticles because of their potential use in biotechnology, diagnostic imaging, magnetic separation, and targeted drug delivery. They can be developed and surface modified with multiple chemical functional groups that allow this category of nanocarriers to be coupled with targeting ligands. These nanocarriers are specifically advantageous in cancer therapy because their charge, size, shape, and surface functionalization can be controlled. The higher density of these nanocarriers is more readily taken up by the cells, offering an advantage for cancer vaccination strategies as compared to other nonmetallic drug delivery systems. They also possess distinctive optical properties (Wojcieszak, Genet, Eloy, Gaigneaux, & Ruiz, 2010). Han et al. (2019) investigated the anticarcinogenic potential of gold nanoparticles against colon cancer. The nanocarrier was prepared from Trichosanthes kirilowii extract. The size of the nanoparticles was found to be B50 nm. For cytotoxicity analysis, MTT assay was performed on HCT116 cells. An approximately 50% cell viability inhibition was reported with gold nanoparticles at a concentration of 15.5 μg/mL against HCT116 colon cancer cells (Han et al., 2019). Majeed et al. (2019) fabricated silver nanoparticles capped with bovine serum albumin for the treatment of colon cancer. The size of the nanoparticles was observed to be in the range of 11.26
23.85 nm. A cytotoxicity assay study showed an IC50 value of 60 μg/mL against HCT116 colon cancer cells. An apoptotic assay demonstrated chromatic condensation due to the production of ROS and the blebbing of the membrane by ethidium bromide and acridine orange dual staining method. The results indicate that the developed carrier system could be a promising strategy for targeting colon cancer (Majeed et al., 2019).

8.4.6 Magnetic nanoparticles The class of nanoparticles that can be modified using magnetic fields are referred to as magnetic nanoparticles. Magnetic nanoparticles typically include metallic nanoparticles, metal oxide nanoparticles, and steel alloy nanoparticles. Iron, cobalt, nickel, silver, and gold are some examples of common magnetic nanoparticles. Metallic oxide nanoparticles primarily include iron oxides (γ-Fe2O3 and Fe3O4) and ferrites (CoFe2O4 and MnO.6ZnO.4Fe2O4), while FeCo, Fept, and others fall under metallic alloy nanoparticles. Among these, the most widely used magnetic nanoparticles are metal oxide Fe2O3 and Fe3O4 magnetic nanoparticles. To fabricate a variety of ferrite nanoparticles (Mn3Zn7Fe2O4, MnO.6ZnO.4Fe2O4, and others), some metal elements such as zinc (Zn) and manganese (Mn) might be added to the nanoscale structure of iron oxide. Such ferrite nanoparticles possess strong magnetism and a high relaxation frequency. Hence they are used in magnetic resonance imaging (MRI). These nanocarriers possess some attractive applications in the field of biomedicine due to their processability, small size, and exotic properties like superparamagnetism, nonvirulence and nonimmunogenic character, and great specific surface area for carrying bioactives, modified compounds, and DNA fragments (Mørup, Hansen, & Frandsen, 2011). They can also be used as a vector after surface functionalization. In cancer chemotherapy, the use of magnetic nanoparticles as bioactive carrier systems allows for bioactives to target tissues and cell types precisely. Licciardi et al. (2019) fabricated SPIONS for the treatment of colon cancer. The authors developed DOX-loaded redox-responsive paramagnetic nanoparticles coated with an amphiphilic copolymer (INU-LA-PEG-FA). The accumulation of bioactives due to magnetic attraction was

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used as a synergistic targeting strategy. A cytotoxicity study demonstrated that the developed nanocarrier formulation killed almost 80% of the HCT116 colon cancer cells. An in vivo study showed that the doxorubicin-loaded paramagnetic nanoparticles exhibited significant suppression of tumor growth in nude mice, being approximately 2- to 6-times smaller than the control at 14 days, which is the time of tumor growth evaluation (Licciardi et al., 2019). Cho et al. (2010) worked on magnetofluorescent silica nanoparticles for targeting colon cancer. They were conjugated with cetuximab. A FACS analysis (cell uptake study) was performed on HCT116 cells. The results revealed that a significant shift in the fluorescence intensity was observed when incubated with magnetic nanoparticles (0.47/99.53) as compared to the free drug (99.99/0.01). Such evaluations showed that the developed nanocarrier formulation could be particularly targeted over 99% of the HCT116 colon cancer cells. This demonstrates that magnetic nanoparticles might be a promising strategy for the therapy of colon cancer (Cho et al., 2010).

8.4.7 Viral nanoparticles These nanoparticle formulations are based on viruses and hold huge potential in the nanomedicine field. They are naturally occurring nanoparticles. They could be used as building blocks with a variety of characteristics. In the medical field, virus-derived material is becoming a growing field of interest. Examples of different novel types of viruses that are commonly used are viruses from bacteria, mammals, and plants. These are selfassembled and genetically engineered into discrete and monodispersive structures of specific shapes and sizes. These nanostructures are well known for atomic resolution and can be fabricated at the atomic level for many systems that are based on viruses. By means of synthetic nanoparticles, this level of quality control and structural engineering cannot yet be attained. For desired applications, they can be structured using several strategies, namely (1) bioconjugate chemistries/approaches may be used to couple bioactives, targeting moieties, and contrast agents to the outer and inner capsid shell, (2) dis- and reassembly protocols can be used to promote the encapsulation of artificial cargoes (loads), that is, contrast agents and bioactives, and (3) genetic engineering is used to enable precise and reproducible changes/modifications to be introduced so that identical particles in huge quantities can be produced, presenting targeting moieties or unique ligation handles for further alterations through bioconjugation (Pokorski & Steinmetz, 2010). Deo et al. (2016) designed and developed viral nanoparticles and surface functionalized them with recombinant single chain fragment variable (rscfv) for targeting colon cancer tumors. Particularly, rscfv binds to the tumor-associated glycoprotein 72. This glycoprotein is overexpressed on the surface of colon cancer cells. Calcein was selected as a model bioactive to target colon cancer cells. The size of the nanocarrier formulation was observed to be 50 nm. Chemotaxis chamber assays demonstrated that the developed nanoparticle formulation significantly attracted macrophages and bound to colon cancer cells (human monocytic cells). The studies showed that tumor necrosis factor-α was secreted by the macrophages, which is a cytokine that is needed to destroy cancer cells. Such results indicate the ability of viral nanoparticles to act as a smart nanobiomaterial for targeting colon cancer (Deo et al., 2016).

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8.4.8 Polymeric micelles Although much progress and advancement have been made in the delivery of bioactives, the design and fabrication of an appropriate delivery system for the delivery of bioactives still remains a major challenge for research scientists. Polymeric micelles are core
shell structured molecules of nanosize. They are usually formed by the selfassociation of amphiphilic block copolymers in aqueous solutions. These nanoparticles possess a hydrophilic shell
lipophilic core structure that promotes the encapsulation of lipophilic bioactives. Due to their target specificity and controlled release of lipophilic anticancer bioactives, they serve as novel drug delivery systems. They are used in drug delivery due to their interesting properties like their tailorability, nontoxicity, controlled drug release, great cargo capacity, and high stability. The enhanced delivery of several poorly aqueous soluble anticancer bioactives by polymeric micelles via concurrent and sequential regimens provide novel and interesting approaches for the incorporation of bioactives into the treatment of cancer (Lu et al., 2019; Zhang, Huang, & Li, 2014). Le and Kim (2019) developed polymeric micelles for the delivery of curcumin to colon cancer cells. For micelle formation, hydrophilic O-(2-aminoethyl) polyethylene glycol (PEG) and hydrophobic octadecylamine were implanted onto a polysuccinimide (PSI) backbone. Folic acid was used as a targeting moiety. To provide pH-sensitive drug release, curcumin was coupled via an acid-cleavable hydrazone bond. Cytotoxicity assay (MTT assay) results revealed that cancer cell viability when treated with the developed nanocarrier formulation was much lower than that of free curcumin at a concentration of .0.25 μg/mL. Western blot assay results demonstrated that curcumin-loaded polymeric micelles inhibited cyclin D1, cmyc, and target genes more strongly as compared to plain curcumin at a concentration of 0.5 μg/mL. It was concluded from these results that curcumin-loaded folic acid-coupled polymeric micelles are expected to be a promising candidate for targeting colon cancer by inhibiting the Wnt/β catenin signaling pathway (Le & Kim, 2019).

8.4.9 Hydrogel A hydrogel, also referred to as an aquagel, is a three-dimensional (3D) network of hydrophilic polymers swollen in an aqueous solution. The 3D polymeric network of an aquagel is preserved in the form of an elastic solid. Hydrogels, by definition, typically contain at least 10% of the total weight of water. Hydrogels are emerging nanocarriers and possess unique and potential characteristics for transporting targeted drug delivery systems in cancer therapy. Cancer is a deadly disease that affects human health worldwide, probably due to several limitations of traditional cancer treatments (Conde, Oliva, Zhang, & Artzi, 2016; Norouzi, Nazari, & Miller, 2016). Hydrogels, however, promote novel and improved opportunities for cancer therapy with limited cytotoxic effects on healthy cells or tissues. Moreover, their structural features and high biocompatibility make the tailoring of hydrogels easy. These characteristics of hydrogels have attracted attention and also allow them to be used as a strong tool for the development of nanomedicines. Zheng et al. (2019) prepared a chitosan-based temperature-sensitive hydrogel for the treatment of colon cancer. The formulation was prepared by dissolving bioactive molecules, that is, doxorubicin and MoS2/Bi2S3-PEG (MBP)

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(a photothermal material) nanosheets into the hydrogel. The gel system could prevent the MoS2/Bi2S3-PEG nanosheets and doxorubicin from entering into the blood stream and destroying normal tissues. At a low MBP concentration (0.5 mg/mL), the developed hydrogel formulation showed a photothermal efficiency of 22.18% in the first near infrared light and 31.42% in the second near infrared light. From the hydrogel, the release of doxorubicin was sustained and controlled. Furthermore, the prepared formulation had antibacterial effects. The fabricated nanocomposite hydrogel is expected to act as a platform for the efficient treatment of cancer due to the different penetration depths of the first and second near infrared lights (Zheng et al., 2019).

8.4.10 Polymerosomes Polymerosomes have a hollow-shell, vesicular structure similar to liposomes and can be used for the delivery of bioactives. Amphiphilic copolymers consisting of covalently interconnected homopolymer blocks are used for the fabrication of polymerosomes. They are considered to be extremely versatile and stable drug delivery systems because they contain a combination of block copolymers of amphiphilic nature. Moreover, their characteristics such as encapsulation efficiency, release capacity, and drug loading can be altered. Biodegradable polymerosomes have been demonstrated to exploit the thick membrane of block copolymer vesicles and their aqueous lumen for drug loading, delivery, pHtriggered release within endolysosomes, and cytosolic uptake of bioactive mixtures. Biodegradable and target-oriented polymers cleave in acidic environment and release bioactives into the endosomes of tumor cells. Unlike liposomes that contain a double layer of phospholipids, a polymerosome consists of two layers of synthetic polymers. For the delivery of hydrophilic bioactives, artificial vesicles, that is, polymerosomes, represent promising pharmaceutical carriers (Meerovich & Dash, 2019; Pakizehkar, Ranji, Sohi, & Sadeghizadeh, 2019). Pan, Gong, Li, Li, and Xiong (2019) developed paclitaxel-loaded folate-conjugated polymerosomes for the treatment of colon cancer. The formulation (polymerosomes) revealed a biphasic release pattern in simulated intestinal and gastric fluids. The Caco-2 colon cancer cell line was selected for cytotoxicity (MTT) assay. The viability of the colon cancer cells decreased to 20% in the case of polymerosomes in a high concentration (0.4 μg/mL). A fluorescence microscopy study revealed that the cell uptake was significantly higher in the case of polymerosomes as compared to free paclitaxel. A pharmacokinetic study demonstrated that the area under the curve of the folate-conjugated polymerosomes was bigger than that of the unconjugated polymerosomes. These results suggest that ligandconjugated polymerosomes could be potential candidates for the delivery of anticancer bioactives (Pan et al., 2019).

8.4.11 Carbon nanotubes These nanocarriers possess unique tubular or barrel-shaped structures of nanoscale diameter. These nanocarriers consist of 10
100 concentric shells of carbons with an adjacent shell separation of B0.34 nm. The network of concentric shells is closely connected to

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the honeycomb organization of the carbon atoms in graphite sheets (Hsu & Luo, 2019). The remarkable electronic and mechanical properties of these nanocarriers arise from the graphite-like arrangements of the carbon atoms in the shell and their quasi onedimensional structure. Depending on their structural parameters, carbon nanotubes might be semiconductor- or metallic-type. Also, they can be single- or multiwalled structures with a large internal volume. The outer surface of these nanocarriers can be easily functionalized. They exhibit a bioactive delivery potential due to their high aspect ratio, structural and morphological control, flexible surface chemistry, and high target specificity ratio (Hassan et al., 2019). Prajapati et al. (2019) developed multiwalled carbon nanotubes (MWCNT) and conjugated them with hyaluronic acid for colon cancer targeting. Gemcitabine was loaded in the developed nanocarrier system. The ligand, that is, hyaluronic acid, was coupled on the outer surface of the pegylated MWCNTs. An in vitro drug release study revealed that in an acidic pH, the gemcitabine releases faster than in physiological conditions (PBS, pH 7.4). The hemolytic toxicity of the developed nanocarrier system was found to be 7.73% 6 0.4%, which is considerably less than that of the plain drug, which was 18.71% 6 0.44%. Cytotoxicity assay results showed that the hyaluronic acid
conjugated MWCNTs exhibited greater cytotoxicity against HT-29 cells (colon cancer cell line). Animal studies demonstrated that in the case of the gemcitabine-loaded, hyaluronic acid
conjugated MWCNTs, an increase in the pharmacokinetic parameters such as the area under the first moment curve (AUMC), the area under the curve (AUC), and the MST in tumor-carrying rats was observed. The P value was found to be ,0.0001. These studies concluded that the developed surface-modified MWCNTs are an effective and safe nanocarrier system for targeting colon cancer (Prajapati, Jain, Shrivastava, & Jain, 2019).

8.5 Conclusion In conclusion, nanoparticle-based drug delivery systems and targeted cancer therapies are advantageous and effective in interacting with specific molecules that are involved in tumor growth, spread, and progression. Nanoparticle-based formulations improve the selectivity and enhance the apoptosis (cell death) of tumor cells, making them a good choice to treat colon cancer. Nevertheless, there are still numerous challenges and hurdles that need to be overcome in order to achieve the optimal and ideal therapy for different types of colon cancer. In spite of the considerable research efforts, only a few formulations of nanoparticles have been approved and are available for cancer treatment. Furthermore, new approaches for particle stabilization and targeting are needed.

Acknowledgment This work was supported by the Department of Science and Technology (DST, New Delhi), India (Grant Number: For Priya Shrivastava DST/INSPIRE Fellowship/2017/IF170447, dated 01/16/2018), the Council of Scientific and Industrial Research (CSIR, New Delhi), India, and the Indian Council of Medical Research (ICMR, New Delhi), India (Grant Number: for Laxmikant Gautam 45/16/2018-Nan/BMS, dated: 05/11/2018).

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Conflict of interest The authors declare no competing financial/personal interest whatsoever.

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C H A P T E R

9 Treating blood cancer with nanotechnology: A paradigm shift Chinmay Thakur1, Pallavi Nayak2, Vijay Mishra2, Mayank Sharma1 and Gaurav K. Saraogi1 1

NMIMS, School of Pharmacy and Technology Management, Shirpur, India School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India

2

9.1 Introduction The Greek physician, Hippocrates (460 BCE
370 BCE), also known as the father of modern medicine, coined the terms “carcinos” for nonulcer forming and “carcinoma” for ulcer forming tumors. Roman physician, Celcus (50 BCE
28 BCE), coined the term “cancer.” And Galen (130 BCE
200 CE) coined the term “oncos,” which refers to swelling that describes tumors. Cancer was first observed in 3000 BCE in Egypt and it was caused by Edwin Smith Papyrus (www.cancer.org). Cancer is believed to occur when the normal cells in the body change and their growth cannot be controlled. Cells are small building blocks. Cancerous cells do not die on their own according to the normal life cycle of cells, rather they grow in number, forming a lump or a mass of cell aggregates known as tumors. Cancers are usually treated by surgery, radiation, and/or chemotherapy (www.cancer.org). Cancers are caused by three factors, namely (1) physical factors in which exposure to UV rays and ionizing radiations occur, (2) chemical factors in which frequent contact with chemicals such as asbestos, aflatoxin, arsenic, and tobacco smoke can cause cancer, and (3) biological factors in which cancer occurs due to infection from viruses, bacteria, or parasites. Risk factors involved in cancer include tobacco, alcohol consumption, an unhealthy diet, and physical inactivity. In cancer, telomerase levels are increased, which helps cancerous cells to maintain integrity and, thus, the normal regulation of apoptosis and cell growth are inhibited. The cancer cells migrate to new sites to form secondary tumors (www.cancer.org). People are unaware about what to watch out for when it comes to blood cancer. Hematological cancer is another name for blood cancer, and it starts in the bone marrow and affects other cells in the blood (www.rgcirc.org). There are various types of blood cancers,

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which include leukemia, Hodgkin lymphoma, multiple myeloma, and nonHodgkin lymphoma. Cancer that originates in blood-forming tissue is known as leukemia. NonHodgkin lymphoma starts in cells that are known as lymphocytes, which are in the lymph nodes or lymphatic tissue. Lymphocytes are white blood cells that fight infections and keep us healthy. The difference between Hodgkin lymphoma and Non-Hodgkin lymphoma can be observed by the physicians based on the presence of large immature Reed
Sternberg cells, These Cells are present in Hodgkin lymphoma, and are rare in Non-Hodgkin lymphoma (www.medge.com/hematology--oncolgy/lymphoma-plasmacelldisorders). A drug is said to be effective and safe if it shows a strong inhibition of the target, a high toxicity toward tumors, and an adequate concentration of the drug at the target site. The insolubility of drugs, the targeting of tumor cells, a lack of bioavailability, and nonspecific toxicity are difficulties in the treatment of cancer. At an early stage, detection can be done by checking blood samples. Cancerous tumor cells, if present in the blood, can be isolated and checked.

9.2 Cancer statistics According to the World Health Organization, bronchial and lung cancers are the highest occurring types of cancer, and leukemia is ninth highest occurring type of cancer in India and the sixth in the United States, even the number of leukemia cases is less than that of India. This proves that the occurrence of leukemia is higher in India than in the United States. In 2017, 347,583 people died due to leukemia (www.who.int, https://ourworldindata.org/cancer; www.cancerresearchuk.org). In 2017, 1.31% of the world’s population were affected by cancer, out of which, 0.31% were from India, 5.42% from the United States, and 3.04% from Australia. About 1,688,780 cases were new, and it is estimated that in the next 20 years, the occurrence of cancer will increase by 70% (Siegel et al., 2017). As per a 2018 estimation, 9.6 million deaths have occurred, and it is expected that deaths due to cancer will increase by 62% by 2040. Figs. 9.1 and 9.2 respectively show the different cancer-associated deaths worldwide and the cancer deaths by age.

9.3 Blood cancer Cancer cells are cells that escape the normal cell life cycle. Cancer cells form different types of cells, and these cells form groups of many cells, which form tumors. Cancer represents over 200 different diseases. Lung, colon, breast, and prostate cancers are the most common types of cancers. Cancers are difficult to treat as there is a variety of cells in the same individual. Normal blood cells are of three types, namely (1) cells that help the body to fight infection and diseases, which are known as white blood cells, (2) cells that help in carrying oxygen from the lungs to the tissues in the body and carbon dioxide (CO2) from the tissues to the lungs, which are known as red blood cells, and (3) platelet cells, which help in controlling bleeding and in the formation of clots. Blood also consists of a liquid called plasma. These cells are formed in the bone marrow, which is the center of bones.

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FIGURE 9.1 Different cancer-associated deaths worldwide.

FIGURE 9.2 Cancer deaths by age.

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The bone marrow is active in the hips, ribs, spines, and skulls of adults. Its contains hematopoietic stem, which are immature cells that can be differentiate and mature into red blood cells and white blood cells.

9.4 Types of blood cancer There are several types of blood cancer, including: Leukemia: Leukemia is a phenomenon of abnormal cell growth usually involving white blood cells that are immature and abnormal as compared to regular white blood cells and that are not able to perform their assigned work. These abnormal white blood cells interfere with the formation of blood cells such as Red blood cells (RBC) and platelets. Lymphoid and myeloid cells are abnormal white blood cells. When cancer occurs due to the presence of lymphoid cells, it is known as lymphoblastic or lymphocytic cell leukemia, and when cancer occurs due to the presence of myeloid cells, it is known as myeloid or myelogenous leukemia. Acute leukemia has a rapid growth rate as it involves immature cells that have a tendency to get worse if they are not treated at an early stage in the right way. On the other hand, chronic leukemia is formed by mature young blood cells that have a slower growth rate, and it takes time to grow to worse conditions. Acute lymphoblastic leukemia is the main type of leukemia, and it occurs mostly in children, whereas acute myeloid leukemia (AML) occurs mostly in adults. In older adults chronic lymphocytic leukemia is seen and chronic myelogenous leukemia (CML) is also common in adults. Leukemia is different from other cancers as it grows in the bone marrow, which is a thick spongy liquid in the bone. As leukemia cells are formed in the bones, they can travel all over the body to any organ, thus, the problems caused by leukemia can be found anywhere in the body. Hodgkin and nonHodgkin lymphoma: NonHodgkin lymphoma in which lymphocytes are the cause occurs in the lymphatic system. In Hodgkin lymphoma, Reed
Sternberg cells, which are abnormal lymphocytes, are present and cause this type of cancer. Multiple myeloma: Multiple myeloma, which occurs due to abnormal plasma cells, is formed in the bone marrow (www.lls.org/treatment/types-of-treatment/clinical-trials).

9.5 Pathophysiology of blood cancer During pathophysiology, patients undergo certain conditions, which are: Anemia: This includes feeling tired, shortness of breath, dizziness, pale skin, chest pain, and hypercalcemia. Poor clotting: Patients experience unusual bruising, bleeding gums and red dots, and red and black bowel movements. Illness: This includes sickness, night sweats, lumps in the neck and armpits, weight loss, joint pain, and chest pain as well as issues related to the bones in which plasma cells secrete proteins that harm other organs of the body, pain in the bones, and nerve damage due to proteins, which may cause pain, weakness, and numbness in the legs and arms.

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Blood cancer is caused due to several conditions and factors such as: Age: AML occurs in elderly people and ALL occurs in children. Radiation: Patients suffering from some other type cancer who go for treatment, if exposed to radiation therapy, are at risk of developing blood cancer. Chemotherapy: The use of chemicals such as platinum agents, alkylating agents, and topoisomerase 2 inhibitors in chemotherapy increase the likelihood of a patient developing blood cancer. Family history and genes: Genetic inheritance causes vulnerability to cancer. Patients with Down syndrome and Bloom syndrome patients are also vulnerable to blood cancer. Exposure to chemicals: This can lead to blood cancer. People working with benzene, blood cancer treatment, in the glue industry, etc., are susceptible to blood cancer. Diseased conditions in which patients have immunodeficiency diseases and HIV positive patients are more prone to developing blood cancer.

9.6 Therapies for blood cancer Blood cancer therapies act on cancerous as well as healthy cells and, thus, damage the healthy cells surrounding the cancerous cells present in the body. Conventional therapies cause a lot of side effects such as fatigue, headaches, mouth sores, muscle pain, diarrhea, vomiting, nausea, constipation, nervous system effects, and blood disorders. Chemobrain occurs after chemotherapy, which leads to changes in thinking and memory. Long term side effects such as damage to the heart, lungs, liver, kidneys, and reproductive systems also occur. These therapies normally takes longer time span for the complete cure of blood cancer. The similar effect may also occur in adults and children and may cause immediate or delayed effects (www.cancer.net/navigatingcancer-care/how-cancer-treated/radiation-therapy/side-effects-radiation-therapy). Changes occur at a fast rate in the treatment of cancer. Personalized medicines are important in the treatment of cancer. They help doctors to treat cancer in a specific way for each patient.

9.6.1 Gene therapy Selecting the appropriate treatment for personalized medicines can be done through the gene determination of that particular person. An advancement is targeted treatments in which the genes, proteins, and blood vessels are the main targets because these are the places that are mainly responsible for cell growth. These therapies are different to others, which have comparatively more side effects in treating cancer. Some examples include trastuzumab in the treatment of blood cancer, afatinib and cetuximab in the treatment colorectal and lung cancers, and dabrafenib in the treatment of melanomas.

9.6.2 Chemotherapy Chemotherapy includes the administration of drug molecules for the treatment of cancer. Combination therapies are included, in which two drugs that are stable and act in a synergistic

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way are administered. Some drugs that cannot be administered orally are injected into the cerebrospinal fluid, and this process of injection is known as intrathecal chemotherapy. Drugs such as antimetabolites are used, which help in tumor cell attachment, and because of which, the cancerous cells can’t produce normal DNA or RNA and, thus, the cell death of cancerous cells occurs. Antimitotic agents block the dividing and multiplying of cells, which is known as mitosis. Antitumor drugs bind to DNA molecules to prevent the cells from duplicating or to inhibit the synthesis of RNA, thus, preventing cell division. Asparagine-specific enzymes slow down the breaking of bone, and help in increasing bone thickness, thus, reducing bone pain and the risk of fracture. Alkylating agents react to change DNA chemically, thus, preventing the cell growth of cancerous cells. Other drugs such as bisphosphonates, DNA-repair enzyme inhibitors, histone deacetylase inhibitors, hypomethylating agents, immunomodulators, monoclonal antibodies, and tyrosine kinase inhibitors are used as drugs in chemotherapy. In chemotherapy, combinations are given, and this represents a leading type of treatment. Robot-assisted surgeries involve the surgical removal of cancerous cells through the help of robotic arms, which are controlled by a doctor with a console; these are used as they are precise and able to reach to the most inaccessible areas and, thus, reduce blood loss (www.cancer.net/). In Hodgkin disease, advanced imaging targeting is used, but it has several side effects. Usually a stem cell transplant is used for the treatment of nonHodgkin disease, but high-dose chemotherapy is given before the stem cell transplant.

9.6.3 Immunotherapy In immunotherapy, the body’s own defense mechanism is used in the treatment of cancer. The defense mechanisms of monoclonal antibodies, which are proteins, help in the detection of cancerous cells. They work by attaching to antigens, which results in informing other cells to attack the different cancerous cells. Checkpoint inhibitors are also a part of immunotherapy, which find hiding cancerous cells. Immune checkpoint inhibitors are used in Hodgkin lymphoma when there is an over production of programmed deathligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Immune checkpoint inhibitors block PD-L1 and this assures treatment where primary treatments don’t give any positive results. Vaccines are used for both preventive and treatment purposes and respectively aim to prevent cancer and strengthen the immune system to fight cancer. Cytokines are proteins that are responsible for the growth and activity of immune cells; examples include interferon and interleukins. Therapy that uses T cells to defend from the body from viruses is known as chimeric antigen receptor (CAR) T-cell therapy. In this type of therapy, vaccines are administered.

9.6.4 Radiation therapy High energy X-rays are used in radiation therapy. These rays are used to kill or shrink cancerous cells. Radiation is used in early-stage tumors in which newer forms are introduced such as intensity-modulated radiotherapy in which the affected area is exposed to the highest possible dose, thus, causing the least damage. In image-guided radiation therapy, magnetic Resonance Imaging (MRI) is used to focus a laser onto the affected area.

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Stereotactic radiosurgery is usually used in the brain and spine as it is delivered at a high dose to a small area. In proton therapy, positively charged energy is focused onto a small area as an intense burst. In multiple myeloma, radiation is used when chemotherapy is not helpful. It is used for the treatment of painful bone damage.

9.6.5 Advancements in blood cancer treatment In the treatment of blood cancer, new advancements have been achieved, including CAR T-cell therapy, in which a 15-month follow up is required. CD19 cells are used to target the chimeric antigen receptor. large B-cell lymphoma (ZUMA-1) were also used for CAR T-cell therapy, in which 82% of patients showed a considerable recovery, whereas 54% were completely cured of the disease. Leukapheresis is a laboratory process used for the separation of T cells from white blood cells, which are than re-engineered with CAR T cells which help the T cells to attack cancerous T cells. Combination targeted therapy yields a good response in AML patients. A complete response was seen in 50% of the patients. Drugs known as monoclonal antibodies and drugs used in stem cell therapy were developed to attack CD20 antigen, which is responsible for the growth of cancerous cells in lymphoma. In leukemia, FLT3 is a gene that is responsible for gene mutation, thus, drugs have been synthesized that inhibit the FLT3 gene. In myeloma, daratumumab, elotuzumab, and ixazomib are used to activate the immune system of the body, which attacks the multiple myeloma cells, thus, inhibiting their growth. This delays the duration of the symptoms in the patients and thus, improve the quality of life. A bone marrow transplant is done after severe chemotherapy in which bone marrow from a sibling of the patient is taken, but not from an identical twin. The survival rate is better if there is a slight difference in bone marrow. Bispecific antibodies work by attaching to T cells and tumor cells at the same time. This method of treatment is commonly used for ALL (www.cancer.net).

9.7 Nanotechnology in treatment of cancer Nanoparticles, if smaller than 50 nm, can enter cells, and if smaller than 20 nm, can move inside the body through the blood. Nanodevices are used in sparing healthy cells and targeting cancerous cells (Fig. 9.1). Thus it can be said that the targeting ability of drugs is effective in the treatment of cancer. The use of nanoparticles can cause the apoptosis of cancerous cells and control the growth of metastatic tumors (Hood et al., 2002) (Fig. 9.3). Nanomedicines help to increase the effectiveness of treatment by carrying multiple therapeutic agents (Wang et al., 2017). The effects of drugs can be visualized through the use of theranostics (Ahmed, Fessi, & Elaissari, 2012). Many insoluble drugs are formulated into crystalline nanosuspensions with the help of surfactants or by combining them with a lipid to increase their solubility (Rabinow, 2004). The targeting ability of drugs and the ability to maintain their concentration at a target site increases their effectiveness and decreases their toxicity. Current treatment therapies are limited to surgery, radiation, and chemotherapy; these treatments damage normal tissues and there is no assurance of the full irradiation of

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FIGURE 9.3 Nanotechnology in the treatment of blood cancer.

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cancerous cells. Cancerous cells and neoplasms are targeted in certain therapies including in the use of nanotechnology, which helps in guiding the surgical approaches of cancer treatment, and enhancing the therapeutic efficacy of radiation. The use of nanotechnologies and nanomedicines helps in decreasing the risk of patients and, thus, increases the probability of survival of patients. Nowadays, new therapeutics have been developed via the use of nanotechnology which can be beneficial in efficient targeting of the cancer and also minimizing the side effects of chemotherapy (www.cancer.gov). Even the word “nanomedicines” gives the idea of small particles, but they are large enough to encapsulate many smaller molecules. Smaller particles give the advantage of having a large surface area; this large surface area can be used to bond with ligands, small molecules, DNA and RNA strands, peptides, and aptamers. This binding gives the advantages of combination drug delivery and combined treatment and diagnostics, which is also known as a “theranostic” action. The energy absorbed and reradiated is used to disrupt diseased tissue. Some of the treatment strategies which follows nanotechnology based approaches are able to improve the pharmacokinetics, reduction in toxicity and selective targeting of drugs to the cancer cells. The advantages that nanotechnology give in chemotherapy include the encapsulation and conjugation of drugs, passive targeting, and site and passive targeting controlled by ultrasound, pH, and heat, thus, decreasing the risk and increasing the effectiveness. Paclitaxel and gemcitabine in mesoporous silica are used to form nanomedicines. Another example is nano-enabled immunotherapy, which has helped experts to think about alternatives to checkpoint inhibition and cellular therapies. This technology is reproducible and shows positive results. In this therapy, the identification of the type of cancer is done by molecular and functional analyses of single tumor cells. Nano-enabled devices are used in the identification and image characterization of T cells, so as to use them in synergy with nanomedicines. Nanomedicines make depots near cancer cells, thus, harming cancer cells. In radiation therapy most of the cancer patients gets treated with high radiation source to shrink the cancerous cells by damaging DNA. The photoelectric effects of radiation therapy can be enhanced by using nanotechnology based approaches. This therapy includes electromagnetic radiation for superficial tumors, which works by photosensitizing the cells and, thus, the activation of reactive oxygen species takes place. Lanthanides or hafnium are injected, which are high-molecular weight atoms that are irradiated externally, and, thus, these atoms emit visible light photons and singlet oxygen forms, leading to the destruction of cancerous cells. Delivering gene therapy is also a kind of new therapy advancement in blood cancer in which therapeutics, including DNA and siRNA, are used to treat undruggable cancer proteins. The half-lives get increased when nanoencapsulation or conjugation is done. The stability is also increased for controlled-release dosage forms. The leaky nature of tumor cells, which possess pores of 100
1000 nm in diameter, can be exploited by a nanoscale drug delivery system. Various methods for the preparation of nanoparticles are used such as bioaggregation (Mirkin, Letsinger, Mucic, & Storhoff, 1996), nanomanipulation (Hansma, Kasuya, & Oroudjev, 2004), imprinting (Cui, 2003), layer by layer electrostatic deposition (Ai, 2002), vapor deposition, and photochemical patterning (Cui, 2003).

9.7.1 Nanoparticles Nanoparticles have sizes ranging between 1 and 100 nm (Wicki, Witzigmann, Balasubramanian, & Huwyler, 2015). Nanoparticles accumulate in the leaky vasculature and,

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thus, their uptake takes place, which is known as the enhanced permeability and retention effect (EPR) (Albanese, Tang, & Chan, 2012). Some nanocarriers that are used for the treatment of cancer are lipid-based nanocarriers such as liposome and stealth liposome and solid lipid nanoparticles. Polymer-based nanoparticles include micelles, albumin-bound technology with nanoparticles, and polymeric nanoparticles. Conjugates based on polymer
protein, antibody
drug, and polymer
drug nanoparticles are also used as well as inorganic nanoparticles such as silica, metal, and hafnium oxide. Viral nanoparticles are also a type of nanoparticles (Wicki et al., 2015).

9.7.2 Drug
protein conjugation In protein
drug conjugates, the protein and drug are directly conjugated by a biodegradable linkage. Due to the presence of the biodegradable linkage, the drug can be released before reaching the target site, which affects the concentration of the drug at the site. This linkage is degraded by enzymes such as proteases or redox altering agents present in the body, which decreases the drug circulation time in the body. Nowadays, newer linkers that are stable have been introduced, which increase the precision of drug delivery at the target site and the circulation time while reducing the toxicity. Antibodies are also used in this type of conjugation to increase the drug targeting ability (Alley, Okeley, & Senter, 2010). This conjugation has certain drawbacks as some drugs are sensitive to proteins.

9.7.3 Liposomes Spherical lipid bilayer systems are called liposomes. Their formulation takes place by the addition of a lipid bilayer into water or other hydrophilic solvents. The size of liposomes is controlled between 50 and 500 nm by the use of techniques such as sonication, reverse-phase evaporation, extrusion, and solvent injection. This method helps in the encapsulation of hydrophilic drug molecules (Sun et al., 2014). These liposomal encapsulates are sensitive to heat, ultrasound microwaves, and radio frequencies (Frenkel, 2008). These can be easily modified on the basis of target site by changing the polymers used in formulating these liposomes (Sun et al., 2014). Liposomes are used nowadays as drug carriers (Torchilin, 2005) as well as in tumor targeting. Some antibodies are also used in targeting as they bind to the antigens of tumor cells. Aptamers are used if antibodies are not present, which act as ligands made up of nucleic acids and work as antibodies. Monoclonal antibodies are used as imaging vehicles as well as for drug targeting and sometimes as carriers (Brongersma, 2003; Crooke, 2004; Fuchs, Damm-Welk, & Borkhardt, 2004). In 2012, vincristine liposome (Marqibo) of 100 nm in size was used to cure lymphoblastic leukemia.

9.7.4 Polymeric nanoparticles Polymeric nanoparticles are made by assembling polymers that are used to deliver chemotherapeutic, diagnostic, and imaging agents in cancer treatment. As polymers are

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easily modified in terms of hydrophobicity, biodegradability can be achieved. They are prepared by nanoprecipitation, the electrospray technique, and emulsification. These are made up of dense matrices that have a known type of degradation, thus, the estimation of drug release can be easily performed and the manipulation to release the drug can also be done (Sun et al., 2014). The only associated limitations are in size, shape, and the fact that various sizes are formed. Replication is done to create particles of uniform size in which the rate and the pathway of the uptake of the drug can be tailored (Xu et al., 2013). For the delivery of proteins and genes, vaccines and drugs made of polymers such as polylactic acid, polyglycolic acid, or a copolymer are used (Katare, Panda, Lalwani, Haque, & Ali, 2003; Nugent, Wan, & Scott, 1998; Panyam et al., 2003).

9.7.5 Dendrimeric nanoparticles Dendrimers are highly branched macromolecules, the size and shape of which can be controlled for the targeting and treating of cancerous cells (Namazi & Adeli, 2004; Pricl, Fermeglia, Ferrone, & Asquini, 2003). The biggest advantages are flexibility, density, and water solubility, which can be specified (Sun et al., 2014).

9.7.6 Quantum dots To enhance the efficacy of antitumoral drugs, quantum dots are used as nanocarriers. Novel studies have developed a natural antiproliferative active flavonoid that acts against several cancers with cadmium telluride quantum dots (4 nm in diameter) used in conjugation with wogonin to cause the apoptosis of cancerous tumor cells. Nanocomposites overcome multidrug resistant leukemia by interacting with the abnormal cells and wogonin.

9.7.7 Carbon nanotubes These are used in binding, and are taken up by the method of endocytosis. The carbon nanotube are formulated as nano-suspensions in which single walled forms a stable suspension as compared to multi walled carbon nanotubes. They get attached with disulfide bond and release of drug takes place when the carbon nanotubes (CNT) are exposed to enzymes. The photochemical damage of tumor cells takes places by the use of CNTs (Son, Hong, & Lee, 2016). They can be used also in the imaging of tumors using the Raman signature technique (Rao et al., 1997).

9.7.8 Metal nanoparticles Metal-based polymers are hollow metal nanoshells. These thin metal shells are coated around silica particles. Metals such as gold, silver, platinum, and palladium are commonly used (Sun, Mayers, & Xia, 2002). There are various studies that involve the strength of metal nanoparticles to increase the effect of newly developed cancer therapies. Metal nanoparticles show biocompatibility, low toxicity, and biodegradability. Metal nanoparticles that engage a magnetic field at tumor sites are used. To tackle the multidrug resistant

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selectively of leukemia cells, metal nanoparticles in the range of 12
23 nm are used in combination with wogonin.

9.7.9 Silver nanoparticles Silver nanoparticles form oxygen species by reacting in acidic environments. The release of oxygen species leads to damage of cellular materials and, thus, cell apoptosis occurs. These nanoparticles have biocompatible shells in which the outer layer breaks and drug molecules can be exposed, which are conjugated with the shells.

9.7.10 Gold nanoparticles Inorganic, metallic gold nanoparticles are used for detection and therapy. The detection is due to strong optical absorbance from gold particles and photo thermal effect from them is used for cancer therapy. Drug and gold are conjugated to form gold drug conjugates. Due to the presence of metals, the thermoresponsive polymers shrink in heat and causes the release of the drug in the vicinity of the cancer site.

9.7.11 Mesoporous silica nanoparticles Silica Nanoparticles have porous structure which can be tuned to modify the drug release in response to pH, light, temperature, redox reaction, enzymes, biomolecules that can be beneficial in cancer therapeutics. Doxorubin has been linked with H-sensitive mesoporous silica nanoparticles (MSNs), which are useful for controlled release even at low physiological pH. MSNs are also formulated as suspensions having porous hollow silica nanoparticles containing calcium carbonate. Sodium silicate is also used; the suspension formed is then dried. The size and shape of the pores can be controlled and the approach used is zero order (Chen, Ding, Wang, & Shao, 2004; Jain, Roy, De, & Maitra, 1998; Li, Wen, Shao, & Chen, 2004; Weis, Montchamp, Coffer, Attiah, & Desai, 2002).

9.7.12 Properties of nanocarriers The physicochemical properties of nanocarriers such as size, shape, and surface can be modified. Particle size is used to improve the distribution throughout the bloodstream and its delivery to specific sites. Particle shape is used to determine the fluid impact dynamics which improves the uptake of carriers in cancer cells. The surface charge of nanoparticles is most effective when it is positively charged or neutral particles are used for quicker diffusion (Stylianopoulos et al., 2010). The surface charge can be modified with ligands, thus, prolonging the circulation of nanoparticles in the blood and improving the cellular uptake as well as the solubility, degradation, and clearance of drugs. Drugs with lesser solubility get eliminated fast without reaching the tumor cells, therefore, hydrophilic nanoparticles are encapsulated to increase their solubility, thus, increasing the bioavailability and effectiveness of the drug (Wicki et al., 2015). Reticuloendothelial system (RES) is used to detect

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hydrophobic materials that are taken up and eliminated by the liver and spleen so carriers when coated with PEG increases the hydrophilicity of carriers thereby increasing the circulation time (Bregoli et al., 2016). Opsonin is a protein secreted by macrophages of RES and they engulf the hydrophobic carrier which leads to decrease in ability of the drug to reach to tumor cells. Target specificity is achieved when ligands are added to the surface of nanoparticles.

9.8 Challenges and remedies in the treatment of leukemia 9.8.1 Challenges Formulations of nanoparticles simplifies the detection of biomarkers and sensitive assays. Nanomedicines play an important role by improving the efficacy and decreasing the toxicity of anticancer drugs, and even prove the possibility of monitoring the treatment along with the diagnosis of liquid tumors. The success of nanomedicines is totally dependent on the availability of tumor models, which mimic the tumor environment of real human patients. Various leukemia/lymphoma models were currently utilized but possess several limitation. In most cases, the parthenogenesis in murine is not related to humans by failing to replicate complex environment in cancer which makes it difficult to diagnose.

9.8.2 Biological barriers The main hurdle in the treatment of blood cancer is the blood
brain barrier (BBB). The BBB is the strongest barrier in the human body because of the presence of tight impermeable junctions of the endothelial cells and basal lamina. Thus the main difficulty in the treatment of blood cancer is the BBB. To overcome this barrier and provide drugs for the treatment of blood cancer, various techniques have been developed. Techniques such as injection into intraventricular or intracerebral areas, implantation, and infusion are used, but the toxicity risks are enhanced and the drug dispersions can be nonuniform (von Roemeling, Jiang, Chan, Weissman, & Kim, 2017). Attaching apolipoproteins also enhances the penetration of drugs through the BBB. Surfactants such as poloxamer 188 and polysorbate 80 are used to increased the penetration of drugs (Kreuter, 2013). As the BBB is most important, the degradation of the BBB is not good, thus, nanoparticles containing copper, silver, or aluminum should be avoided to prevent the risk of neurotoxicity (ShankerSharma & Sharma, 2012).

9.8.3 Reticuloendothelial system The RES is also known as the mononuclear phagocyte system. This system consists of cellular and noncellular components. The release of the cytokines takes place when nanoparticles bind to phagocytic cells, leading to the increased clearance of particles from the bloodstream (von Roemeling et al., 2017). The surface of the nanoparticles can be modified by using hydrophilic moieties which helps them to get escaped from RES uptake thus increasing time in bloodstream and prevents unnecessary exposure to normal tissues. Examples of modifications include the addition of zwitterionic ligands such as cysteine

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and glutathione (Garcia et al., 2014). PEG can also be linked to nanoparticles. The blood circulation time of nanoparticle can, thus, be increased by coating the membranes with leukocytes or erythrocyte derivatives.

9.8.4 Renal system The renal system has the main function of filtering the circulating blood. For filtration, the blood moves through the glomerular basement membrane and, thus, nanoparticles in the blood pass through this membrane. Factors that affect the clearance of particles include size, charge, and shape. Particles less than 6 nm show renal clearance (Cho, Wang, Nie, Chen, & Shin, 2008). The basement through which the filtration takes place is negatively charged and, hence, cationic particles are easily cleared (Liu, Yu, Zhou, & Zheng, 2013). A patient’s renal deficiencies should be considered as the circulation of optimum sized particles should take place along with their elimination to prevent the side effects caused by an increased circulation time of nanoparticles in the blood (von Roemeling et al., 2017).

9.8.5 Remedies Hematological cancers have many challenges due to the poor selectivity of conventional chemotherapy, which has a low therapeutic efficacy and many adverse effects. These effects may be reduced by innovative approaches involving nanoparticles. Nanotechnology has advanced so much that it helps in the treatment of leukemia and lymphoma by assisting biomarkers to get detected and also in targeted treatment. Liquid biopsy can be used to predict the patients tumor profile which thereby helps in decided correct therapeutic regimen. To reach the site of action, solid tumors require nanoparticles and liquid tumors are spread throughout the bloodstream. The most difficult part about liquid tumor is to get them detected because they are in continuous circulation in blood stream when compared with localized solid tumor. Tumors that are liquid in nature need different strategies for detection and treatment. Targeting takes place in three major steps, namely passive, active, and stimulated. In passive targeting, the EPR accumulates particles passively in the leaky blood vasculature of tumors. In active targeting, ligands that are target specific are used (Cho et al., 2008). The conjugation of the ligand reduces the nonspecific uptake of the carriers. Ligands such as transferrin, folic acid, enzymes, and engineered antibodies are used. RES uptake is based on the density of nanoparticles, hence, modifications in density can be used to avoid their uptake by the RES and interactions with proteins, which will prolong the blood circulation time (Wicki et al., 2015). Stimulative targeting is classified into two types based on internal and external factors. Internal factors such as pH, redox, ionic strength, and stress in the target cells stimulate the release of the drug. Sodium alginate
coated iron oxide particles showed a drug release profile that is pH responsive. Cellular apoptosis increases when disulfide bonds containing nanoparticles carry out redox reactions, which oxidize the glutathione present in tumor cells (Cho et al., 2008; Yang, Duan, Zhang, Wang, & Yu, 2016). External parameters include light, temperature, ultrasound, electric force, and magnetic force. Temperatures of 37 C to 42 C increase the delivery of nanoparticles as the

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permeability of blood vessels is increased (Chen et al., 2012). Near infrared is used to increase the penetration into the body. The release of contrast agents is used to diagnose cancer (Rapoport, Gao, & Kennedy, 2007). Electric fields and magnetic fields are used to aggregate nanoparticles at specific sites (Guduru et al., 2013). Earlier treatments for cancer management were mostly time consuming and complex. In traditional treatment, collection of a large data from the patients were done and identification profile of the patients were taken for analyzing the biomarkers which are used for chemotherapy protocols standardization.

9.9 Diagnosis of blood cancer Blood cancer diagnosis is morphological, clinical, and immune phenotypic, which is done by molecular characterization. Treatment totally depends upon the type of leukemia, stage of disease, treatment history, age of the patient, overall condition of the patient, and genetics. Therapies such as radiotherapy, chemotherapy, stem cell transplantation, and targeted therapy can be used in treatment. The advancement of cytogenetic and molecular methodologies has greater benefit in hematological disease. CML is being one of the good example. There are several methods used for the detection of leukemia and lymphoma, including antibody microarray flow cytometry using fluorescent markers, morphological analysis, immunohistochemistry, in situ hybridization, and DNA sequencing. The limited detection of immature white blood cells is a major issue in lymphoid and myeloid neoplasm diagnosis as they are severely depleted at the initial phases of disease. The effectiveness of the treatment depends on the sensitive diagnosis and accuracy in the treatment. For the early detection of cancer, nanoparticles are coupled with signal amplification. In biopsies, molecular management and diagnosis are performed, allowing for the genetic and histological characterization of tumors, which is an important tool to characterize and to correlate the protocol of therapy for the prediction of therapeutic response. In solid tumors, biopsies are done by the evaluation of the neoplasm. The dynamics of tumor is performed at specific time intervals it neither represent the whole cancer nor it assess the variations in the genetic mutation patterns. Performing multiple biopsies on a single patient is costly, difficult, risky, and uncomfortable for the patient. Liquid biopsies involve circulating tumor cells, nucleic acid, and exosomes for solid and liquid tumors.

9.9.1 Current theranostic approach Theranostics is a concept that combines the terms therapy and diagnostics. It is a relatively newer concept that is a step toward the personalization of medicines. These delivery systems are potent for the simultaneous and real-time detection of drug delivery. They can be used for monitoring drug response, diagnosis, and also for drug delivery (www.nanowerk.com). Nanocarriers play an important role in personalized treatment of cancer by efficiently detecting the cancer biomarkers. Nanoparticles have versatile structures and functional properties as well as the potential for the specific, sensitive, and rapid diagnosis of cancer.

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They are an effective means in cancer therapeutics as the size range of nanocarriers helps them to cross biological barriers more efficiently, thereby enhancing the function of nanoparticle. Moreover surface ligand attachment provides specific targeting to the tumors. They can also play an important role in therapeutic imaging as agents on their own or as carriers of multiple molecules having specific surface functions for the targeting of tumors, the ablation of cancerous cells, and the simultaneous real-time diagnosis of cancer cells due to their size increase. They are important for theranostics. For solid tumors, mostly nanoparticlebased strategies are used, whereas other cancers such as leukemia, which is a nonsolid tumor, can also be detected by this method of theranostics. In the blood, tumor cells freely circulate, which requires active targeting and should be highly specific. However, there are some tumors that are present in lymphoid tissues and in the bone marrow that are detectable by nanoparticles due to the EPR effect. Some preclinical studies have been done on lymphoma using nanotheranostic techniques with metal nanoparticles, nanoantibodies, and diatomite nanoparticles. For example, nanotheranostics was performed using nanoantibodies or rituximab conjugated to albumin-bound paclitaxel nanoparticles (Vinhas, Mendes, Fernandes, & Baptista, 2017) and the imaging burden of tumors was reduced when abraxane (ABX) was linked with Alexa Fluor 750. By combining the two antibodies at the nanoscale, the therapeutic efficacy was increased as compared to the efficacy of the two antibodies, rituximab and ABX, given individually.

9.9.2 Recent and ongoing clinical trials Nucleic acid nanoconstructs were made by the Northwestern University for the treatment of cancer at the Cancer Centre of the Northwestern University. In cancer clinical trials, cancer patients were studied carefully in a research study by doctors to improve the care and treatment of patients. This is done when newer therapies are more effective than the existing standard therapies and also when newer therapies have fewer side effects. It is done to increase the treatment options, the survival rate of patients, and the quality of life of patients. The second trail is providing insight to the genetics of leukemia, the customization of treatment is necessary as chromosomal and genetic abnormalities make it more challenging. Patients with AML show DNMT3A gene mutation, thus, they respond better to high doses of anthracyclines, while patients with RVNX1 gene mutation show greater positive results with stem cell transplants. There are new drugs and treatment regimens for the treatment of blood cancer in which the newer doses and schedules modify traditional therapies; examples are given here. Targeted therapies include FLT3 inhibitors as the mutation in the FLT3 gene increases the division rate of AML cells; examples include drugs such as sorafenib, quizartinib, and crenolanib. BCL-2 inhibitors are used as the BCL-2 gene causes the programmed cell death of normal cells. Venetoclax and low doses of cytarabine are used, which act by binding to leukemia cells, leading to the apoptosis of cells. Isocitrate Dehydrogenase genes inhibitors (IDH1 and IDH2) such as enasidenib which causes mutation in cancerous cells and, thus, the cancrous cells remain immature. Serine/threonine-protein kinase inhibitors (PLK inhibitors) such as volasertib act by inhibiting the PLK1 enzyme, which is responsible for cell

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division, resulting in cell death. Histone deacetylase inhibitors are substances that cause chemical changes in cells and, thus, cause cell death; drugs such as vorinostat are histone deacetylase inhibitors. The recent ongoing trials are related to immunotherapy in which the drugs either boosts or suppresses the immune system of the patients. Monoclonal antibodies, vaccines, and CAR T-cell therapy are types of immunotherapies. The therapy of cancer can be done using nanoparticles as they can be used as hyperthermic agents that destroy cells or as injectors that can be directly injected into cells and then activated by heat or a magnetic field, which will cause cell death. X-rays and light can also be used to activate these nanoparticles. For example, gold nanorods are excited by infrared light in tumor cells. (www.nanowerk.com/nanotechnology_to_fight_and_cure_cancer.php).

9.10 Regulation aspects of nanotechnology-based tools Continuous development has taken place since the inception of nanomedicines, which was introduced 10 years ago. These developments have created sophisticated medicines. Nanotechnology-based medicines are comprised of nanoparticles, liposomes, nanocrystals, nanoemulsions, polymeric
protein conjugates, and nanocomplexes. Nanomedicines are comprised of products that are of biological origin and also of nonbiological origin. However, products of biological origin are under certain rules and regulations fixed by the European Medicines Agency. Health technology assessments are used to assess safety, effectiveness, and cost-effectiveness to generate support for healthcare and to make political medicines. To harmonize and to enhance the entry of new medicines, the European network for Health Technology Assessment (EUnetHTA) was created. EUnetHTA is to define and implement scientific and technical co-operation of HTA in Europe. Changes such as toxicity, solubility, and bioavailability are checked in nanomedicines. No regulations are present as such to develop protocols, characterize, or evaluate nanomedicines. However, in Europe, the EUnetHTA is working in this direction. There is a lack of standardization of manufacturing procedures and controls, which should be levied by recognized regulatory agencies such as the US Food and Drug Administration or the European Medicines Agency.

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C H A P T E R

10 Nanoparticles and skin cancer Vishal Gour, Poornima Agrawal, Vikas Pandey, Indu Lata Kanwar, Tanweer Haider, Rahul Tiwari and Vandana Soni Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India

10.1 Introduction Nanotechnology is a novel technology with great potential in many scientific and technological applications such as drug and gene delivery, as biomarkers, in tissue engineering, and in cosmetics, etc., for diagnosis, treatment, and analytical purposes (Jain, Haider, Kumar, & Jain, 2016; Lee, Kim, Chung, Demirci, & Khademhosseini, 2010; Raj, Jose, Sumod, & Sabitha, 2012; Soni, Kohli, & Jain, 2005; Zhao et al., 2010). Nanocarrier systems are used for the delivery of drugs and therapeutic agents for the treatment of different diseases. There are mainly two types of carrier systems, namely nanoparticulate [nanoparticles (NPs), solid-lipid NPs, etc.] and nanovesicular (liposomes, ethosomes, niosomes, etc.) and their modifications for targeted and modified release drug delivery systems (Jain et al., 2015; Soni et al., 2005; Soni, Kohli, & Jain, 2008). NPs are sub-nanosized particulate dispersions or solid particles with a size range of 10
1000 nm (Mohanraj & Chen, 2006) and that have biomimetic features. These biomimetic properties are increased in combination with a high surface-to-volume ratio and the ability to modify these properties also increases in the use of biomedicine with potential applications in imaging, diagnosis, and treatment (Dianzani et al., 2014). NPs may encapsulate, dissolve, or attach therapeutic agents either in their matrix or on their surface. On the basis of preparation, NPs are classified as nanospheres or nanocapsules. Nanospheres are matrix types in which a drug can be uniformly distributed, whereas nanocapsules represent systems in which a drug is confined within the cavity of the polymeric membrane (Chang, Xiong, Wang, Cheng, & Zhao, 2013; Jain et al., 2016; Mohanraj & Chen, 2006). Various materials are used for the preparation of NPs such as polymers (silk, poly(lactic co-glycolic acid) (PLGA), hydroxymethyl cellulose, etc.) ceramic, metals (silver, gold, zinc, etc.), lipids [solid-lipid NPs (SLNs)], etc. (Moreno-Vega, Gomez-Quintero, Nunez-Anita,

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Acosta-Torres, & Castan˜o, 2012; Pandey, Gajbhiye, & Soni, 2015; Pandey, Haider, Jain, Gupta, & Soni, 2019; Wahab et al., 2013). Nanomedicine has enormous potential to improve the selectivity in targeting neoplastic cells by allowing the preferential delivery of drugs to tumors owing to the enhanced permeability and retention effect (Naves et al., 2017). NPs can also improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase the half-life of drugs by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. NPs are efficient drug delivery systems for the treatment of cancer. They have tremendous potential for enhancing selectivity by targeting cancer cells, allowing drugs to be preferred over tumors through improved permeability and retention (Gajbhiye, Gajbhiye, Siddiqui, Pilla, & Soni, 2017). Additionally, the specific binding of nanocarrier systems to target tumor components as well as the tumor microenvironment enhances the effectiveness of cancer treatment while healthy cells remain unaffected (Jain et al., 2015; Pandey et al., 2015; Yang et al., 2010). Jain et al. prepared polysorbate-coated PLGA NPs loaded with conjugated transferrin
methotrexate to target and deliver drugs to brain tumors (Jain et al., 2015). NPs are used for the treatment of various cancer like brain cancer (Jain et al., 2015; Soni & Jain, 2017; Soni, Kohli, & Jain, 2007), breast cancer (Shenoy & Amiji, 2005), prostate cancer (Panda et al., 2019), colorectal cancer (Yang et al., 2010), pancreatic cancer (Lee et al., 2013), and skin cancer (Ma, Qu, & Zhao, 2015; Zhao et al., 2010), etc. In this chapter, the various NPs and their advances in terms of effective targeting and treatment of skin cancer are discussed. Skin is an outermost superficial defending layer that is known as the largest organ and covers an approximately 1.7
2 m2 area of the body, having a thickness of 1
6 mm. It acts as a boundary or barrier to entry for exogenous substances into the body. Human skin is composed of various layers of different tissues, cells, and appendages, namely, from outside to inside, the epidermis, dermis, and hypodermis, forming the full thickness of the skin. The epidermis is a multilamellar structure divided into the stratum corneum (SC), stratum lucidum, stratum granulosum, stratum spinosum, and stratum germinativum. The SC and lucidum are nonvital layers made up of dead hexagonal cells (corneocytes) and lipids, which constitute an important barrier to entry for exogenous substances into the body, prevent water loss from the body, and also provide protection against harmful radiations (Haque, Rahman, Thurston, Hadgraft, & Lane, 2015). The SC allows the penetration of only lipophilic and small particles (less than 500 Da) (Giannos, 2015). Melanocyte cells of the stratum germinativum or basal layer synthesizes melanin pigment, which is responsible for the skin color of human beings. Melanin blocks the entry of harmful UV radiation into the body (Ito & Wakamatsu, 2003). The epidermis regulates body temperature and pressure with the help of the dermis. The dermis is a 20 to 30-time thicker layer compared to the epidermis and it consists of elastic connective tissues and collagen fibers. It also regulates nutrition and oxygen supply to the epidermis (Haque et al., 2015). The innermost layer of the skin is the hypodermis, which acts as an insulator, protects against shock, and stores energy in the form of fat (Murphree, 2017). Schematic representations of the epidermis and dermis are shown in Fig. 10.1. Skin cancer is mostly found in Caucasian populations or faired-colored persons due to their lack of melanin pigments and a common cause of malignancy in the United States (Wysong et al., 2019). Skin cancer is mainly classified into melanoma and nonmelanoma [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] (Murphy, 2010). Nano Drug Delivery Strategies for the Treatment of Cancers

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FIGURE 10.1 Schematic representation of the epidermis and dermis.

Exposure to UV radiation causes a loss of function of the p53 gene due to mutation. DNA damage is one of the most important factors in the development of skin cancer. Other factors include ionization radiation, biological therapy, human papillomavirus ˇ (HPV), immunosuppression, and organ transplant (Ceovi´ c, Petkovi´c, Mokos, & Kostovi´c, 2018). There are various conventional approaches such as surgery, cryotherapy, radiation, and photodynamic therapy (PDT) as well as modern drug delivery systems like NPs, nanovesicles, nanoemulsions, and nanogels that are used for the treatment of skin cancer (Mota, Rijo, Molpeceres, & Reis, 2017). Surgery like Mohs micrographic surgery and surgical excision are the best choices of treatment in younger patients (Mosterd et al., 2008). Modern drug delivery systems reduce the side effects associated with conventional approaches, that is, inflammation, toxicity, and scars, which cause poor patient compliance. Topical drug delivery systems such as lipid nanocapsules, SLNs, micelles, nanoemulsions, microemulsions, liposomes, transfersomes, cubosomes, ethosomes, virosomes, niosomes, and spongosomes, etc., are used via intercellular, transcellular, and transappendageal routes for drug delivery through the skin (Mota et al., 2017).

10.2 Classification of skin cancer Skin cancer can broadly be divided into two classes, namely nonmelanoma and melanoma. BCC, SCC, adnexal carcinomas, cutaneous sarcomas, and Bowen’s disease are subtypes of nonmelanoma. Nonmelanoma is the cancer of non-melanocyte cells while melanomas are found in melanocyte cells of skin (Mota et al., 2017).

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10.2.1 Nonmelanoma skin cancer Nonmelanoma skin cancer (NMSC) is cancer of the basal cell and squamous cell of the epidermis. It mostly occurs in various parts of the body such as the head, neck, palm, hands, and face due to direct exposure to sunlight. In addition, burns, wounds, and cuts also cause skin cancer (Miller & Weinstock, 1994). In the early stages, NMSC can be 99% curable by surgical excision (Kauvar, Cronin, Roenigk, Hruza, & Bennett, 2015). The rate of mortality is lower in BCC than in SCC, but BCC covers more than 80% of cases and SCC covers only 20% of cases of NMSC. While other types of NMSC only cover less than 1% of cases of skin cancer (Eisemann et al., 2014; Katalinic, Kunze, & Schafer, 2003). BCC is less harmful than SCC due to the fact that it shows slow growth, less destruction to adjacent tissues, and rarely metastasizes (Gandhi & Kampp, 2015). On the basis of histology and growth patterns, BCC can further be divided into various forms like nodular, sclerodermiform, superficial, micronodular, infiltrative, and mixed-form, etc. (Marzuka & Book, 2015).

10.2.2 Malignant melanoma Melanocytes are the melanin-producing cells of the skin responsible for the different colors of human skin that provide protection against harmful UV radiations of sunlight. Melanoma is the most aggressive cancer or tumor among the melanocyte cells (Hussein, 2005). During growth, it shows five different histological phases, namely (1) acquired and congenital nevi without dysplasia, (2) dysplastic nevi, (3) radial-growth phase, (4) verticalgrowth phase, and (5) hard melanoma (metastatic melanoma) (Pacheco, Buzea, & Tron, 2011; Pons & Quintanilla, 2006). Factors responsible for melanoma are exposure to UV radiation, sunburn, immunosuppressant agents, chemical exposure (polychlorinated biphenyl, polycyclic aromatic hydrocarbons, pesticides, and ionizing radiation), and activation of human endogenous retrovirus (Erdmann et al., 2013).

10.3 Pathogenesis of skin cancer There are various factors that are responsible for skin cancer such as chronic exposure to UV radiation, ionization radiation, HPV, the use of immunosuppressants, and biologic ˇ therapy (Ceovi´ c et al., 2018).

10.3.1 Ultraviolet radiation UV radiation is an important risk factor in the development of skin cancer (Rodrigues, 2017). The ozone layer around the Earth protects us from the harmful effect of sunlight by absorbing UV-C radiation; some chemicals like chlorofluorocarbons, which deplete the ozone layer, are dangerous to human health. The UV light from sunlight can be divided into three types, namely UV-A (320
400 nm), UV-B (280
320 nm), and UV-C (200
280 nm) (Pons & Quintanilla, 2006). UV-B is absorbed by the skin and creates many problems related to the skin like sunburn, erythema, and skin cancer. UV-A alone is not a

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carcinogenic, it only enhances the carcinogenicity of UV-B and is less absorbed by human skin as compared to UV-B (Nghiem et al., 2002). UV radiation alters the ability of skin cells to control the cell cycle and cell proliferation through the formation of cyclobutane pyrimidine dimers (CPD) in the DNA, which causes mutation in the cells (Ananthaswamy & Pierceall, 1990). Each cell has its own mechanisms for cell proliferation, cell damage repair, and apoptosis. CPD shows carcinogenic effects by inhibiting the binding of transcription factors and blocking the elongation of transcription in the normal cell cycle (Rochette et al., 2009). Mutation in the p53 gene (tumor suppressor gene) by UV radiation is another cause for skin cancer because it has all the codes for DNA binding proteins, which are required in the tumor suppression process (Madan, Lear, & Szeimies, 2010). In addition to this, mutation of the ras and ptc genes cause skin cancer (Mizuno et al., 2006). The induction of skin cancer is caused by UV rays as shown in Fig. 10.2.

10.3.2 Immunosuppression and organ transplant recipients Immunosuppressant drugs like azathioprine, prednisone, cyclosporine, tacrolimus, and mycophenolate mofetil are prescribed to organ transplant recipients for the prevention of graft

FIGURE 10.2 Induction of skin cancer caused by ultraviolet rays.

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rejection; the relationship between immunosuppressive therapy and skin cancer or other cancers is not clear, but it was found that the incidence of different cancers (nonmelanoma and Kaposi’s sarcoma) is greatly increased in immune-compromised persons (Coghill et al., 2016). Immunocompromised persons are 2
9 times more susceptible to malignant melanoma while 68% for Merkel cell carcinoma as compared to normal persons. It is reported that NMSC causes death in heart transplant patients (Kuijken & Bavinck, 2000).

10.3.3 Human papillomavirus HPVs (family papovaviridae) are small-sized (52
55 nm), circular DNA viruses. They have 8000 nucleotide base pairs and are covered by an icosahedral capsid. HPVs are major risk factors for SCC, cervical cancer, and NMSC patients (Bzhalava, Eklund, & Dillner, 2015). These are classified into three groups, that is, cutaneous HPVs, mucosal HPVs, and epidermodysplasia verruciformis
associated HPVs. β and γ genera of HPVs act as a cofactor for skin cancer with UV radiation and immunosuppressant agents (Corbala´n-Ve´lez, Ruiz-Macia´, Brufau, & Carapeto, 2007). β-papillomaviruses induce skin cancer by interrupting various pathways, namely (1) they block the DNA repair pathway by interrupting the thymidine dimer repair mechanism of XRCC1 protein, (2) they inhibit the action of BAK and BAX proteins, which are required for cell apoptosis, (3) they cause SCC in immune-compromised patients by encoding oncogenic proteins E6 and E7 (E6 degrades tumor suppressor gene p53, and telomerase enzyme causes cell immortality, while E7 inactivates tumor suppressor protein retinoblastoma), and (4) HPV-8 and HPV-5 decrease cell immunity through inhibiting interleukin-8, which stimulates an immune response against damage cell by UV radiations (Bernat-Garcı´a, Sua´rez-Varela, Vilata-Corell, & Marquina-Vila, 2014). Other factors that are also responsible for skin cancer are various chemicals like arsenic and ionizing radiations like X-ray, β-ray, and α-ray, which cause mutation in the p53 or patch gene (Li & Athar, 2016).

10.4 Detection of skin cancer It was found that the number of new cases of nonmelanoma and melanoma have increased in the past few decades. Early-stage detection and diagnosis of skin cancer enhance the patient survival rate, reduce mortality and morbidity, as well as improve the quality of treatment. It is important to know the complete patient history of skin cancer patients such as whether it is due to repeated trauma (ulcers) or to burns, the use of immunosuppressant agents, or exposure of patients to a carcinogenic environment or harmful radiation. Currently, there are various techniques have been improved for diagnosing skin cancer, like visual inspection, histopathologic evaluation, and biopsy (Craythorne & Al-Niami, 2017; Geller et al., 2019). Dermoscopy is a type of visual inspection method where a magnifying glass is used for diagnosis. It is a quick and economical method for evaluating lesions with 90% sensitivity and specificity (Ye´lamos et al., 2018).

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Biopsy is a method of sampling in which less than 2% of tumors or lesions are removed from the body for histological evaluation. There are three types of biopsy techniques used in the case of skin cancer. (1) Shave biopsies are used for actinic keratosis or seborrheic, early SCC, and BCC, in which the epidermis or upper dermis are shaved with the help of a razor blade or scalpel. (2) Punch biopsies (2
4 mm punch) are used for the scalp, inflammatory diseases, and hair follicles. (3) Incisional and excisional biopsy are used for the melanoma or ulcerative condition of skin where deeper specimens are required (Neitzel, 2005). Due to the harmful effects and invasiveness of biopsy, newer, less invasive, and more accurate techniques have been developed for skin cancer for diagnostic purposes. The various diagnostic techniques are shown in Table 10.1.

10.5 Skin cancer treatment modalities 10.5.1 Curettage and electrodesiccation Curettage and electrodesiccation (C&E) involve scrapping away the lesion with a sharp instrument curette down to a firm layer of normal dermis, and then an electric current is applied to denature the area, destroying any other cancer cells and to control bleeding (Yakish, Graham, & Hossler, 2017) This technique is effective for properly selected, lowrisk tumors, and up to three cycles may be performed in a session. Although it is a fast and cost-effective technique for superficial lesions, it does not allow histologic margin assessment. Observational and retrospective studies have reported overall five-year cure rates in patients with BCC who were selected for C&E. It should also be noted that the results are highly operator-dependent, and optimal cure rates are achieved by experienced practitioners (Yang & DiCaudo, 2018). Several precautions must be kept in mind when using this technique. First, this technique is avoided when treating regions such as the beard area, the scalp, the pubic region, and axillary regions due to the risk of inadequate removal of a tumor extending down to follicular structures (Bichakjian et al., 2018). Second, the accuracy of the C&E technique resides in the ability of the clinician to distinguish between firm, soft tumor tissue and normal dermis when the sharp curette is in the hands; if the subcutaneous layer is reached during the course of surgery, surgical excision should be performed for better results. This change in therapy is necessary because subcutaneous adipose is relatively softer than tumor tissue, and here, the ability of the curette to distinguish tumor cells selectively disappears (Alam et al., 2018). Third, if the curettage is used early on the basis of the appearance of a low-risk tumor only, biopsy results of the tissue taken at the time of curettage should be reviewed to make sure that there are no high-risk pathologic features that would require additional therapy (Shelton & Adamson, 2019).

10.5.2 Cryotherapy Cryotherapy is a common technique that is performed using liquid nitrogen, and that is widely accepted as a treatment modality for both BCC and SCC (Sapijaszko et al., 2015).

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TABLE 10.1 Different methods for the detection of skin cancer. S. no

Technique

Principal principle

Use

1

Reflectance confocal microscopy (RCM)

Near-infrared (NIR) rays and Identify malignant melanoma horizontal sections of skin are used and NMSC of face and skin for imaging.

Ahlgrimm-Siess et al. (2018), Jain, Pulijal, Rajadhyaksha, Halpern, and Gonzalez (2018)

2

Optical confocal tomography (OCT)

Nonionizing NIR is used for the 2D imaging of tissue.

For diagnosis of superficial BCC

Halani, Foster, Breslavets, and Shear (2018), Xiong et al. (2018)

3

Highfrequency ultrasound

Ultrasound of high frequency ( . 15 MHz) is used.

Measure the depth of skin cancer Halani et al. (2018) and the level of metastasis

4

Multispectral digital skin lesion analysis (MSDSLA)

Visible, infrared light, and computer algorithms are used.

Determine the probability of lesion malignancy

Fink and Haenssle (2017)

5

Electrical impedance spectroscopy (EIS)

Alteration in electrical impedance of normal and malignant tissues. Different stages of lesions score different values on a 0
10 scale.

0
3 score represents benign

Winkelmann, Farberg, Glazer, and Rigel (2017)

6

Raman spectroscopy

This method is based on the measurement of energy difference of incident photons and inelastically scattered photons. Normal skin molecules scatter photons inelastically, while suspicious tissues scatter elastically.

It constructs a molecular fingerprint of tissue, and is useful in the differentiation between benign and malignant tumors or lesions

Lui, Zhao, McLean, and Zeng (2012), Zhao, Zeng, Kalia, and Lui (2017)

7

Multiphoton tomography

Naturally, fluorescing compounds like flavins, NADPH, keratins, melanin, and porphyrins present in the skin, which show fluorescence in the presence of NIR and are used for the mapping of skin tissues.

Used in the characterization of benign nevi, SCC, BCC, and malignant melanoma

Dimitrow et al. (2009)

4
10 score represents malignant

References

The principle behind the use of cryotherapy in cancer is to have tumors with well-defined borders. Cryosurgery employs subzero temperatures between 250 C and 260 C with freeze times ranging from 40 to 90 s to selectively damage the tissue. This method requires two freeze
thaw cycles inflow. The bigger the lesions, the longer the freeze times reported. With reiterative lesions, the cure rate is reduced as compared to primary lesions (Singh, Stone, Schwartz, & Micali, 2016). Cryotherapy is adapted for its safety, promptness, high cure rate (especially in the elderly), and the fact that it is uncomplicated, quick, and well-tolerated with low cost. Excellent cosmetic outcomes have also paved the way for its greater use. Hypertrophic scarring, edema, and bullous formation with pain are reported as disadvantages of cryosurgery. The healing time after cryosurgery is long because the marked necrosis of healthy

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tissue or ulceration may occur in some patients with diabetes mellitus (Tchanque-Fossuo & Eisen, 2018).

10.5.3 Photodynamic therapy (PDT) PDT involves an exogenous photosensitizing agent, which, upon application, is selectively taken up by malignant or premalignant cells. The introduction of a light source causes the activation of protoporphyrin (photosensitizer), which promotes the formation of reactive oxygen species (ROS) and cytotoxicity in malignant cells (Griffin & Lear, 2016). Various protoporphyrin precursors or prodrugs like methyl aminolevulinate (MAL) and 5-aminolevulinic acid (ALA), when applied topically to cancer or target cells, convert these prodrugs into protoporphyrin IX via the heme synthesis pathway and lead to cell death. PDT improves the cytotoxicity effects when combined with other available treatments like lasers, surgery, radiotherapy, vitamin D, methotrexate, diclofenac, 5-fluorouracil (5-FU), and imiquimod for both BCC and SCC-type nonmelanoma SCCs (de Souza et al., 2016).

10.5.4 Radiation therapy Radiation is a form of ion (electrically charged particle), which, when passed through the cells of tissues deposits as energy. This deposited energy causes different aberrations or mutations resulting in the cell death of neoplastic cells. The amount of high-energy corrugated by these radiations acts as a damaging agent for deoxyribonucleic acid, as a result, it blocks the proliferation of neoplastic cells (Baskar, Lee, Yeo, & Yeoh, 2012). Although, damage to normal cells as well as cancer cells remains the same with radiation. Yet in the context of normal cells, the repairing capacity of normal cells is faster and they retain their normal functions easily, while cancer cells lack this efficiency, which results in differential cancer cell killing. Radiotherapy is adapted where excision is not an option; when cancer is medically/ technically inoperable, this therapy can be applied to major lesions and is used as adjuvant therapy for incompletely resected tumors.

10.5.5 Hedgehog pathway inhibitors Hedgehog (Hh) signaling is a fundamental signal transduction pathway known to play a vital role in embryonic development. There are three types of Hh proteins known to participate in various formative activities in the body. These three proteins are Sonic Hh (Shh), Indian Hh, and Desert Hh proteins (Athar, Tang, Lee, Kopelovich, & Kim, 2006). Shh proteins contribute to the development of stem cell population, hair follicles, and the sebaceous glands of the skin. Abnormal activation of Shh signaling with mutational activation of protooncogenes like Smo or mutational inactivation of the tumor suppressor PTCH (patched proteins) has been reported as a progressive cause of BCC. Smo and PTCH, both being membrane proteins, together mediate the cellular response to Hh. It has been reported that PTCH1 inhibits SMO (Smoothened) signaling, and this inhibition is

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activated by binding of Shh protein with PTCH1 receptor. This binding leads to the uncontrolled activation of SMO and the generation of Gli1, Gli2, and other factors, responsible for BCC development. Vismodegib and sonidegib are USFDA-approved SMO selective inhibitors, recognized for their interference with the Hh pathway, thus, mitigating the pathogenesis of BCC (Wahid et al., 2016). Vismodegib showed clinical benefits in patients considered inappropriate for surgery with advanced BCC (Basset-Seguin et al., 2015).

10.5.6 Nonbiologics Nonbiologics are large synthetic or natural medicinal compounds, fully identifiable with active pharmaceutical properties that are also applied for skin cancer treatment.

10.5.7 Synthetic chemotherapeutic agents 10.5.7.1 Doxorubicin Doxorubicin (DOX) is a tetracyclic compound of the anthracycline family and is known to have an established anticancer activity. It slows down or, in some cases, stops the growth of cancer cells. Its mechanism of being anticancerous works by blocking an enzyme called topoisomerase-2 needed by cancer cells to divide and grow. Commercial availability is found to range from 2% to 5% solutions. In comparison to the DOX solution, DOX-loaded SLNs have reported superior cytotoxic results (Tupal, Sabzichi, Ramezani, Kouhsoltani, & Hamishehkar, 2016). Multitarget inhibitors to combat resistance in cancer patients have been in use, where celecoxib (CEL) acts synergistically with DOX to inhibit multiple key signaling pathways (Singh, 2018). Over time, opportunistic pathogens have been seen to provoke infections leading to ulceration of cutaneous melanoma (Capanema et al., 2019). The use of hybrid hydrogels of silver NPs in carboxy methyl cellulose conjugated with DOX may act as a dual weapon against skin cancer with combined antibacterial effects via topical chemotherapy delivery. The efficacy of the prepared system can be evaluated by MRI scans with the calculation of apoptotic index, HMGA1 protein expression, etc. (Sharma, Sharma, Jagannathan, Ray, & Raja Rajeswari, 2019). 10.5.7.2 5-Fluorouracil Antimetabolites act by hindering the de novo pathways in cancerous cells. 5-FU acts as an antimetabolite and is a pyrimidine analog (Longley, Harkin, & Johnston, 2003). 5-FU is approved by the USFDA for the treatment of BCC-type nonmelanoma SCC and actinic keratosis (noncancerous) (Clark, Furniss, & Mackay-Wiggan, 2014). Though approved for superficial BCC, it has permeation inefficiencies for which the integration of microneedle technology into the topical mitigation was suggested (Naguib, Kumar, & Cui, 2014). Immune modulators on aberrant activation are responsible for mutagenic cell growth, for which inhibitors and inducers, depending on their end signaling, are used in combination with approved anticancer drugs. Calcipotriol is an inducer of thymic stromal lymphopoietin, an epithelium-derived cytokine with robust antitumor immunity in barrier-defective skin when given in combination with 5-FU optimally activated CD4 1 T cell-mediated

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immunity against actinic keratosis and cancers of the skin and other organs (Cunningham et al., 2017). 10.5.7.3 Bleomycin Bleomycin is derived from Streptomyces verticillus and is known as a chemotherapeutic antibiotic for its anticancer properties by preventing the incorporation of thymidine into DNA strands, causing DNA breakups (Lau, 2003). Bleosomes were studied in 118 clinical cases of equine sarcoid and the results were found to be comparably better than radiation therapy (Yousuf, Amini-Nik, & Jeschke, 2018). The benefits of bleomycin over other anticancer drugs are that it bypasses myelosuppression and it has a low toxicity to normal cells. The efficacy of bleomycin in patients with older than 65 years has been reported to be greater for BCC than electrochemotherapy (Groselj et al., 2018). 10.5.7.4 Cisplatin Cisplatin is a platinum-based alkylating agent, which via its ability of crosslinking causes DNA damage, subsequently inducing apoptosis in cancer cells (Claerhout et al., 2010). HaCaT keratinocytes were taken as a model of proliferating epidermal cells to test the effect of vitamin D on cellular response to H2O2 or the anticancer drug, cisplatin, and it was found that the anticancer effect of cisplatin was enhanced by vitamin D and calcipotriol (Piotrowska et al., 2016). BRAFV600E melanoma cell lines were checked for the effect of fasting in terms of nutrient deprivation, and it was found that it enhanced tumor cell death by cisplatin due to ROS generation in the absence of ER (Endoplasmic Reticulum) stress (Antunes et al., 2017). Due to the development of resistance, a combination of cisplatin and sulforaphane was studied, and the results proved it to be an option to be explored for advanced epidermal SCC in future (Kerr, Adhikary, Grun, George, & Eckert, 2018). 10.5.7.5 Mitoxantrone Mitoxantrone is classified as an anthracycline antitumor antibiotic obtained from the soil fungus Streptomyces (Faulds, Balfour, Chrisp, & Langtry, 1991). Due to its serious side effects, including producing cardiac toxicity, its use is preferred only when patients are nonresponsive to other chemotherapeutic drugs. Pegylated hollow gold NPs as a nanocarrier for mitoxantrone have been reported for their improved optical properties, and their use improved the antineoplastic activity of PDT (Imanparast, Bakhshizadeh, Salek, & Sazgarnia, 2018). On the basis of their therapeutic efficacy, their role has been explored in other nanocarriers and mitoxantrone cubic phases (Csa´nyi et al., 2019; Yu et al., 2016). 10.5.7.6 Imiquimod Imiquimod is an immunomodulator that acts as a toll-like receptor-7 agonist and activates macrophages and other immune cells. It promotes interferon-alpha, tumor necrosis factor-alpha, and other cytokines to increase TH1-type immunity (Urosevic & Dummer, 2004). It acts as a Hh-pathway inhibitor. Imiquimod administration through a vehicle has been suggested for controlling its side effects. Decreased melanocytic hyperplasia in imiquimod-treated sites was reported in lentigo maligna, the most common subtype of

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melanoma occurring in the head and neck regions, as assessed in 13 women and 39 men (Flores, Luby, & Bowen, 2018).

10.5.8 Natural-origin bioactives 10.5.8.1 Curcumin The natural, phenolic compound, curcumin, is obtained from Curcuma longa (turmeric) (Pushpalatha, Selvamuthukumar, & Kilimozhi, 2019). It is a routine spice used in Indian recipes and is widely known for its wound-healing, anticarcinogenic, antibacterial, antiinflammatory, neuroprotective, and antidiabetic properties (Singh et al., 2018). However, the clinical use of curcumin is restricted due to its poor water solubility leading to a major concern in bioavailability and making it susceptible to alkaline degradation (Vakilinezhad, Amini, Dara, & Alipour, 2019). In order to solve this problem, many formulations have been studied. Curcumin is a cutting-edge phytochemical that exhibits chemopreventive activity because it is an effective regulator of multiple molecular targets in multiple signaling cascades (Batra, Pawar, & Bahl, 2019). Some molecular targets of curcumin used in cancer treatment are CDK (Cyclin-dependent kinase)/cyclin complex and CDK inhibitors as well as the p53 pathway (Rodrigues, Anilkumar, & Thakur, 2019). In addition, its role has been studied in various signaling pathways like Ras signaling (Cao et al., 2015; Ono, Higuchi, Takeshima, Chen, & Nakano, 2013), Wnt/b-catenin signaling, and transcription pathways like the NF-kB and AP-1 families and the STAT family of transcription factors (Rakariyatham et al., 2019). 10.5.8.2 Tea polyphenols Tea polyphenols are usually tannins, and their precursors are found naturally in tea leaves. The major polyphenols present in green tea are catechins, namely (2)-epigallocatechin-3-gallate (EGCG), (2)-epigallocatechin (EGC), (2)-epicatechin-3-gallate (ECG), and (2)-epicatechin (EC). EGCG is the most active component in green tea (Alshatwi, Periasamy, Athinarayanan, & Elango, 2016). EGCG has been revealed as cancer preventative and showed therapeutic effects in skin cancer cells. It possesses a wide range of biochemical and pharmacological activities, including antiinflammatory, antioxidant, and antiangiogenic effects that have been demonstrated both in vitro and in vivo using animal models (Rady, Mohamed, Rady, Siddiqui, & Mukhtar, 2018). Studies have shown that tea polyphenols can prevent stem cell populations (such as the CD44-positive population) and their self-renewal (Hh/Gli1 pathways and Wnt/β-catenin), and they also regulate distinct key regulatory genes such as downstream signaling events through the cell cycle (cyclin D1, p21, cMyc, etc.), signaling (EGFR, hRas, ERK1/2, NF-kβ, Nrf2, etc.), angiogenesis (VEGF), epithelial to mesenchymal transition (E-cadherin), and apoptosis (p53, Bax, Bcl2, caspase-3, etc.) (Katiyar, Mohan, Agarwal, & Mukhtar, 1997; Li et al., 2016). This complex is composed of cytochrome C, apoptotic protease activating factor 1 (Apaf-1), and procaspase-9, which activates caspase-9, caspase-3, and caspase-7. Moreover, EGCG induced apoptosis through both intrinsic and extrinsic pathways, regulatory proteins, and endoplasmic reticulum stress via the activation of caspase-dependent, caspaseindependent, death receptors, the down-regulation of antiapoptotic proteins BCL-2, BCL-XL,

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and XIAP, and the upregulation of proapoptotic BAD and BAX in NCI-H295 human adrenal cancer cells (Katiyar, 2011). Singh et al. showed that EGCG inhibits cell proliferation and prompts the death of A431 and SCC13 human skin cancer cells by targeting β-catenin and its signaling molecules (Singh & Katiyar, 2013). 10.5.8.3 Trehalose Trehalose is a nonreducing, natural disaccharide comprised of two glucose units found in various organisms, including fungi, bacteria, and invertebrates. Trehalose is wellknown as an important protein stabilizer and reduces corneal damage of the eye caused by UV-B. Due to the poor skin permeability of trehalose, it has limited use as a photoprotectant in topical formulations. Related to other compounds, trehalose-loaded liposomes showed maximum efficiency in decreasing the levels of three markers after irradiation with HaCaT cells with UV-B (P , 0.001) when compared to four other photoprotective compounds. Therefore these results show that trehalose-loaded liposomes may have clinical applications and additional studies are still required to assess their possible use in skin photoprotection and the inhibition of NMSC (Emanuele, Bertona, Sanchis-Gomar, ParejaGaleano, & Lucia, 2014). Trehalose has been reported to work as an autophagy modulator, an innovative drug in the treatment of several diseases in which autophagy plays an important role. Its use has opened a new scenario of intervention in conditions difficult to be treated like cancer and neurodegenerative disorders (Hosseinpour-Moghaddam, Caraglia, & Sahebkar, 2018). 10.5.8.4 Diallyl sulfide Diallyl sulfide (DAS), a flavor component present in garlic (Allium sativum) has been found to play a role in the inhibition of chemically-induced cytotoxicity and carcinogenicity in animal models (Grudzinski, Frankiewicz-Jozko, & Bany, 2001). DAS is a fat-soluble, organic sulfur, volatile compound from garlic with a characteristic pungent odor. DAS is an effective antioxidant with antiinflammatory, antimutation, and cancer prevention effects (Thejass & Kuttan, 2007). DAS supplementation showed enhanced expression of the 2B1, CYP1A1, and 3A1 genes at the protein and mRNA levels. These inhibitory effects are related to the stimulation of apoptosis and regulation of the expression of the antiapoptotic gene (bclK2), the proapoptotic gene (bax), and the p53 tumor suppressor gene (Singh & Shukla, 1998). 10.5.8.5 Aloe-emodin Aloe-vera is a succulent xerophyte resembling a cactus belonging to the genus Aloe (Majumder, Das, & Mandal, 2019). Aloe-Emodin (AE) is a hydroxyanthraquinone compound present in aloe and other families such as Asteraceae and Polygonaceae. It has drawn considerable interest as an antitumor drug (Hsu & Chung, 2012). Based on its unique in vitro antitumor activity, selective toxicity, and cellular pharmacokinetics, AE can be considered a new type of anticancer agent for the treatment of skin and other cancers (Chou & Liang, 2009; Liu et al., 2018).

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10.5.8.6 Luffin Luffin is a single-stranded ribosome-inactivating protein (sc-RIP) from Luja cylindrica seeds with a molecular weight of approximately 29,500 Da and a high isoelectric point ( . 10). The liposome-mediated transfer of luffin-inactivating type-1 ribosome protein to human melanoma cells proved that luffin can replace human immunotoxins to treat human melanoma (Poma, Marcozzi, Cesare, Carmignani, & Spano`, 1999). 10.5.8.7 Glycans Glycans are present in mammalian tissues both in free and conjugated forms. These are found as glycoconjugates in various glycolipids, glycoproteins, and proteoglycans. The removal of glycan parts from glycoconjugates helps in the treatment of cancer. The deletion of specific glycans or the modification of glycan chains with fucose or sialic acid increases antibody-dependent cellular cytotoxicity (ADCC) and helps in the destruction of cancerous tissues (Taniguchi & Kizuka, 2015; Unger et al., 2012).

10.5.9 Photosensitizers 10.5.9.1 5-Amino levulinic acid 5-Amino levulinic acid (5-ALA), is an amino acid noted to be effective in the photosensitization of cells. Over the past decade, 5-ALA has been used in local PDT for the treatment of NMSC (Fang, Tsai, Wu, & Huang, 2008). The mechanism of use of 5-ALA in PDT is based on the intracellular conversion of 5-ALA into protoporphyrin IX, followed by exposure to cause phototoxicity (de Leeuw, van der Beek, Neugebauer, Bjerring, & Neumann, 2009). 10.5.9.2 Temoporfin Temoporfin is a most potent second-generation photosensitizer (Dragicevic-Curic, Scheglmann, Albrecht, & Fahr, 2008). It is activated at 652 nm with a light penetration depth of 1 cm, and it exhibits a high tumor selectivity with residual photosensitivity for two weeks (Dragicevic-Curic, Scheglmann, Albrecht, & Fahr, 2009a). It has been shown to be effective in PDT in cases of head and neck carcinoma and refractory oral carcinoma (Yakavets, Millard, Zorin, Lassalle, & Bezdetnaya, 2019). Dragicevic et al. demonstrated that liposomes containing 20% (w/v) ethanol deliver the maximum amount of mTHPC to the skin, which is sufficient for topical PDT. mTHPC-loaded ethanol-containing liposomes followed by illumination, might be beneficial in PDT for the treatment of skin cancer (Dragicevic-Curic, Scheglmann, Albrecht, & Fahr, 2009b). 10.5.9.3 Zinc phthalocyanine Phthalocyanine is a synthetic dye obtained in 1907 by Braun and Tcherniac. Zinc phthalocyanine has advantageous properties, including low toxicity, minimal skin photosensitivity, high chemical and photochemical stability, high therapeutic effect, and great penetrating radiation in tissues (Roguin, Chiarante, Vior, & Marino, 2019). These can be used in topical PDT for skin cancer treatment (Freitas et al., 2017; Primo et al., 2008).

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10.5.10 Miscellaneous products 10.5.10.1 Tretinoin Tretinoin is a natural retinoid that is widely used in proliferative and inflammatory skin diseases such as acne, epidermal T-cell lymphoma, psoriasis, and epithelial skin cancer (Weinstock et al., 2012). This can be used as a penetration enhancer for delivery systems into the skin (Manconi et al., 2011; Manconi, Sinico, Valenti, Lai, & Fadda, 2006). 10.5.10.2 Celecoxib (diaryl heterocycle) CEL is a drug that inhibits cyclooxygenase-2 (Gowda, Sharma, & Robertson, 2017), is a nonsteroidal antiinflammatory drug, and is generally used for the management of osteoarthritis, rheumatoid arthritis, and acute pain. The administration of CEL is an effective means of inhibiting the progression of skin cancer (Ahmed, Shan, Mao, Qiu, & Chen, 2019), and potentiates the effectiveness of other chemotherapeutic agents (Uram et al., 2018).

10.5.11 Biologics 10.5.11.1 DNA repair enzymes 10.5.11.1.1 Photolyase

Photolyase is an enzyme of bacteria that can repair UV-B-induced CPD in eukaryotic cells (Decome et al., 2005). Blue light is used by photolyase as a source of energy to reverse UV-induced photoproducts to normal bases (Kavakli, Ozturk, & Gul, 2019). 10.5.11.1.2 T4 endonuclease V (dimericine)

T4 endonuclease V, or dimericine, is a bacterial enzyme isolated from Escherichia coli infected with T4 bacteriophage (Wolf et al., 2000). The bacterial DNA repair enzyme (T4NV), when administered intracellularly, increases the repair rate of DNA damage induced by sunlight in human skin cells (Gilchrest, Zhai, Eller, Yarosh, & Yaar, 1993).

10.6 Nanocarriers as a potential tool for effective treatment of skin cancer 10.6.1 Nanoparticles NPs are sub-nanosized particulate dispersions or solid particles with a size range of 10
1000 nm (Mohanraj & Chen, 2006) that have biomimetic features. These biomimetic properties increased in combination with a high surface-to-volume ratio and the ability to modify these properties also increases in the use of biomedicine with potential applications in imaging, diagnosis, and treatment (Dianzani et al., 2014). 10.6.1.1 Polymeric nanoparticles Polymeric NPs are formed of one or more polymers with different molecular weights, structures, and hydrophobic chains. Polymeric NPs are present in the forms of polymeric micelles, nanospheres, nanosponges, nanocapsules, etc. (Dianzani et al., 2014;

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Gao, Li, & Lee, 2013; Minelli et al., 2012). Polymeric micelles are core
shelled micellar assemblies that are composed of more than one polymer chain with different hydrophobicities (Mohamed, Parayath, Taurin, & Greish, 2014; Torchilin, 2007). Yadav et al. prepared N-isopropylacrylamide/vinyl pyrrolidone thermoresponsive nano-polymeric micelles loaded with paclitaxel, and evaluated their anticancer activity in a breast cancer cell line (MCF-7) and a skin melanoma cell line (B16F10). They found that the nano-polymeric system had therapeutic efficiency with a sustained release action and showed biodegradable-compatible properties (Yadav et al., 2014). Similarly, Varshosaz et al. prepared folic acid
targeted micelles of synperonic PE/F 127-cholesteryl hemisuccinate via dialysis method, in which docetaxel was incorporated for the effective treatment of melanoma. The results suggested that micelles had greater cytotoxic effects with higher cellular uptake and reduced the tumor volume effectively (Varshosaz, Taymouri, Hassanzadeh, Haghjooy Javanmard, & Rostami, 2015). The available research data showed that polymeric nanomicelles are one of the most efficient chemotherapeutic carriers for targeting skin cancer cells and have efficient cytotoxic effects. Nanospheres are nanosized, polymeric, spherical NPs, in which therapeutic compounds are uniformly distributed throughout the polymer matrix. Various polymeric NPs are available for the treatment of cancer that have excellent antiproliferative properties as well as proapoptotic effects (Mukerjee & Vishwanatha, 2009; Shen et al., 2008). Nanospheres have excellent entrapment efficiency, a small size range, a smooth-surface, and a controlled and sustained release pattern. Nanospheres are also efficient in skin cancer treatment. Surface modifications to nanospheres may increase the efficiency of the treatment of skin cancer because surface modification reduces the toxicity and increases the cellular uptake and cytotoxicity (Das, Das, Samadder, Paul, & Khuda-Bukhsh, 2013; Siddiqui et al., 2014). Das et al. prepared PLGA NPs loaded with apigenin (a dietary flavonoid) and evaluated the cytotoxic effect of both free apigenin and the apigenin-loaded NPs in human melanoma A375 cells and found that the NPs provided better effects due to their smaller size, faster mobility, and site-specificity. The NPs had better cellular uptake and could intercalate with double-standard DNA, which caused conformational change, later increasing ROS accumulation and causing DNA damage, thus, leading to apoptosis via mitochondrial dysfunction (Das et al., 2013). Elevated ROS is a key feature of cancer. But the elevation of ROS beyond the tolerable limits causes the apoptosis of cancer cells (Haider, Tiwari, Vyas, & Soni, 2019). Similarly, Siddiqui et al. prepared chitosan NPs to encapsulate polyphenol EGCG (from green tea) and evaluated their antipreoperative and proapoptotic effects in melanoma cells (Siddiqui et al., 2014). Thermosensitive nanospheres are also important NPs that release drugs by thermal stimulation. Thermosensitive polymeric nanospheres may provide better delivery to tumor sites and induce apoptosis in cancer cells. Shen et al. prepared thermosensitive poly(N-isopropylacrylamide-co-acrylamide-co-allylamine)conjugated albumin nanospheres with a size range below 200 nm that were loaded with adriamycin and the release of the drug was dependent on the cloud-point temperature, which induces the shrinkage of polymers (Shen et al., 2008). Surface-modified nanospheres are promising candidates for the treatment of skin cancer. The improvisation/improvement in nanospheres for tumor targeting is continuously rising nowadays. Nanosponges are NPs that have nanosized mesh-like structures containing many nanometer-wide holes, and have the capacity to encapsulate both lipophilic and

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hydrophilic substances. Nanosponges may increase the solubility of poorly soluble substances. Compared to other NPs, they are insoluble in both water and organic solvents, porous, nontoxic, and stable at high temperatures of up to 300 C (Selvamuthukumar, Anandam, Krishnamoorthy, & Rajappan, 2012). Their nanoporous structure has many advantages such as the ability to carry proteins, enzymes, drugs, and other small molecules. Nanosponges have the ability to carry water-insoluble drug and are made up of the complex of drug and polymers. They can increase the dissolution rate, solubility, stability, and unpleasant flavor of drugs. β-cyclodextrin-based nanosponges have already been reported to be three to five-times more effective than direct drug delivery to the target (David, 2011; Selvamuthukumar et al., 2012). β-cyclodextrin-based nanosponges are obtained with crosslinking using a crosslinker like carbonyldiimidazole, diphenyl carbonate, hexamethylene diisocyanate, pyromellitic anhydride, etc. (Swaminathan, Cavalli, & Trotta, 2016; Trotta, Shende, & Biasizzo, 2012). These types of systems may provide revolutionary benefits in the treatment of a disease like cancer and manifold better efficacy than plain drugs (David, 2011). Various researchers have prepared and investigated nanosponges in the treatment of melanoma. Clemente et al. prepared pyromellitic nanosponges loaded with paclitaxel, and evaluated the anticancer efficacy of the nanosponges compared with paclitaxel in a melanoma cell model in vitro and in vivo, and the results suggested that the nanosponges lowered the antitumor effective doses and improved the effectiveness in inhibiting melanoma growth in vivo (Clemente et al., 2019). Nanosponges may provide a promising nanoparticulate carrier system for skin cancer treatment and a promising delivery system in future research in the case of melanoma. Nanocapsules are nanovesicular systems characterized by core
shell structures in which a drug can be contained in the form of a liquid or solid or as a molecular dispersion within the reservoir or cavity surrounded by a polymeric membrane or coating (MoraHuertas, Fessi, & Elaissari, 2010). Various researches have established the efficacy of therapeutic agent
loaded nanocapsules in the treatment of skin cancer (Ferreira et al., 2019; Mazzarino et al., 2011; Wang & Chang, 2012). Barbugli et al. prepared photodynamic chloroaluminum phthalocyanine
loaded nanocapsules to encapsulate in PLGA (50:50), and evaluated their cytotoxic effects in human melanoma cell line WM 1552C (Barbugli, Siqueira-Moura, Espreafico, & Tedesco, 2010). Similarly, another team of researchers, Siqueira-Moura et al., prepared nanocapsules by using soybean lecithin, poloxamer, soybean oil, and PLGA in a ratio of 1.25% (w/v):188% (w/v):2.5% (v/v):75% (w/v) that were loaded with chloroaluminum phthalocyanine, and the obtained nanocapsules had an average size of 230 nm and an encapsulation efficiency of 70% (Barbugli et al., 2010). Nanocapsules are also used in the imaging of cancer. David et al. prepared DNA lipid nanocapsules and encapsulated the fluorescent probe, DiD, which was analyzed by in vivo imaging on an orthotropic melanoma mouse model and by subsequent treatment with ganciclovir (David et al., 2012). Polymeric NPs are the most used type of NPs in the treatment of skin cancer because of their biostability, biocompatibility, easy preparation, etc. Drug entrapment is also feasible and therapeutic agents are released in a sustained manner. Polymeric NPs may encapsulate cytotoxic drugs, siRNA, genes, proteins, enzymes, etc. The overall performance of polymeric NPs provides a promising delivery system not only in skin cancer, but also in other diseases.

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10.6.1.2 Metallic nanoparticles Metallic NPs have a variety of biomedical applications, that is, their use in highly sensitive diagnostics, drug and genetic material delivery, thermal ablation as well as in radiotherapy enhancement (Conde, Doria, & Baptista, 2012; Huang, Jain, El-Sayed, & El-Sayed, 2007; Selvan, Tan, Yi, & Jana, 2009; Yavuz et al., 2009). Metallic NPs have better penetration and are less toxic toward nondiseased cells in comparison to the conventional dosage forms. Metal NPs have high surface-to-volume ratios, broad optical properties, are easy to synthesize, and their facial surface chemistry and functionality play an important role in the clinical field of cancer treatment (Conde et al., 2012; Huang & El-Sayed, 2010; Truong, Kim, & Sim, 2012). Metallic and metallic oxide NPs have efficient anticancer activity in different types of cancers, including breast (Khan, Dwivedi, Konwar, Zubair, & Owais, 2019), pancreatic (Du et al., 2019), lung (Cyril, George, Joseph, Raghavamenon, & Sylas, 2019), colorectal (Li et al., 2019), and skin cancers (Janani, Lakra, Kiran, & Korrapati, 2018), etc. Various metallic and metallic oxide NPs have a better cytotoxic effect in skin cancer than that of the conventional dosage forms. The efficacies of metal NPs are manifold greater than plain drugs in vitro. Dong et al. prepared calcium carbonate
polydopamine composite hollow NPs loaded with photosensitizer chlorine-6, which showed inherent biocompatibility, multimodal imaging functionality, high antitumor PDT efficacy, and reduced skin phototoxicity, and they provided recovered fluorescence and enhanced singlet oxygen generation in tumor acidic pH (Dong et al., 2018). Similarly, Nirmala et al. prepared gold NPs stabilized with Vitis vinifera peel polyphenols to obtain efficient cytotoxic effects and cause apoptosis via elevated ROS production and significant membrane potential loss in skin cancer cell line A431 (Nirmala, Akila, Narendhirakannan, & Chatterjee, 2017). Other than the treatment of skin cancer, these metallic and metallic oxide NPs can be used for the diagnosis and imaging of cancer cells. Postnikov et al. prepared an old NPs-based system that converts terahertz to infrared for the terahertz imaging of skin cancer (Postnikov, Moldosanov, Kairyev, & Lelevkin, 2019). Hence metallic and related NPs are significant tools for the treatment and diagnosis of skin cancer. 10.6.1.3 Lipid nanoparticles Lipid NPs were considered as drug delivery systems by R. H. Mu¨ller and M. Gascon in the early 19th century. These NPs were made up of solid lipids or a mixture of liquid and solid lipids using emulsifiers as stabilizing agents. SLNs are considered to be firstgeneration lipid-based nanocarriers and nanostructured lipid carriers (NLCs) are considered to be second-generation lipid-based nanocarriers, which were developed from those lipids that remain solid at body temperature (Ghasemiyeh & Mohammadi-Samani, 2018; Vishwakarma et al., 2019). 10.6.1.3.1 Solid-lipid nanoparticles

SLNs are gaining a reputation as being alternative drug delivery systems to polymeric NPs, liposomes, emulsions, and others due to their skill of incorporation of both hydrophilic and lipophilic drugs, better physical and chemical stability for labile molecules, lower skin irritation, potential for site-specific and controlled drug delivery, reduced

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particle size, high and effective drug payload, low production cost, avoidance of carrier toxicity, etc. (Gonc¸alez, Rigon, Pereira-da-Silva, & Chorilli, 2017; Pandey et al., 2015; Rai et al., 2015). The small size of SLNs increases the contact of these nanocarriers with the SC to increase their retention along with the controlled release of the drug. The permeation of the drug into the deeper skin layers could be increased due to the composition of SLN matrices, which helps to permit the exchange of lipids between the various layers of the skin (Gonc¸alez et al., 2017). Geetha et al. developed SLNs bearing sesamol for the treatment of skin cancer. In vitro MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay for antiproliferative activity as well as DNA fragmentation studies were performed on HL 60 cell lines, which showed the enhanced apoptotic nature of sesamol in the SLNs. In vivo anticancer activity was performed in mouse epidermis revealed the normalization of skin cancers on the treatment with sesamol-bearing SLNs (Geetha et al., 2015). Tupal et al. formulated DOX-bearing SLNs as a dermal delivery system to treat skin cancer (Tupal et al., 2016). The dermal delivery of DOX provided an improved therapeutic effect while minimizing the side effects and, thus, could serve as an ideal approach in the treatment of skin cancers. In vitro study on B16F10 and in vivo study on melanoma-induced BALB/c mice revealed the superiority of DOX-loaded SLNs as compared to a plain DOX solution to treat skin cancer. The use of peptides for the treatment of skin cancers is also gaining attention to provide improved and effective therapeutics approaches. Tyr-3-octreotide is one such peptides that could be employed in formulations to provide modified systems. Banerjee et al. used this peptide to modify SLNs bearing paclitaxel. A peptide-modified SLN formulation of paclitaxel modulated the immunity and outperformed dacarbazine in a murine melanoma model. Tyr-3-octreotide is engaged in the treatment of melanoma having overexpressed somatostatin receptors and helps to produce better antiinvasive and apoptotic effects in B16F10 melanoma cancer cell lines when compared with dacarbazine, an official chemotherapeutic agent to treat aggressive melanoma (Banerjee et al., 2019). Apart from the available synthetic drugs, some natural substances also show chemopreventive activity, which could be due to their antiinflammatory and antioxidant abilities. When these natural-origin drugs are incorporated in a nanocarrier system they could potentially enhance the activity to cure diseases by overcoming drawbacks associated with them. For example, curcumin possesses the potential to cure skin disorders but it has poor oral bioavailability, hence, its administration through the dermal route provides a convenient and alternative route to target the site of action. Thus curcumin-loaded cationic SLNs provide targeted drug delivery to promote better efficacy to diseased tissue while reducing the minimum adverse effects on normal cells. The positive charge on SLNs provide better drug targeting to cells. These cells have a high density of negative charges due to exposure to phosphatidylserine on the cell membrane surface (Gonc¸alez et al., 2017). 10.6.1.3.2 Nanostructured lipid carriers

NLCs have been used as a kind of nanocarrier system that can provide the penetration of drugs to deeper layers of the skin and have acquired a better place for topical delivery of active moieties. The percutaneous absorptions of drugs could be remarkably enhanced through the use of NLCs, which may be due to their unique composition of spatially incompatible binary lipids (solid and oil lipids), providing a higher encapsulation

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efficiency to an incorporated drug. These NLCs help to improve the efficacy of topical delivery through better adhesiveness, occlusion, and efficient and valuable skin targeting (Jain, Rahi, Pandey, Asati, & Soni, 2017; Qidwai et al., 2016). Iqbal et al. developed a silymarin-loaded NLC gel for skin cancer treatment due to its antioxidant, antiinflammatory, antiproliferative, and antitumor activity. A B16 melanoma cell line for an in vitro study and an albino mice model for an ex vivo study were used to demonstrate its superior effects as compared to conventional silymarin gel. The silymarin-loaded NLC gel led to a significant reduction in the tumor volume from 5.02 to 3.05 mm3. Also, the levels of TNF-α and IL-1α were considerably lowered while levels of catalase, superoxide dismutase, and glutathione increased significantly when the tested groups were treated with the silymarin-loaded NLC gel (Iqbal, Ali, Ganguli, Mishra, & Baboota, 2019). NLCs could be employed in PDT as a talented substitute therapy for malignant skin diseases like BCC. Qidwai et al. developed PDT through the use of NLCs, providing an enhanced penetration of photosensitizer 5-ALA into the skin for the treatment of BCC. A controlled drug release with enhanced skin penetration was observed due to their ability to reach deeper skin layers through NLCs, thus, resulting in increased cytotoxicity (Qidwai et al., 2016). NLCs provide targeted drug delivery to encapsulated drugs through active targeting, thus act as a better and effective therapy in skin cancer treatment.

10.7 Conclusion Over the past few decades, it has been revealed that NPs-based systems have emerging potential to deliver anticancer drugs/biomolecules to effectively target skin cancer. NPs, including SLNs, liposomes, nanospheres, etc., have offered huge impact on both the therapeutic as well as diagnostic approaches to skin cancer. Various strategies have been implemented by altering the targeting moieties to increase their effectiveness. Moreover, numerous materials have been selected to make them more sophisticated to upgrade the therapeutic effects to cancerous sites. The sole purpose of the implementation of nanotechnology in treatment approaches for skin cancer is to minimize the toxic effect with maximizing the target ability of the delivery systems. Although nanotechnology has many possibilities, more emphasis is still needed on both qualitative and quantitative studies that improvise the penetration ability of NPs and their therapeutic efficacy. The understanding behind the mechanisms of NPs transport through the various skin layers should be clear, which could help in the design of novel nanocarrier systems. Consequently, several technical challenges along with many unsolved problems will exist, which offer significant opportunity to be studied in further investigations.

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C H A P T E R

11 Nanoparticles and prostate cancer Ashish Garg1, Sweta Garg1 and Nitin Kumar Swarnakar2 1

Department of P.G. Studies and Research in Chemistry and Pharmacy, Rani Durgavati University, Jabalpur, India 2Scientist III at BASF, Tarrytown, NY, United States

11.1 Introduction 11.1.1 Cancer Cancer is the primary cause of mortality across the world and stands in second place in countries that are developing, and it displays increased pervasiveness with time (Jemal et al., 2011). This disease is identified by cell proliferation in the absence of cell death, leading to uncontrolled cell division, thus, causing tumor development. A tumor develops and in time it obtains new vascularization and becomes metastatic with the potential to attack different cells or organs of the body. Malignant growth is brought about by different potential factors; the majority share of which is due to any harm or transformations to hereditary materials, acquired hereditary qualities, ecological variables like pollutants, way of life, the use of tobacco, stress, weight, contaminants, radiation, and a lack of physical activity. The present malignancy treatment approaches depend on medical procedure, radiotherapy, and chemotherapy, where the latter shows more prominent adequacy for treatment, explicitly in the advanced stages.

11.1.2 Prostate gland and prostate cancer The prostate gland is situated before the rectum and secretes a thick, white liquid that blends in with the sperm from the gonads to make semen. This white prostatic liquid is released into the urethra at the main discharge divisions, together with the vast majority of the spermatozoa. Inside the prostate, there are 30
50 L sacs that make and hold the white liquid. It additionally creates a protein called a prostate-specific antigen (PSA) (Lilja, Ulmert, & Vickers, 2008), which transforms the semen into a fluid. Fig. 11.1 depicts the essential structure of the prostate gland and the cancerous prostate. The prostate gland is typically situated between the urethra (bladder) and rectum (Hodson, 2015).

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FIGURE 11.1

(A) Structure of prostate gland and tumor in prostate gland and (B) schematic representation of various nanocarriers applied for prostate tumor targeting and treatment. Source: Figure created by BioRender.com.

Prostate malignant growth is the second most common reason for death in most countries, and its frequency has expanded altogether. In the United States, the probability of this disease is one in six. In 1997, around 209,900 men were determined to have prostate malignant growths and over 41,800 expired from the disease (Parker, Tong, Bolden, & Wingo, 1997). In England, death rates have fluctuated over the course of 30 years, where 1 out of 13 men are afflicted and 20,000 cases are analyzed every year; age is a significant hazard factor as this disease is found to be uncommon in people younger than 40, while its frequency rises with age. There are also differing topographical rates. Investigations of migrant populaces have proposed that natural components are in any event as critical as race. Ecological elements embroiled in prostate malignant growth include a high admission of soaked fat and a low degree of dietary selenium, vitamin E, and vitamin D. It has been assessed that under 5% of all prostate malignant growths are genetic. The danger of prostate disease is expanded by a factor of 1.3 if there is a diseased father in the family. Prostate malignant growth is thought to emerge after a grouping of eight hereditary mutations. Early mutations lead to a loss of tumor suppressive qualities, for example, p53, which is changed in up to 64% and p21 in up to 55% of tumors. The suppressor gene p73 bears homology to p53 and seems, by all accounts, to be transformed in prostate disease (Burton, Oakley, & Anderson, 2000). MMAC1/p10, in any case, is the most generally transformed suppressor gene in prostate malignant growth and may add to the acquisition of a metastatic phenotype. The development of the hormone refractory phenotype appears to be related to the over expression of mutant p53 and bcl-2 family of proteins as well as amplification of the androgen receptor. Tumor suppressive qualities, for example, p53, is altered in up to 64% of tumors, while p21 is altered in up to 55% (Apakama et al., 1996).

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Prostate cancer is the most common disease found in men and is the primary cause of death. Its occurrence varies from country to country due to the screening of PSA. It is more prevalent in the west, and the data obtained from migrants prove that the risk factors are due to both environmental and lifestyle factors. Major advances have been undertaken in its treatment and in understanding its biology. This includes numerous drugs that boost the survival ability of patients with advanced-stage cancer, and most cancers are hormone-driven in spite of a kind of castration resistance (Chen et al., 2004; Taplin et al., 1995). Nonetheless, several areas of urgent unmet need remain, including (1) a validated biomarker to complement PSA for screening, (2) molecular differentiation of indolent and aggressive disease and prognostic biomarkers with clinical utility, (3) molecular stratification methods and predictive biomarkers, (4) adjuvant therapies to increase cure rates in high-risk locally advanced disease, (5) treatment of metastatic disease, (6) imaging of bone metastasis for staging and response measures, and (7) surrogate biomarkers for overall survival benefit. Treatment of this cancer could be attained through administering anticancer drugs by the method of systemic infusion. Based on the body area coverage and the type of administration, regional and systemic are two approaches for chemotherapeutic delivery. Systemic delivery has the drawback of inconsistent distribution in the body. This nonspecific distribution eventuates in the death of normal cells like hair follicles, bone marrow, gastrointestinal mucosa, and gonads, leading to systemic toxicity and acute complexities. Likewise, inconsistent drug uptake by normal cells cuts down the drug content conveyed to malignant cells, therefore, a greater amount of drugs need to be delivered to gain efficient treatment. Though chemotherapy and radiation treatments could fight cancers, there is an immediate need for a targeted approach that aids in increasing their treatment efficiency and that also has fewer side effects. Nanomedicine could be effectively used for spotting cancer at a level of microscopic and macroscopic organelles (Hofheinz, Gnad-Vogt, Beyer, & Hochhaus, 2005) through the functionalization of ligands such as oligopeptides, antibodies, aptamers (Apt), vitamins, carbohydrates, and hormones. These proposals have enhanced the biodistribution and pharmacokinetics of nanomedicine and, hence, improve the treatment protocol efficacy (Jha, Jha, Chaudhury, Rana, & Guha, 2014). Specifically, nanomedicine is known to be a good option in conveying drugs to tumor cells via a locoregional approach that could lead to reduced adverse effects to a compelling level. This type of locoregional drug delivery (DD) chemotherapy was put in place and analyzed in clinical trials to reduce the toxicity of anticancer medicines in systemic-type exposure. At present, numerous strategies of locoregional chemotherapies have been discovered to treat liver and prostate cancer with lesser side effects. In mice model of metastasized colon cancer, galactosylated liposomes loaded with doxorubicin administered through spleen (locoregional) showed higher deposition of the galactosylated (functionalized moiety) and nongalactosylated liposomes (nonfunctionalized) in the liver than the tail vein injection displaying significant decrease of tumor progression in the liver and mesenteric lymph nodes, with no substantial result in the nontargeted formulations (Zhao et al., 2013). In another randomized controlled clinical trial of advanced pancreatic cancer, it was shown that the patients receiving regional intra-arterial chemotherapy were more effective than systemic chemotherapy with fewer complications, showing better

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median survival rate, superior partial remission and lower hematological side effects (Liu et al., 2012). Based on such studies, it could be identified that targeting solid tumor from different accessing points shows a varied response, better in locoregional delivery while assuaging the complications implicated due to systemic delivery and increasing the efficacy of the treatment profile. However, the problem of drug’s side effects on normal cell apart from cancerous cells remain same even in locoregional approach but it is very less when compared with systemic approach. Due to the anatomical and physiological parameters of the prostate, it could be regarded as a potential candidate for targeted locoregional therapy.

11.2 Nanotechnology Nanotechnology is a developing and promising field that utilizes nanoparticles (NPs) to encourage the analysis and treatment of disease (Farokhzad & Langer, 2009; Ferrari, 2005; Petros & DeSimone, 2010). NPs offer answers for the present challenges in malignant growth treatments due to their size and enormous surface to volume proportions. The size, surface nature, and shape of NPs play a primary role in their biodistribution in vivo (Alexis, Pridgen, Molnar, & Farokhzad, 2008). Utilizing nanotechnology, it might be conceivable to overcome a few issues, which include (1) improved conveyance of ineffectively water-solvent medications, (2) site-coordinated conveyance of medications toward explicit organic and subatomic targets, (3) developing new diagnostic tools, and (4) providing remedial specialists with demonstrative tests. With the progression of nano innovation and the comprehensive properties of materials at the nanoscale level, a few therapeutic agents have been endorsed or entered clinical improvement for a few therapies. In any case, regardless of the huge advances in the course of the past few years, relatively few instances of nanosystems for utilization in the administration of prostate cancer treatment have been accounted for. As of late, nanotechnology has been in the spotlight in medicine due to the facility with which nanostructures collaborate at a molecular scale. New treatments in cancer treatment using nanomedicine are being created to improve the particularity and adequacy of medication delivery, consequently with 100% effectiveness and viability with negligible symptoms. Nanomedicine is a division of nanotechnology applied to medication, and is defined as the process of determining, evaluating, and averting disease and damage, assuaging torment, and safeguarding and enhancing human well-being by utilizing tools at a molecular level and the human body’s molecular information. Miniaturization could impact the basic features of a material when compared to its bulk forms. This impact is due to the expansion of a particular surface region to the molecule size. Besides, atom arrangement also varies with alterations to the surface area, which can present new optical, electronic, magnetic, and thermal properties that consecutively impact the biological communications. For instance, alterations to the surface and size of a material influences its cell uptake (He, Hu, Yin, Tang, & Yin, 2010). NPs can be customized to a specific application. Regardless of their small size, NPs can be stacked with atoms or DNA in curative and investigative agents (de Barros, Tsourkas, Saboury, Cardoso, & Alavi, 2012).

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11.3 Drug delivery DD has been a significant hub of biotechnology, its objective being to convey a particular agent to a site of activity to generate an ideal pharmacological impact. Along with knowing about the target component, other factors like the carrier nature and the course of execution should be monitored while building up the DD strategy. This concept of DD was first put in place a century ago by Paul Ehrlich, who developed a procedure to specifically attack pathogens, and is referred to as a “magic bullet.” The most challenging issue in the production of DD products is the system’s biocompatibility. This term refers to the ability to conquer the protective systems within the body while not triggering or being toxic to any immune responses within the organism. Moreover, stability, dispersibility, penetrability, and better interactions with the cellular membrane are unequivocal elements for designing an effective DD system. Advances in the understanding of biological and chemical interactions between the tissues and DD systems have allowed for the optimization of these systems (Fig. 11.2).

FIGURE 11.2 Representation of the (A) prostate gland (normal and cancerous prostate), (B and C) genetic profiling of normal and cancerous prostate, and (D) nanoparticle-based approach for prostate cancer targeting and therapy.

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FIGURE 11.3 Structure of nanoparticles with their building blocks.

11.3.1 Drug targeting toward tumor cells The greatest challenge in medical sciences is to create an antineoplastic treatment. Regular chemotherapy conveys a cytotoxic agent aimlessly to both normal and neoplastic cells. Medication focusing on malignant growth treatment is intended to keep from harming the normal functioning of tissues and organs while expanding its tumor uptake. NT chemotherapeutics can be customized to convey high amounts of medication to tumor tissues by altering their dispersion (Hu, Aryal, & Zhang, 2010). This procedure can likewise improve the clinical effect by utilizing therapies in combination (Chow & Ho, 2013). Significant components for building NPs are displayed in Fig. 11.3.

11.3.2 Active and passive targeting Gathering NPs inside tumors can be accomplished by both passive and active strategies. The passive type of targeting depends on phenomena like diffusion and convection. The process of convection occurs through pressure-driven blood movement and is highly accountable for the delivery of large-sized molecules via the aperture within the endothelium, while diffusion is accountable for deporting low molecular weight and lipophilic compounds through the membrane as per the gradient developed. The enhanced permeation and retention (EPR) effect can increase the aggregation of nanocarriers inside tumors (Danhier, Feron, & Pre´at, 2010). This was observed in prostate malignancy by Sandanaraj et al. utilizing a fluorescent nanoprobe and microscopy (Sandanaraj, Gremlich, Kneuer, Dawson, & Wacha, 2010). In inactive targeting, the surface of NPs is altered to attain point-specific interactions between the carrier and target via fastening to receptors within the tumor sites. However, to bind the target cells the nanocarriers must first reach the tumor and the EPR effect is still necessary. Active targeting by itself does not improve overall drug accumulation inside the tumors but it improves cell recognition and uptake. Examples of ligands used for targeting tumor cells are galactosamine (Xu, Qian, et al., 2013;

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Xu, Xie, et al., 2013), transferrin (Tortorella & Karagiannis, 2014), and folate (Wang, Li, et al., 2014; Wang, Zhang, et al., 2014).

11.4 Routes of drug delivery to the prostate The approaches used for DD to prostate cancer cells are based on two different routes, namely the systemic route and the locoregional route, as displayed in Fig. 11.4.

11.4.1 Systemic route Among the serious issues associated with prostate tumors is the use of animal models in research that don’t echo the human system conduct due to variations in genetic parameters, localization, and interaction with the gene-environment. Additionally, the majority of research using animal models is done with tumor cells that are induced externally, subcutaneously or orthotopically, and that are obtained from the prostate tumor cells of humans, either without or with genetic variations. It may have similarities of pathogenicity of cancer in disease progression, but massive differences in physiological, genetic,

FIGURE 11.4 Routes for drug delivery and therapeutics of prostate cancer. (A) Systemic route, (B) transvas route, (C) transrectal route, and (D) intraprostatic route. Source: (C) Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.

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tumor micro-environment of prostate between the animal and human systems. Moreover, in the case of animal models, prostate tumors are orthotopically or subcutaneously induced cancer cell lines without or with genetic alterations. By and large, the systemic type of DD and NPs are generally used to study prostate disease in research models that spread over an expansive range of microenvironment varieties. Various ways of administrating drugs such as intraperitoneal (Hine, Seluanov, & Gorbunova, 2012), subcutaneous (Ghosh et al., 2012), retro-orbital (Zhu et al., 2015), tail vein (Wadajkar et al., 2013), and intravenous (Thomas, Waterman, Chen, & Marinelli, 2011) are also performed through systemic delivery. The administered nanoparticles enter into the blood, circulate throughout the body to get deposited at the tumor site based on the enhanced permeation and retention effect of passive targeting and ligand mediated active targeting delivery. This validates that systemic-type delivery is the most common route of administration that promotes drugs and NPs to tumor locales. Through active targeting, siRNA delivery to prostate tumor cells has been investigated in a xenograft model of mice by intravenous delivery (Xiang et al., 2013). In this, potent in vivo knockdown of target Plk-1 was achieved using bifunctionalized liposomes with prostate-specific antigens like PSAresponsive and prostate-specific membrane antigen (PSMA) for active targeted delivery which leads to significant decrease of tumor growth (Xiang et al., 2013). However, the problem associated with systemic delivery of nanoparticles was quite evident as fluorescence signal intensity was also observed in other parts of the mouse body. Interestingly there was another study, reporting the similar concept of systemic route mediated targeting delivery of siRNA to the prostate tumor using poly glutamic acid-graft-poly(ethylene glycol) (PGA-g-PEG)-folate functionalized with polycaprolactone-graft-poly(N,N-dimethylaminoethyl methacrylate) (PCL-g-PDMAEMA) polymeric nanoparticles. Quantitative estimation of the obtained results detailed in the investigation demonstrated a reasonable circulation of siRNA to different organs rather to the prostate tumor (Huang et al., 2012). It was evident that some nonspecific distribution of nanomedicine, especially to critical organs like liver, lungs, kidney occurred, which was administered through systemic route mediated by the active targeted delivery approach. Comparing the in vivo study results, it is quite evident that in the dual modified siRNA containing liposomes, the target was more restricted and less nonspecific, like in single modified nanoparticles, the testis and almost all the organs were showing signal with varied intensities although the folate was used in both the nanoparticles for active targeting. While in the double-modified liposomes, the DD turned out to be increasingly specific and a large portion of the organs did not show a signal like the testes, digestive tract, cerebrum, and heart, yet at the same time, other organs like the liver, lungs, pancreas, kidney, and other submandibular organs showed the signal of Cy5-labeled siRNA (Huang et al., 2012). Borgman and Gandehari used RGDfK-functionalized HPMA copolymer aminohexylgeldanamycin conjugates (Borgman, Aras, Geyser-Stoops, Sausville, & Ghandehari, 2009) in gold NPs with differing symmetries for focusing on prostate tumor through systemic-type delivery (Gormley, Malugin, Ray, Robinson, & Ghandehari, 2011). The therapeutic results displayed a random particle distribution in the spleen and liver with lesser aggregation in the tumor. The accumulation of particles in spleen and liver might be due to the role of lymphatic system and net negative charge of nanomedicine. Another investigation exhibiting a lesser collection of particles at the tumor site, which was conveyed by the systemic administration of

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nanomedicine, wasn’t really “focused” from a point-delivery viewpoint (Gormley et al., 2011). These accentuate the point that controlling the synthetic and biophysical features of nanomedicine isn’t the only significant factor, picking the right administration route is similarly significant as can be seen in all the mentioned investigations relating to focused nanomedicine administration through systemic-type delivery.

11.4.2 Locoregional route 11.4.2.1 Intraprostatic route The intraprostatic sedate conveyance route has been contemplated in preclinical and clinical arrangements where various modalities of medication conveyance approaches have been utilized. Medicated implants have been broadly considered in preclinical models, while brachytherapy has effectively been utilized in the clinical field (Wolinsky, Colson, & Grinstaff, 2012). The goal of intraprostatic organization is to convey an enormous amount of medication to the objective tissue with negligible exposure. This would, thus, decrease systemic administration
related reactions and toxicities to noncancerous tissues and basic organs. Choosing an animal model for intraprostatic DD study is significant because of the physical and anatomical variations among living models. In an examination on beagle dogs, the conveyance and dispersion of fluorescent medication, doxorubicin, was analyzed after intraprostatic organization. Intravenous and intraprostatic infusions indicated diverse doxorubicin dispersions in the prostate both subjectively and quantitatively. The fibromuscular stroma assumes a critical role in drug dethroning as it isolates the lobule, which is a significant hindrance to medication transport. The convective progression of liquid was a significant transporter in the prostate during the intraprostatic delivery of the medication. One basic aim in locoregional treatment is to accomplish minimum viability of medication to different organs as in the systemic route. Interestingly plasma concentration of the intraprostatic group was significantly lower than intravenously delivered doxorubicin, suggesting the systemic exposure by intraprostatic route is comparatively low which could reduce nonspecific delivery of the drugs to the normal tissue. In an examination, the intraprostatic implantation of a doxorubicin-stacked poly(lactide-co-glycolide) (PLG) polymeric embed was performed to convey the medication and further analyzed for its spatial dissemination and fixation in a beagle prostate model. The spatial medication appropriation showed a higher accumulation of doxorubicin bound to the lobule with diminishing fixation inclinations at the septa splitting the lobule. The doxorubicin fixation conveyed by the doxorubicin-PLG embed was 8-times greater than that conveyed through intravenous infusion of a similar measure of doxorubicin. This proposes that intraprostatic infusion is good for conveying a huge amount of medication to the prostate compared to the traditional route (Ortiz, Au, Lu, Gan, & Wientjes, 2007). Aside from utilizing counteracting agents like antibodies for functionalized NPs to promote active targeting in prostate tumor studies, nucleic acid-functionalized NPs have likewise been conveyed intratumorally. Apts are little oligonucleotides that have definite binding properties toward their targets and, in this manner, can be utilized for the targeted conveyance of NPs in disease treatment. In-vitro studies showed 77-fold higher increase in binding versus control (where number of cells were 150 per group). Curiously,

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it was likewise detailed that cells that didn’t express PSA didn’t show NP uptake. An in vivo study in a xenograft prostate tumor model indicated that a single intratumoral infusion of the docetaxal-NP-Apt conjugate was fundamentally progressively adequate in decreasing the tumors when compared with the nontargeted NPs and the control (Fig. 11.4) (Farokhzad et al., 2006). Intraprostatic implantations of therapeutic products are currently used in clinical treatments, which is referred to as brachytherapy. In the treatment of prostate malignant growth, brachytherapy could be given as a temporary, high-dose therapy or as a permanent, low-dose therapy. In this method of intraprostatic delivery, radioactive iodine-125 or palladium-103 are ordinarily embedded 1 cm apart in the prostate as seeds, which may range between 50 and 100 seeds depending on the tumor size, visualization, and dose prescribed for treating prostate tumors (Sylvester, Blasko, Grimm, & Ragde, 1997; Tapen et al., 1998). 11.4.2.2 Vas deferens The vas deferens is a channel for sperm to transit from the testis to the urethra (Koslov & Andersson, 2013). A formulation called RISUG AdvR, comprising of high- and lowmolecular weight styrene maleic anhydride (SMAh and SMAl), where SMAl acting as a model drug, when injected in the vas deferens resulted in the transfer of in vivo formed liposomes encapsulated chains of SMAl to prostate through vas prostate junction in male wistar rats for prevention of prostate cancer. (Guha, 2009, 2012). In another work, a finasteride
SMAh
SMAl complex was tested in male rats to study the treatment of benign prostate hyperplasia (Guha, 2013). These technologies show that the vas deferens can be utilized as a drug depot for NPs and as a route for DD and NP conveyance to the prostate gland. 11.4.2.3 Transrectal The proximal anatomical area for the prostate is the rectum (Schutzer et al., 2015). In such a manner, computerized rectal assessment and transrectal prostate biopsies are the most broadly utilized urological strategies for prostate-related illness analysis (Penzkofer & Tempany-Afdhal, 2013). Employing the utility of ultrasound, which is not only useful for diagnosis, but its exploitation as an external modality for either direct or indirect nanoparticle-based actively targeted drug delivery to prostate increases ultrasound significance. Along these lines, the transrectal route for prostate-related infection treatment is a locoregional contender for malignancy treatment (Kosheleva, Lai, Chen, Hsiao, & Chen, 2016). Low and high recurrence ultrasound appear to have potential, while low recurrence ultrasound demonstrates the most extreme tissue penetrance (George et al., 2016). In humans, the rectal channel is the nearest course to get access to the prostate noninvasively. Along these lines, plenty of researches focusing on anatomical boundaries use DD to the prostate through photothermal- (Wang, Li, et al., 2014; Wang, Zhang, et al., 2014), ultrasound- (Taylor & Sillerud, 2012; Wang et al., 2013; Wang, Li, et al., 2014; Wang, Zhang, et al., 2014), and hyperthermia- (Johannsen et al., 2005; Johannsen, Thiesen, Wust, & Jordan, 2010) based methodologies that viably and locoregionally target the prostate for confined medication deposition using NPs. The basic concept is the utilization of rectal route to provide the external stimuli like ultrasound to activate nanomedicines which,

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in turn, shows its therapeutic activity by bursting of nanobubble and releasing the content at the site of burst. A research paper depicting the improvement of multifunctional Bi2S3/ PLGA nanocapsules for consolidated high intensity focused ultrasound/radiation treatment in a mice model of PC3 cells indicated a vague distribution. This could be because of the bigger size of nanocapsules. The utilization of ultrasound brought about the high deposition of nanocapsules, in this way showing the role of ultrasound, which increases the concentration of nanocapsules at the tumor site (Yao et al., 2014). This channel has been broadly utilized for nanotechnology-based mediation where ultrasound-like modalities were investigated to treat and determine prostate hyperplasia and prostate tumors in preclinical and clinical arrangements.

11.5 Classification of nanoparticle systems for prostate targeting 11.5.1 Liposomal nanoparticles in prostate cancer Liposomes are vesicles of circular shape that have solitary or different, two-layered, lipid structures that usually assemble by themselves in water systems (Torchilin, 2005). They, as a rule, arrive at their site of activity through eruption from the circulatory system into the interstitial space (Malam, Loizidou, & Seifalian, 2009). Liposomes can target specific tissues by passive and active processes, with the active type of targeting promoted by adding up ligands over the surface of the lipid layer (Malam et al., 2009). These are utilized both for disease imaging and for DD (Park et al., 2014). An enormous amount of the exploration efforts in nanotechnology applied to tumor growths concerns liposomal bearers. These are biodegradable and can hold hydrophilic and hydrophobic matter due to their aqueous nature. They vary extensively in terms of size and structure based on the method of synthesis and composition. Generally, their size ranges from 90 to 150 nm and they can be made out of natural or synthetic molecules. The fundamental segment is made up of phospholipids along with cholesterol (Medina, Zhu, & Kairemo, 2004). Liposomes can interact with cells to convey their substance in four unique manners, namely endocytosis, adsorption, exchange, and a combination of these; although endocytosis is the most significant for DD. The size, structure, and targeting agents used will impact a given system, just like the kind of cell and the nearby microenvironment will. In 1995 the first nanocarrier based therapeutic was approved by the FDA: this was Doxils, a pegylated doxorubicin loaded liposome approved for the treatment of Kaposi’s sarcoma. Despite its potential for prostate tumor treatment, it is approved for ovarian cancers only (Hubert, Lyass, Pode, & Gabizon, 2000). While, Myocet is nonpegylated liposomal doxorubicin used in the treatment of phase 2 prostate tumors and breast cancer. Montanari et al. (2012) conducted studies to compare the impact of Myocet and Caelyx on prostate cancer cells They observed a better efficacy of Myocetsthan of the pegylated form, despite the theoretical advantage of a long circulation time. Narayanan, Nargi, Randolph, and Narayanan (2009) performed a few studies on drugs like resveratrol and curcumin (CUR) enclosed in liposomal carriers and they displayed a reduction in prostate adenocarcinoma in animal models like mice, while in vitro studies with similar formulas promoted apoptosis and inhibited cell growth. In studies carried out by

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Thangapazham et al. formulations having CUR were used and specifically targeted prostrate tumor cells by linking an antibody to prostate-specific membrane antigen (PSMA). This particular grouping was found to be 10-times more effective than the drug C4-2B in LNCaP cell lines (Thangapazham, Puri, Tele, Blumenthal, & Maheshwari, 2008). Liposome-based DD strategies have benefits regarding biocompatibility on account of the likeness of their lipid composition to that of the cell layer. They present low toxicity values and they can fuse both hydrophobic and hydrophilic medications. Certainly, their precariousness and their short half-life are restricting components for their application. Indeed, serum proteins can interact with the liposomes, destabilizing the membrane and facilitating their opsonization leading to fast clearance.The most significant research challenge for liposome use is to locate the best functionalization system to overcome these issues (Allen & Cullis, 2013). Shao et al. (2019) developed a liposome nano vector for boosting docetaxel (DTX) for the treatment of prostate disease, and they showed that TE-targeted therapy of gene silencing utilizing liposomal vectors is a promising therapeutic system as a monotherapy and to improve the adequacy of chemotherapy in subjects with advanced prostate disease. Another group of researchers, Li et al. prepared Herceptin-conjugated liposomes coloaded with doxorubicin and simvastatin, and their results revealed that the Herceptinconjugated liposomes are a potential novel therapeutic strategy for overcoming prostate cancer. Yari, Nkepang, and Awasthi (2019) prepared a surface-modified liposome, and their results suggest that the surface functionalization of liposomes with small PSMAbinding motifs such as PSMAL can provide a viable platform for to specific delivery of theranostics to PSMA⁺ prostate cancer cells. Nassir et al. (2019) present surfacefunctionalized folate-targeted oleuropein nanoliposomes for prostate tumor targeting, and the study provides conclusive evidence for the utilization of a combination of passive and active targeting strategies to enhance the anticancer effect of the developed liposome. Mahira, Kommineni, Husain, and Khan (2019) formulate cabazitaxel (CBX) and silibinin (SIL) coencapsulated cationic liposomes for CD44-targeted delivery for prostate cancer and the outcome of this combinational therapy with CD44 targeting indicated the suitability of HA-coated CBX and SIL coloaded liposomes as a potential approach for eradicating prostate cancer and might provide insights for future studies (). Patil et al. (2018) prepared folate-conjugated liposomes and revealed that the cytotoxic activity of the drug-loaded folate-targeted liposome was found to be significantly enhanced when compared to nontargeted liposomes in LNCaP cells. Folate-targeted liposomes may provide a new tool for the targeted therapy of cancers that overexpress the PSMA receptor (Patil et al., 2018).

11.5.2 Albumin-bound system Human serum albumin was studied as a potential drug carrier due to its nontoxic, endogenous, and nonimmunogenic nature (Hawkins, Soon-Shiong, & Desai, 2008). This molecule acts as a natural shipper of hydrophobic particles, which allows for the transfer of molecules throughout the body and their delivery to the surface of cells (Elzoghby, Samy, & Elgindy, 2012). A colloidal suspension of Nab
paclitaxel blended with human albumin (3%
4%) allowed for the impregnation of higher drug doses than that of a

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standard formulation with fewer side effects, a low infusion time, and no pretreatment (Cucinotto et al., 2013). Its usage in a prostate tumor was found to be experimental; however, a similar method could be used to improve the delivery of inhibitors to prostate tumor cells (Shepard et al., 2009).

11.5.3 Polymeric nanoparticle systems for cancer treatment Polymeric NPs refer to nanocapsules and nanospheres (Thakor & Gambhir, 2013). The latter are usually spherical in shape and can adsorb molecules onto their surface. While nanocapsules are vesicles with matter confined in their cavities (Rao & Geckeler, 2011). Numerous polymers have been produced for ligand-targeted and passive delivery of therapeutic formulations (Prabhu et al., 2015). NPs arranged from a wide scope of polymers have demonstrated their adequacy to enhance the pharmacokinetic and bioavailability properties of affirmed chemotherapy drugs for prostate tumor treatment, prompting an extraordinary development in this field (Sanna & Sechi, 2012). Natural polysaccharides, for example, chitosan and egg whites as well as polyesters, for example, poly(D, L-lactic-co-glycolic acid) (PLGA) (Makadia & Siegel, 2011), poly(D, L-lactic acid) (PLA) (Riley et al., 2001), and poly(caprolactone) (PCL) (Pohlmann et al., 2013), which can be adjusted with PEG units shaping pegylated copolymers, are the most commonly utilized polymers for DD. They are biocompatible, biodegradable, and they can embody an assortment of medications (Chan et al., 2002). Nanoparticulate bearers can have different structures, for example, dendrimers, nanospheres, nanocapsules, and micelles (Soppimath, Aminabhavi, Kulkarni, & Rudzinski, 2001). Nanocapsules are vesicular frameworks made out of focal fluid or an oily center enclosed by a polymeric shell. The fundamental methods that can be utilized to shape this sort of NP are interfacial or emulsion polymerization, interfacial polycondensation, emulsification, and nanoprecipitation (Couvreur, Barratt, Fattal, & Vauthier, 2002). Nanospheres are particles with a lattice structure in which medications and ligands can be scattered, epitomized, artificially bound, adsorbed, or ensnared over the surface or inside the molecule (Talevi, Gantner, & Ruiz, 2014). Nanocapsules and nanospheres are typically shaped from straight polymers or copolymers. Exceptionally branched polymers can likewise form dendrimers. The name dendrimer implies tree, from the Greek word “dendron.” Tomalia et al. published a paper on poly(amidoamine) (PAMAM) dendrimers in 1985 (Tomalia et al., 1985), and from that point forward, numerous examinations have been engaged in this sort of polymeric compliance for application in the treatment of tumors, among others. Polymeric micelles are colloidal particles framed by amphiphilic copolymers with a higher extent of hydrophilic chain than those used to shape the NPs, organized in a center
shell structure. They have appealing properties as DD frameworks. They, as a rule, have a hydrodynamic breadth between 5 and 100 nm and their capacity to join solvent particles makes them a decent contender for DD in the treatment of malignant growth (Oerlemans et al., 2010). Regardless of the assortment of confirmations that polymers have received, the properties of NPs that make them suitable for DD are comparative. In this way, numerous authors do not determine the precise structure of their nanocarriers, concentrating on their arrangement and their adequacy, while alluding to

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them in a general way as polymeric NPs. Farokhzad et al. (2006) were pioneers in the improvement of functionalized Apts utilizing prostate tumor treatment as a model. According to in-vivo findings, it was suggest that these NPs could decrease the tumor size in LNCaP xenografts in bare mice, prompting 100% endurance over 109 days of concentrates after a solitary intratumoral infusion, contrasting to the 14% endurance of the group treated with free DTX. These outcomes exhibit the capability of these bioconjugates in prostate disease treatment (Farokhzad et al., 2006). Farokhzad et al. likewise typified cisplatin in PLGA
PEG
Apt NPs, demonstrating an improvement of 3-fold in the drug index and a decrease in nephrotoxicity in mice bearing LNCaP xenografts when compared with free cisplatin (Dhar, Kolishetti, Lippard, & Farokhzad, 2011). A blend of DTX encapsulated inside PLGA
PEG and PLA
PEG containing cisplatin was additionally tried. This technique was intended to overcome single medication presentation difficulties, for example, drug resistance. A cooperative energy between the two medications was found in vitro against LNCaP cell line, presenting 5.5-fold more cytotoxicity than NPs conveying just one of the medications (Kolishetti et al., 2010). A CUR-stacked nanocarrier was created by Anand et al. (2010) for passive-type targeting. This was set up from biodegradable PLGA
PEG with a molecule size of around 81 nm. In vitro tests indicated that the prostate line DU-145 had a lower practicality after 72 h with encapsulated CUR as compared to the free medication (Anand et al., 2010). A DD approach was applied to treat prostate tumors using hormones for quite a while. Indeed, several formulations of PLGA microparticles for luteinizing hormone-releasing hormone (LH-RH) agonists release are commercially available. In these formulations, drugs are discharged continuously from the grid by dispersion and polymer debasement (Allen & Cullis, 2013). This technique of controlled discharge diminishes the recurrence of infusions required for ordinary hormonal treatment down to one at regular intervals, prompting a superior adherence and viability of the treatment (Saltzman & Fung, 1997). Notwithstanding being out of the nanosize range and not focusing on treatment, these polymer-based strategies assume a significant role in prostate treatment (Cross & McPhail, 2008). Polymeric NPs are, in general, steadier than liposomes in view of their lesser connections with serum proteins, especially if their surface is functionalized. Size, molecule corruption, and controlled discharge are factors that can be changed depending on the grid constituents and the focused tissue. Notwithstanding the favorable circumstances, the wide scope of options in functionalization and composition makes it hard to anticipate the pharmacological conduct of polymeric NPs. Be that as it may, the primary difficulties for various types of NPs are to keep away from insusceptible reactions and to amplify their compensation to dynamic medications (Babu, Templeton, Munshi, & Ramesh, 2013). PEG-covered and Gd-stacked fluorescent silica NPs were set up by Jiang et al. (2019) and the examination showed that the integrated Gd/Cy5.5/SiO2-PEG-Ab NPs have incredible potential as MRI/fluorescence agents for distinguishing PSMA receptor
positive prostate tumor cells. An another research work proposed by Wei, Sun, and Liu (2019) is enhanced targeting of prostate cancer-initiating cells by salinomycin-typified lipid-PLGA NPs and showed this as the principal concentrate to report improved impacts against cancer-initiating cells (CICs) accomplished by the upgrade of targeted DD by means of NPs conjugated with CD44 antibodies. In this manner, the NP-based treatment using salinomycin-epitomized lipid-PLGA NPs connected with CD44 antibodies (SM-LPN-CD44)

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represents a novel way to deal with prostate CICs and is a promising potential treatment technique for prostate tumors. Along these lines, different polymeric nanoparticulate bearers have been created by various researchers to propose DD toward prostate malignancy and for prostate disease treatment strategies, including CUR-loaded PLGA NPs (Azandeh et al., 2017), Plumbagin-loaded aptamer-targeted poly D,L-lactic-co-glycolic acidb-polyethylene glycol nanoparticles (Pan et al., 2017), Apt-modified conveyance of DTX to prostate malignant growth through polymeric NPs (Chen et al., 2016), and bicalutamidestacked PLGA NPs (Ray, Ghosh Ray, & Mandal, 2016).

11.5.4 Carbon-based system Carbon NPs have been utilized in fluorescent bioimaging tests (Bhunia, Saha, Maity, Ray, & Jana, 2013). Their suitability is because of their inborn fluorescence and high biocompatibility (Kumar, Toffoli, & Rizzolio, 2013). Likewise, their absence of harmfulness and the way that they can be changed with exogenous synthetic substances makes them appropriate for fluorescent DD. Carbon nanotubes (CNTs) for initiating hyperthermia have been examined in prostate malignancy xenografts in bare mice, with a tumor reaction being illustrated (Krishnan, Diagaradjane, & Cho, 2010). Apt-conjugated multiwalled CNTs were set up by Gu et al. (2018), and both in vitro and in vivo ultrasound imaging exhibited that the new nanoultrasound agents had a decent improvement, appropriation, and digestion, and may prove to be a decent targeted ultrasound agent, particularly for prostate tumors. Another group of specialists proposed a fluorescent CNT sensor for the identification of metastatic prostate disease (Williams, Lee, & Heller, 2018). Xia et al., in 2018, detailed functionalized multiwalled CNTs, and the results obtained proposed that H3R6 polypeptide (MHR-CpG) was a promising multifunctional nanoframework for prostate malignancy immunotherapy (Xia et al., 2018). Erdmann, Ringel, Hampel, Wirth, and Fuessel (2017) prepared carbon nanomaterials sensitize prostate cancer cells to docetaxel (DTX) and mitomycin C (MMC) via induction of apoptosis and inhibition of proliferation and summarized that carbon nanomaterials in combination with DTX and MMC evoked additive to partly synergistic anti-tumor effects. Carbon nanofibers (CNFs) and CNTs have the capacity to sharpen malignancy cells to a wide scope of fundamentally various chemotherapeutics and signify an intriguing alternative for the improvement of multimodal tumor treatments. A combination of chemotherapeutics and carbon nanomaterials could bring about a decrease of the chemotherapeutic measurement, and along these lines, limit fundamental symptoms. In this specific way, carbon nanomaterial approaches are extraordinary for upgrading the impact of anticancer medication as well as in malignant growth discovery (Salaam, Hwang, McIntosh, et al., 2014; Salaam, Hwang, Poonawalla, et al., 2014).

11.5.5 Dendrimeric platform Dendrimers are a new group of polymeric substances (Nanjwade, Bechra, Derkar, Manvi, & Nanjwade, 2009; Wu, Ficker, Christensen, Trohopoulos, & Moghimi, 2015). The structures of the higher generations of dendrimers are found to be globular and more dense than those of the dendrimers of lower generations (Wu et al., 2015). And their

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unique design enables them to be used as gene and DD bearers as well as sensors (Svenson, 2009; Wang, Li, et al., 2014; Wang, Zhang, et al., 2014). Lasker et al. formulated a camptothecin-functionalized dendrimersome system that was redox-responsive for gene and DD to prostate cancer cells, and concluded that this system led to an improved cellular uptake of DNA (by up to 1.6-fold) and amplified gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison to the unmodified dendrimer and, therefore, is promising for single carrier
based combination cancer therapy. Similarly, Laskar et al. (2019) prepared redox-responsive camptothecin-functionalized dendrimersomes for effective gene delivery. Lim et al. (2019) prepared triazine dendrimers decorated with 4, 16, and 64 PSMA-targeted ligands for the enhancement of tumor uptake. Another group of scientists proposed a dendrimer-based platform for the effective capture of tumor cells after TGFβ1-induced epithelial
mesenchymal transition, and demonstrated that the system possesses a significantly enhanced capture sensitivity (Myung et al., 2019). Lesniak et al. (2019) developed a PAMAM dendrimeric NP system and concluded that the system may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents. Chlorambucilconjugated Ugi dendrimers with a PAMAM-NH₂ core system were synthesized by Seixas et al. (2019), who proposed that the system enhances the targeting capability toward the prostate. Sanchez-Milla et al. (2019) successfully exhibited the anticancer potential of their developed system of dendriplexes against prostate cancer.

11.5.6 Quantum dot device Semiconductor nanocrystals or quantum dot (QDs) are a set of atoms derived from the II
VI or III
V groups within the periodic table (Chan et al., 2002). When compared to fluorescent proteins and organic dyes, semiconductor QDs are found to have numerous benefits. QDs that are coated can be used for fastening to numerous diagnostic and therapeutic agents for cancer detection (Gao et al., 2005). Cai and Chen (2007) labeled human prostate tumor cells by utilizing QDs along with an antibody for PSMA (). CdTe QDs were synthesized by Jigyasu et al. (2020), who demonstrated their antiproliferative activity against prostate cancer. A dual-color magnetic quantum dot nanobead (MQBs) system was developed, and the results proposed that dualcolor MQB-based fluorescent lateral flow immunoassay is a promising point-of-care diagnostics technique for the accurate diagnosis of prostate cancer even in resource-limited settings (Rong et al., 2019). In this way, another group of researchers developed a paper-based fluorometric immunodevice with QD
labeled antibodies, and they demonstrated that the system efficiently detects carcinoembryonic antigens and PSAs simultaneously (Chen, Guo, Liu, & Zhang, 2019). Another system was developed by Wang et al. (2018) that acts as a biomarker and has the capability to detect a prognostic value of prostate cancer. In this manner, Wang et al. (2018) created a QD
based system for immune fluorescent
based imaging and detection of DNER, that is, delta/notch-like epidermal growth factor (EGF)-related receptor.

11.5.7 Gold nanoparticulate system Gold NPs contain valuable properties, for example, a huge surface to volume ratio, phenomenal biocompatibility, and low lethality (Yeh, Creran, & Rotello, 2012). Various

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combinations of different shapes and sizes show varying properties that can be used for theranostic purposes, for example, optical properties that allow for use as a contrast agent alongside photothermal capacities in the infrared and near infrared range (Arvizo, Bhattacharya, & Mukherjee, 2010). Their unequivocally improved radiative properties, for example, dispersion, assimilation, and a plasmonic field for surface-upgraded Raman imaging of nearby atoms make gold NPs helpful for subatomic malignant growth diagnostics (Huang, El-Sayed, Qian, & El-Sayed, 2006). Gold NP tests have been utilized to distinguish tuberculosis (Soo et al., 2009) as well as malignancy biomarkers in an ex vivo setting. In an examination performed in 2010, a group of researchers functionalized the outside of gold NPs (AuNPs) with an RNA Apt that ties to a prostate-specific layer antigen and built up a subatomic CT imaging framework (Kim, Jeong, & Jon, 2010). AuNPs are known to be nontoxic and nonimmunogenic and are viably utilized as DD vehicles for targeting tumors, momentarily improving the impact of specific medications known to be constrained by serious limitations (Connor, Mwamuka, Gole, Murphy, & Wyatt, 2005). Brown et al. (2010) indicated that platinum-based anticancer medication, oxaliplatin, when conjugated to AuNPs, gave an improved DD. Stripped AuNPs were functionalized with a thiolate PEG monolayer-topped with a carboxylate group. A platinum complex, [Pt(1R, 2R diaminocyclohexane) (H2O)2]2NO3, was added to the PEG surface to yield a supra-atomic complex with around 280 medication particles for every NP. The platinum-fastened AuNPs were inspected for cytotoxicity, medication uptake, and the restriction of the A549 lung malignancy cell line and the colon cancer cell lines, HCT116, HCT15, HT29, and RKO. The fabricated platinum-fastened NPs indicated a better cytotoxicity compared to oxaliplatin alone in all the cell lines, and furthermore showed the capacity to infiltrate the core of the lung malignancy cells (Patra, Bhattacharya, Mukhopadhyay, & Mukherjee, 2010). The capability of AuNPs for DD was exhibited with the utilization of 5 nm AuNPs covalently bound to cetuximab as a targeting operator and gemcitabine as a helpful medication in pancreatic malignancy. Patra et al. (2008) showed that high intratumoral gold fixations (4500 μg/g) could be accomplished utilizing this methodology with 600 μg/g untargeted AuNPs. The AuNP
cetuximab
gemcitabine nanocomplex was seen to have a higher effectiveness than any of the different operators or in a blend of both in vitro and in vivo. Non-conjugated agents showed 30% inhibition whereas low doses of complex gemcitabine led to . 80% tumor growth inhibition in an orthotopic pancreatic cancer (Patra et al., 2008). (Tomuleasa 2012) assessed the in vitro antitumor viability of AuNPs settled with a monolayer of L-aspartate in a mixture with antimalignancy drugs cisplatin, doxorubicin, and capecitabine, which were effectively utilized as tumor targeted DD operators for the treatment of liver disease. The cell expansion rates in hepatocellular carcinoma cells were accounted to be altogether lower than those of the cells presented with chemotherapeutic medications alone. The AuNP
medication mixtures showed that AuNPs encouraged an expanded vulnerability of disease cells. Ultrasmall AuNPs of about 2.8 nm in size conjugated to chemotherapeutic medication doxorubicin (Au
DOX) were observed to be 5-fold as harmful to B16 melanoma cells as the medication alone. AuNPs are nonlethal to the cells despite the fact that they are endocytosed. The cell death with DOX alone was apoptotic, while with Au
DOX, the cell death was necrotic. Transfection of cells with Bcl-2 protected the cells against plain DOX treatment but not against cells treated with AuNPs. A few investigations uncovered that AuNPs immuno-targeted to

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subatomic markers on the surface of disease cells can be utilized for targeted malignancy treatment. AuNPs functionalized with hostile epidermal growth factor receptor (EGFR) antibodies have been found to encourage the photothermal demolition of dangerous cells overexpressing EGFR. To elucidate the cell death only minimum laser light dosimetry required than the dose needed for healthy cells (Huang, Jain, El-Sayed, & El-Sayed, 2006). Thus the uptake rate of AuNPs can be improved by means of ligand-receptor interceded endocytosis. Tsai et al. (2008), utilizing human breast cancer cell lines, MDA-MB-435S and T-47D, demonstrated that the expression of the folic acid (FA) receptors in the former are much higher than that of the latter. Upon surface modification of AuNPs with FA, the uptake rate of AuNPs in MDAMB-435S cells, which had adequate FA receptors, was seen to be higher (Tsai et al., 2008). A similar research work on targeted cancer treatment by Banu et al. (2014) indicated that AuNPs can be utilized in potentiating the cytotoxicity of anticancer medications; for example, cyclophosphamide in alpha human folate receptor (αHFR) positive breast cancer cells by conjugating the AuNPs to malignant growth focusing on ligand of FA (Banu et al., 2014). AuNPs can act as a transporter for anticancer medications, for example, DOX and DTX. Dhamecha, Jalalpure, and Jadhav (2015) combined DOX-functionalized AuNPs with a green strategy and assessed their anticancer properties against human disease cell lines. Kim et al. (2010) introduced multifunctional NPs for targeted atomic CT imaging and treatment of prostate cancer. The outer layer of the AuNPs was functionalized with PSMA RNA Apt, which ties to PSMA. The resulting PSMA apt conjugated AuNPs showed more than 4-fold selective CT intensity and loading of DOX showed antiproliferative activity against targeted LNCaP cells than a nontargeted PC3 cell. Lukianova-Hleb et al. (2011) reported the physical and natural impacts of specific targeting and enactment of plasmonic nanobubbles (PNBs). The impacts of PNBs were examined in the heterogeneous natural microenvironment of prostate tumor and stromal cells. Androgen deprivation treatment is one of the most commonly suggested treatment choices for advanced prostate cancer. Antiandrogen AuNPs with multivalent analogs of antiandrogens are currently utilized in the clinical treatment of prostate malignant growths. Dreaden et al. (2012) found that antiandrogen AuNPs specifically target and connect with both the AR and a novel trans layer G-protein coupled receptor (GPRC6A) that is likewise unregulated in prostate cancer. Wolfe et al. (2015) reported that potent radio-sensitization of prostate cancers for in-vitro and in-vivo analysis used goserelin conjugated gold nanorods (gAuNRs) and pegylated gold nanorods (pAuNRs). The gAuNRs delivered a more noteworthy enhancement than the pAuNRs. They aggregated in the cells at fixations multiple times higher than straightforward pegylated NPs. Fitzgerald, Rahme, Guo, Holmes, and O’Driscoll (2016) anisamide labelled AuNPs for targeted delivery to siRNA which binds to the sigma receptor, over communicated on the outside of human prostate tumor cells. This study provides the proof of principle that anisamide-labelled AuNPs can be targeted to the prostate cancer cells. Further optimization of the formulation can increase the serum stability which will enhance to treat the prostate cancer.

11.5.8 Metallic nanoparticle platform Metallic NPs are adaptable devices in biomedical research because of their strength along with their small size, valuable optical properties, and simple functionalization.

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Applications, for example, radio treatment improvement (Berbeco, Ngwa, & Makrigiorgos, 2011), thermal ablation (Cardinal et al., 2008), analytical measurements (Chandra et al., 2013), and DD have been the focal points of the latest investigations. Additionally, the characteristic properties of metals are good for combinational treatments and diagnostics in a similar molecule, in the technique known as theranostics. Other than the demonstrated biocidal impact of silver NPs (AgNPs) (Rai, Yadav, & Gade, 2009), they likewise appear to have some particular benefits for applications in the treatment of malignant growths. For instance, AgNPs may have antiangiogenic properties and restrain cell expansion in tumor development. Gopinath, Gogoi, Chattopadhyay, and Ghosh (2008) examined the cytotoxicity of AgNPs toward tumor cells, and observed cell death and a synergic impact with the chemotherapeutic operator 5-fluorouracil. Firdhouse and Lalitha (2013) documented the “green” amalgamation of 100 nm sized AgNPs utilizing a fluid concentrate of Alternanthera sessilis. The subsequent NPs were shown to have activity against PC3 prostate cancer cells (Firdhouse & Lalitha, 2013). In spite of the empowering results obtained with AgNPs, AuNPs are at the best metal NPs for tumor applications. Cai (2008) portrayed the adaptability of AuNPs as a “gold bullet” since they offer incredible flexibility regarding surface operation and different remedial substances. Zhang et al. (2008) examined AuNP functionalization to improve radiation cytotoxicity in various cancer subjects. They fabricated glucose-bound AuNPs, which exhibited an expanded toxic effect and affectability to DU-145 prostate cancer cell line (Zhang et al., 2008). Arnida and Ghandehari (2010) studied the danger and cell uptake of AuNPs in PC3 prostate cancer cell line in relation to their shape, size, and surface features. They found that NPs of 50 nm without a pegylated surface had a superior uptake when compared to other materials (Arnida & Ghandehari, 2010). AuNPs were modified with various surface functionalization strategies by Zhao, Grillaud, Salmon, Ruiz, and Astruc (2012). Great outcomes against LNCaP prostate cancer cell lines were found when AuNPs were utilized to typify the antineoplastic medication, DTX (de Oliveira et al., 2013). One significant property of AuNPs for malignant growth applications is their diffusivity with temperature. The use of local hyperthermia guided by gold nanoparticles accumulation with the tumor is a recent strategy to provoke cancer cell necrosis. Super paramagnetic compounds such as iron oxide arebeing used for local delivery. In this case, the nanoparticles are guided to the targeted area by an external magnetic field where the nanocarriers can release antineoplastic drugs (Abdalla, Turner, & Yates, 2012). A few investigations have demonstrated that the danger of metallic NPs is chiefly because of their ability to eject particles. In this way, the ionic structure appears to exhibit a higher lethality than the basic state (Golovina & Kustov, 2013). Metal ions can experience redox cycling and create reactive oxygen species (ROS), for example, hydrogen peroxide, hydroxyl radicals, and superoxide matter. The natural movement of ROS results in damage to DNA, improved lipid peroxidation, and disabled intracellular calcium homeostasis, upsetting the typical cell cycle (Stohs, 1995). Among these NPs, superparamagnetic iron oxide NPs are not just approved by the food and drug administration (FDA), but on the other hand, are broadly utilized as pigment agents for the imaging of the liver, spleen, and gut because of inalienable biocompatibility and remarkable magnetic qualities. These formulations are generally synthesized through the co-precipitation approach in the presence of dextran polymer or a suitable stabilizing agent. Nonhydrolytic strategies are utilized to deliver high-crystalline

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iron oxide NPs with uniform size dissemination. Pluronic polymers are viewed as stabilizers for NPs because of their improved circulation, limited reticuloendothelial system retention, and improved tumor targeting due to the improved pervasion and enhanced permeation and retention impact (Lu, Salabas, & Schu¨th, 2007; Martina et al., 2007). Moreover, polymers, for example, polyvinylpyrrolidone (Rose et al., 2013), poly (vinyl alcohol) (Petri-Fink, Chastellain, Juillerat-Jeanneret, Ferrari, & Hofmann, 2005), chitosan (Parsian et al., 2016), and starch have been effectively utilized for this purpose. PLGA, PCL, and their iron oxide NP-based mixes have been broadly investigated as malignant growth DD systems (Ling, Wei, Luo, Gao, & Zhong, 2011). Dextran is an allinclusive stabilizer and approved-FDA material for imaging applications using magnetic NPs. Numerous dextran-based mixtures are utilized in this role. Egg whites represent another flexible covering for creating stable attractive NPs for use as a carrier (Zeybek, S¸ anlı-Mohamed, Ak, Yılmaz, & S¸ anlıer, 2014). Thus polymerosomes (Bleul et al., 2013; Hickey et al., 2014), dendrimers (Sun, Mignani, Shen, & Shi, 2016), and Pluronic polymers (Jain, Morales, Sahoo, Leslie-Pelecky, & Labhasetwar, 2005) are appropriate for stabilizing. Paclitaxel is a commonly utilized chemotherapeutic agent for a wide assortment of malignancies. Pegylated NP micelles with paclitaxel have the capacity to improve the intensity of paclitaxel against C4-2 cells as determined in xenograft tumors in athymic naked mice (Taylor & Sillerud, 2012). DTX (Taxotere) is another FDA-approved chemotherapeutic agent for prostate malignancy; in any case, its unfavorable harmful symptoms limit its clinical use. An attractive NP detailing can improve the conveyance and viability of DTX in prostate tumors (LNCaP, DU 145, and PC3) (Sato et al., 2013). Also, an improved anticancer action of DTX was accomplished with an attractive NP plan embellished with polymer vesicle layers (Ling et al., 2011). Mitoxantrone
iron oxide NPs help in expanding the targeting ability of mitoxantrone in tumor tissue as compared to mitoxantrone alone (Krukemeyer, Krenn, Jakobs, & Wagner, 2012). Along these lines, attractive NPs represent a promising bearer for numerous anticancer medication atoms, for example, DOX (Ranney et al., 2005), 5-fluorouracil (5-FU), zoledronate (antiosteoclastic properties) (Benyettou, Lalatonne, Sainte-Catherine, Monteil, & Motte, 2009), flutamide (Licciardi et al., 2013), and bicalutamide (antiandrogen) (Lee, An, Shin, & Kim, 2012). Additionally, lipid-based magnetic NPs are proposed widely because of their medication deposition capacity in hydrophobic layers and ability to incorporate seed-development strategies (Huang et al., 2009). The clinical administration of prostate malignant growth treatments is regularly troublesome because of the absence of explicit and targeted restorative interventions. Conventional methodologies include the utilization of anionic glycosaminoglycan (dermatan sulfate) with magnetic NPs, which focus on the upregulated transport activities of neovascular endothelium (Ranney et al., 2005). Numerous other attractive NP strategies can target prostate tumor cells and tumors by focusing on folate receptors (An et al., 2013), Mucin 1 (Guo et al., 2016), urokinase plasminogen activator (Abdalla et al., 2011), gastricreleasing peptide receptors (Lee et al., 2010), prostate disease explicit R11 peptides (Sundaresan, Menon, Rahimi, Nguyen, & Wadajkar, 2014), secreted protein, acidic and rich in cysteine (Ghosh et al., 2012), luteinizing hormone
releasing hormone (Branca et al., 2009), prostate stem cell antigens (Guo et al., 2012), and heat shock protein (Rylander, Stafford, Hazle, Whitney, & Diller, 2011).

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Iron oxide NPs are composed of a center made of iron oxide with a hydrophilic layer of dextran or another biocompatible compound to expand their strength (Weissleder et al., 1990). These operators display size-dependent super magnetism, which enables them to be charged with the use of a magnet field. The particles never again show collaboration after the expulsion of the magnetic force. Superparamagnetic iron oxide NPs have been effectively utilized as T2-weighted MRI staining agents to track and screen cells (Bulte & Kraitchman, 2004). They offer benefits over gadolinium, including a slower renal clearance and higher imaging affectability and particularity (Talelli et al., 2009). Ferumoxtran-10 is a monocrystalline superparamagnetic iron oxide center containing a thick covering of dextran that is devotedly taken up by the lymph hubs (Harisinghani et al., 1999). Ferumoxtran-10 is gradually extravasated from the vascular space into the interstitial space and from that point to the lymph hubs by means of lymphatic vessels causing decreased intensity inside ordinary lymph tissue on T2-weighted iron-delicate MRI successions (Fortuin, Smeenk, Meijer, Witjes, & Barentsz, 2014).

11.5.9 Nanocolloidal The sentinel node idea depends on the theory that the transmission of metastatic cells inside a lymph node continues in a methodical manner through numerous anatomic levels. In the event that the sentinel lymph node is liberated from harmful cells, at that point, the rest of the lymph nodes ought to likewise be liberated from metastatic sickness (Emerson et al., 2012). Customary sentinel lymph node mapping is performed utilizing 20
600 nm radiocolloids. A short study on utilizing the multireporter test 99mTc-marked Cy7 tilmanocept exhibited in vitro and in vivo receptor restricting properties for effective sentinel lymph node mapping with optical and atomic imaging (Emerson et al., 2012). 99mTc-tilmanocept has a dextran outline connected with various diethylenetriaminepentaacetic acid and mannose deposits. 99mTc is joined to diethylenetriaminepentaacetic acid, and the mannose deposits tie to mannose receptors (CD206). 99mTc-tilmanocept can relocate rapidly through the afferent lymph vessels as a result of its small size, as well as its capacity to dwell inside sentinel lymph nodes in view of its binding. A cross breed fluorescent radioactive tracer has likewise been applied for sentinel node recognition by blending indocyanine green with 99mTc-albumin colloid (Brouwer et al., 2012; Wallace, Hoh, Vera, Darrah, & Schulteis, 2003).

11.6 Treatment for prostate cancer: nanotechnology and prostate cancer NPs can likewise be designed to play different roles by connecting multimodal imaging, diagnosis, and treatment in synergetic “theranostics” and multifunctional strategies (Gindy & Prud’homme, 2009; Janib, Moses, & MacKay, 2010). Consolidating atomic imaging and DD, theranostic NPs can be utilized in a variety situations that range from improving the diagnosis of diseases and the treatment of prostate cancer to better understanding different significant parts of DD procedures. To date, a few exquisite investigations have been done to show the standard theranostic process by utilizing NPs. For instance, considering

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prostate cancer as a target infection, Farokhzad and Langer additionally assessed the capability of Apt-conjugated cross-connected superparamagnetic iron oxide nanoparticles (SPION) NPs (thermally cross-linked-SPION-Apt) for focused MRI and DD (Wang et al., 2008). Also, an influenza fluorescent QD-DOX-Apt framework dependent on a CdSe/ZnS center shell was designed to recognize the intracellular arrival of DOX, and to empower the synchronous fluorescent limitation and slaughtering of tumor cells (Bagalkot et al., 2007). Kim et al. (2010) designed multifunctional NPs for focused atomic CT imaging and treatment of prostate cancer by functionalizing the surface of the gold nanoparticles (GNPs) to bind to PSMA. The subsequent PSMA Apt
conjugated GNPs indicated a particular CT force and antiproliferative action (when stacked with DOX) for prostate tumor cells. Moreover, Agemy et al. (2010) revealed that the pentapep-tide CREKA (Cys-Arg-Glu-LysAla) explicitly homes tumors by fibrin and fibrin-related coagulated plasma proteins in the vessels of tumors. A few treatment options are accessible for prostate tumors contingent upon the circumstance and the seriousness of the malignant growth. A proficient treatment for prostate cancer incorporates medical procedures like chemotherapy, radical prostatectomy, radiation treatment, and PSMA combinational and targeted treatments (Al-Mamgani et al., 2010; Moore, Pendse, & Emberton, 2009; Peschel et al., 2000). A radical prostatectomy is a careful technique that includes the whole removal of the prostate organ along with the urethra and bladder and a portion of the tissues around it to forestall the additional spread of the prostate tumor to different organs. The two fundamental vesicles, the small liquid-filled sacs around the prostate, will likewise be removed (Ramsay et al., 2012). Newly, laparoscopic radical prostatectomy and robot-assisted laparoscopic prostatectomy, which are insignificantly obtrusive, have been created. On the off chance that a tumor has spread to different organs or tissues in the body past the prostate organ, it cannot be relieved. There are some other treatment alternatives that are accessible for high-hazard prostate disease, such as radiation treatment, hormonal treatment, and chemotherapy. Radiotherapy harms dangerous cells and prevents them from separating and developing. Ordinary cells can recuperate from the harm; however, disease cells can’t endure. Radiotherapy involves the use of energy beams to kill tumor cells to monitor disease and soothe indications to improve the daily lives of patients (Bostrom & Soloway, 2007). Three-dimensional conformal radiation therapy (3D-CRT) has the highest level of quality, while intensity-modulated radiotherapy, a streamlined type of 3D-CRT, is more commonly utilized as is image-guided radiotherapy. External beam radiation treatment is one of the primary sorts of radiotherapy techniques that are utilized for the treatment of prostate tumors. Dose escalation range 74
80 (Gy) (Gray-unit of ionization radiation) has a significant impact on 5-year survival relapsed. Hormonal treatment, for the most part, includes androgen treatment. Antiandrogen drugs or inhibitors are utilized to deny the emission of testosterone. Luteinizing hormonereleasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists), CYP17 inhibitor were used for androgen deprivation therapy. Auxiliary hormonal treatments contain adrenal androgen inhibitors, enemies of androgens and estrogens. Chemotherapy is considered to be a significant remedial methodology in which different cytotoxic medications are utilized. Dtxl is one of the most well-known medications given for the primary treatment of prostate tumors along with the steroid sedate prednisone (Petrylak et al., 2004). CBX is the second most common medication that is utilized for

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further treatment (Ning et al., 2010). However, conventional chemotherapeutic approaches are limited, due to their low therapeutic index, severe side effects, poor pharmacokinetics and non- specificity. In this way, there is increasing interest in the advancement of novel treatment modalities that can treat prostate diseases.

11.6.1 Nanochemoprevention of prostate cancer Chemoprevention is the use of materials especially naturally occurring phytochemicals which are capable of impending the process of one or two more steps in the carcinogenesis process. “Nanochemoprevention” is the utilization of nanotechnology for improving the results of chemoprevention intercession (Siddiqui et al., 2009). Epigallocatechin-3-gallate (EGCG) is a well-known chemopreventive agent and it has shown wonderful potential in preclinical examinations and a wide scope of cell cultures (Khan, Afaq, Saleem, Ahmad, & Mukhtar, 2006). Moreover, EGCG has a compelling chemopreventive impact against prostate tumors (Stuart, Scandlyn, & Rosengren, 2006). Siddiqui et al. (2009) detailed the exemplification of green tea polyphenol, EGCG, in PEG NPs. From the study, it was observed that encapsulated EGCG retains its biological effectiveness with over 10-fold dose advantage over non-encapsulated ECGC which showed increased bioavailability and reduced unwanted toxicity of chemopreventive agents (Siddiqui et al., 2009). In another examination, ECGC was joined into a starch lattice of gum arabic and maltodextrin, and according to in vitro tests, the exemplified EGCG held its natural action, diminished cell suitability, and incited apoptosis in prostate tumor cells, namely DU-145 cell lines (Rocha et al., 2011). CUR
PLGA nanospheres were made utilizing the soil/water/solid emulsion solvent evaporation method. In vitro examinations were completed with prostate tumor cell lines and it was uncovered that these CUR
PLGA nanospheres had an articulated impact on the tumor cells when compared with free CUR. Narayanan et al. (2009) utilized liposomeepitomized resveratrol and CUR independently and in a blend. In vitro examination utilizing PTEN-CaP8 tumor cells were performed to research the consolidated impact of CUR with resveratrol. It was observed that the mix of liposomal types of CUR and resveratrol adequately restrained cell development and actuated apoptosis (Thangapazham et al., 2008). Sanoj Rejinold, Muthunarayanan, Chennazhi, Nair, and Jayakumar (2011) detailed CUR-stacked fibrinogen NPs and it was uncovered that curcumin loaded fibrinogen nanoparticles were harmful to PC3 and MCF7 disease cells and relatively nonpoisonous to L929 and could be a promising remedial agent for tumor treatment (Sanoj Rejinold et al., 2011). DTX is an elective treatment for metastatic prostate malignancy; DTX-stacked NPs can possibly initiate clinical reactions. In an investigation by Sanna et al. (2011), two biodegradable copolymers, namely polylactide-co-caprolactone and polylactide-co-caprolactoneco-glycolide were investigated for the definition of DTX-stacked NPs, and the potential anticancer action of these nanoformulations was assessed by in vitro studies utilizing prostate tumor cell lines. In clinical practice, current medicines for prostate cancer treatment include directed chemotherapy, medical procedure, and radiotherapy (Heidenreich et al., 2011). Chemotherapy with drugs, for example, paclitaxel, DTX, and DOX, is powerful in terms of increasing the endurance and improving the lives of patients. Be that as it may, chemotherapeutics can

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cause many reactions, for example, male pattern baldness, body weight changes, sickness, and liver, cardiovascular, and kidney harm, as well as a ruinous “observer” impact to neighboring cells (Yazdan, 2011). Likewise, because of the poor infiltration of medications into tumor tissues, the remedial viability is restricted (Jia et al., 2009). So as to overcome the fundamental harmfulness and low remedial adequacy, numerous advancements, for example, medication analogs, nanomaterials, and prodrugs have been created for clinical applications (Cheng, Wang, Feng, Yang, & Liu, 2014; Ryu et al., 2012). Currently, nanomaterials are amongst the most encouraging devices to essentially improve antitumor adequacy due to their physical and compound properties (Shapira, Livney, Broxterman, & Assaraf, 2011), and an ever increasing number of studies have been dedicated to the treatment of prostate cancer by means of chemotherapy with nanomaterials to expand its medication adequacy, cut down drug toxicity, and keep up with the high centralization of medication at the site of intrigue.

11.6.2 Treatment of prostate cancer via gene delivery with nanomaterials As one of the most effective approach in cancer cure, gene delivery has caused wide concern over the recent years. To realize quality malignancy treatment, toxic genes should be redirected to disease cells and toward cells demise consistently and precisely (Soltani, Sankian, Hatefi, & Ramezani, 2013). As a compelling regulator of different conditions, including formative, physiological, and pathological, microRNA, endogenously communicated noncoding RNA particles, have been viewed as potentially helpful targets in numerous illnesses (Barbato, Ruberti, & Cogoni, 2009; Hwang et al., 2011). While, because of the existence of cell membranes and other obstacles, naked genes cannot realize cancer gene therapy alone. Consequently, a satisfactory vector that can redirect genes proficiently and safeguard them from corruption in the circulatory system ought to be found (Li, Wei, & Gong, 2015). Nonviral, gene delivery frameworks, including polymers, lipids, and nanomaterials, have been created for siRNA conveyance (Park, Jeong, & Kim, 2006). An another group reported the delivery of small interfering RNA (siRNA) through layer-by-layerassembled microcapsules (Becker et al., 2011). In their report, in view of the layer-by-layer joining of a crosslinked poly(methacrylic acid) film, two unique kinds of microcapsules were utilized to convey siRNA focusing on surviving, and the expression of the counter apoptotic protein was seen. This film showed the capacity to maintain the integrity of the capsule in the oxidizing circulatory system and in the extracellular condition, in this manner, shielding the siRNA from denaturation and ensuring the siRNA were discharged in the diminishing intracellular condition. Also, a group of researchers announced the creation of siRNA NPs covered with lipids by a one of a kind delicate lithography molding process known as particle replication in nonwetting templates (Hasan et al., 2012). Mixing polymers and lipids, hybrid NPs with high drug encapsulation yields, tailored and continued medication discharge profiles, and sound serum qualities could be a pertinent DD strategy. Polycationic monodispersed poly(L-lysine) is one such promising transporter among the assortment of polymers intended for gene delivery as an effect of its controllable shape, size, and adaptable chemical alteration (Walsh et al., 2006). Nonetheless, the low transfection effectiveness constrained the use of poly(l-lysine) ( PLL)-based polyplexes

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in clinical treatments (Guo, Bourre, Soden, O’Sullivan, & O’Driscoll, 2011). Through the pegylation of poly(L-lysine-cholic acid), a sort of amphiphilic polycation has been orchestrated (Guo et al., 2012). With ‘stealth’ capacity, the benzoic imine linker between PEG and PLL-cholic acid is stable at physiological pH. It is cleavable at lower pH especially in the extracellular environment of tumours and the interior of endosomes/lysosomes.It was observed that lipid polyethylenimine (PEI) nanocarriers have various benefits, including silencing effectiveness in vivo and in vitro, low harmfulness, and immunogenicity. As one of the most famous polycationic polymers, PEI has generally been utilized in nonviral gene carriers (Jere et al., 2009). Due to their high charge density, PEI atoms can shape dense models with nucleic acids and can reinforce the collaboration with cell surfaces. Besides, nucleic acids can be discharged effectively from the endosomes through the proton sponge effect (Dehshahri, Oskuee, Shier, Hatefi, & Ramezani, 2009). Those exceptional properties lead to high transfection proficiency of PEI among nonviral gene bearers. An another group of researchers detailed a lipid PEI mixture nanocarrier which consolidates direct PEI with hydrophobic, hexadecyl groups (Xue, Narvikar, Zhao, & Wong, 2013). The LPN would solve or improved several key issues of siRNA/PEI systems. It includes physical encapsulation of the siRNA rather than coating them on carrier surface, reduction of the loss of siRNA and easiness of controlled, continuing intracellular siRNA release, prevented cells from quick exposure to a high level of unencapsulated PEI molecules,provided more sites for grafting cell-targeting (Stevens, Sekido, & Lee, 2004; Wang et al., 2010; Xu et al., 2009). However, the extreme cytotoxicity of PEI due to its high positive charge has constrained the utilization of PEI (Huang, Lv, & Gao, 2011). In this current method, a sort of nonviral cationic polymer vector mPEG-PEI NPs were utilized as a transporter and the siRNA plasmid was remade (Wu et al., 2014). With grafted moieties of PEG, PEI polymers indicated a lower cytotoxicity and better steadiness. To additionally build cell biocompatibility, a disulfide linkage was presented in the PEI containing various amines (Son et al., 2011). Disulfide polyethylenimine derivative (SSPEI) polymer labeled with poly-arginine (R11) which has the highest uptake by different prostate cancer cell lines compared with other four cell permeable peptide was used to deliver miR-145 to the prostate cancer. Additionally, SSPEI presented a PEG chain linker that could improve its biocompatibility and lengthen its flow time in the circulatory system (Zhang, Xue, He, & Hsieh, 2015). The outcome indicated that the R11-SSPEI/FAM-miR-145 complex could significantly repress tumor development and increase survival time. To construct a superior gene delivery framework, its targeting capacity is noteworthy. With the improvement of gene therapy innovation, remedial impacts of single-gene targeted treatment and numerous gene silencing were proposed. Recently, the combinatorial RNAi technology and simultaneous multiple gene silencing have been attempted to cancer therapy and received a big success (Han et al., 2010; Tai, Qin, & Cheng, 2010). Therefore, a new class of dualgenes targeted two distinct sequences of siRNA (vascular endothelial growth factor (VEGF) and B-cell lymphoma 2 (Bcl-2) and its their delivery systems for proficient cancer treatment was were created (Lee et al., 2015). Carrying glycol chitosan nanoparticles, the dual-poly-siRNA encapsulated thiolated glycol chitosan (tGC) nanoparticles (dual-NPs) can give productive and controlled double poly-siRNA conveyance and accomplished multigene sequencing with synergistic impacts of tumor treatment. A Recently, researches showed that the suppression of crucial gene products such as REV1, REV3L can resistant

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the sensibility of tumors to chemotherapy reduce the drug resistance of relapsed tumors during the error prone translation DNA synthesis pathway. In view of these researches, a promising system that consolidates siRNA-based therapeutics with DNA-damaging chemotherapy was brought forward to treat cancer patients (Wang, Gao, Ye, Yoon, & Yang, 2006; Zhang et al., 2012). Clearly, the outcome demonstrated a superior remedial viability both in vitro and in vivo to that of the use of the prodrug cisplatin alone (Xu, Qian, et al., 2013; Xu, Xie, et al., 2013). The result reported a less values of IC50 and a higher median survival, provided a promising synergistic delivery system for clinical treatment of Prostate cancer. To understand the use of RNAi in the clinical treatment of prostate disease, a way to deal with the assessment of siRNA conveyance at the target site is critical. In this manner, theranostics NPs that combined imaging with therapeutic properties were proposed and created (Tandon & Farahani, 2011). A decent strategy for the theranostic imaging of prostate tumors was planned and created (Chen et al., 2012). These theranostic NPs were joined by three core segments including the prodrug-activating enzyme bacterial cytosine deaminase (βCD), the imaging bearer poly-l-lysine which followed with a near infrared fluorescent test Cy5.5 and the transporter which isn’t just for siRNA conveyance yet in addition for labelling with [111In] DOTA for Single photon emission computed tomography (SPECT) imaging. The outcomes confirmed the practicality of the strategy of partner identification and treatment (Lin et al., 2014). The siRNA conveyance in an orthotopic tumor model was assessed by CT and fluorescence subatomic tomography, and it accomplished an effective RNAi treatment.

11.6.3 Treatment of prostate cancer via cancer immunotherapy with nanomaterials Immunotherapy is a method of provoking a lymphocyte reaction from a tumor inducing gene. Vaccination approaches have been extensively studied and were found to be ineffective (Mocellin, Mandruzzato, Bronte, Lise, & Nitti, 2004; Rosenberg, Yang, & Restifo, 2004). In comparison with the conventional approaches, NPs could protect antigens from their biological environment, increase their half-life, promote their convergence to antigen-presenting cells (APCs) and cut down systemic toxicity as well as potentially aiding in the triggering of tumor-associated antigens (TAA)-specific T-cells. In the past few years, numerous NP-based molecules have reached the stage of clinical trials, while the NP-based system of TAA delivery to the APCs was documented as being a potential nanovaccine medication (Cho, Wang, Nie, Chen, & Shin, 2008; Taurin, Nehoff, & Greish, 2012). Also, a few NP designs have consisted of immunostimulatory features and these can induce B- and T-cell responses in the absence of adjuvants (Dwivedi, Tripathi, Ansari, Shanker, & Das, 2011). Lee et al. (2011) developed a platform for chemoimmunotherapy where they designed a system of delivery using a dendrimer and a SSDNA-A9 PSMA RNA Apt hybrid, which was actually developed to conquer the drawbacks of conventional tumor therapy. Sun et al. (2017) designed a prodrug redox-responsive immunostimulatory polymeric PSSN10 carrier for the delivery of the immune checkpoint inhibitor NLG919 and DOX. Jankun (2011) used LnCAP human prostate cancer cells targeted by antibody (against

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prostate-specific membrane antigen) to conjugate with hematoporphyrin (HP) through protein-based nanotechnology and the results show that mAb/HP conjugates effectively deliver hematoporphyrin to cancer cells. Promoting interactions at the T-cell synapse to cut down autoimmunity or boost anticancer immunity is the main goal in immunotherapy (Carren˜o, Gonza´lez, Bueno, Riedel, & Kalergis, 2011). Stephan, Stephan, Bak, Chen, and Irvine (2012) demonstrated that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T-cell/APC contact zone during antigen recognition.

11.7 Nanotechnology approach and prostate cancer diagnosis It is also overcoming challenges of early detection and imaging in current cancer therapies. As far as the biological markers are concerned, the prostate specific antigen (PSA) a serum biomarker utilized for prostate tumor screening, is close to only a result of the physiology and pathophysiology of prostatic epithelial cells. Although some researchers and clinicians contend about the PSA levels as a standard screening device for prostate malignant growth, PSA can be utilized as an unambiguous pointer of reaction to treatment and repeat on account of patients who have experienced radical prostatectomy. Thaxton, Elghanian, and Thomas (2009) utilized an amazingly sensitive nanotechnologybased apparatus, known as a “bio-standardized tag” framework, to recognize the already imperceptible degrees of PSA in prostate malignant growth patients. In order to induce optical contrast in non-pigmented cancer cells, the researcher group has attached GNPs to a Prostate cancer cell line, enabling the detection of such cells in a photoacoustic flow meter, designed to find circulating tumor cells in blood samples (Viator et al., 2010). The obtained results supported that photoacoustic response from PC cells treated among white blood cells in the flowmeter is able to demon-strate the ability to detect single cells under flow. To identify the feasibility of thermotherapy using biocompatible superparamagnetic iron oxide NPs (SPION) in patients with locally recurrent Prostate cancer, and to evaluate an imaging-based approach for noninvasive calculations of the three-dimensional temperature distribution, a noninvasive and specific technique of magnetic fluid hyperthermia was formulated (Johannsen et al., 2007). It was the first clinical application of interstitial hyperthermia using magnetic NPs in patients with biopsy-proven local recurrence of Prostate cancer following radiotherapy with therapeutic purpose. Since the adverse prognostic implications of lymph-node metastases have been widely established, the means to identify clinically occult lymph-node metastases is an essential component of the approach to cancer treatment. In this context, Weissleder group found that the use of highly lymphotropic superparamagnetic nanoparticles holds considerable promise, permitting the MRI of clinically mysterious lymph-node metastases in patients with prostate malignant growth, which are not recognizable by other noninvasive methodologies (Harisinghani et al., 1999). Lee et al. (2010) announced the planning and characterization of magnetofluorescent polymeric NPs for prostate malignant growth imaging in vivo. Specifically, bombesin-conjugated N-acetyl histidine-glycol chitosan (BC-NAHis-GC) NPs were utilized in the targeting of gastric-discharging peptide receptors (GRPR), which are overexpressed in prostate

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disease cells. The NPs designed (BC-NAHis-GC NPs) is signigficantly demonstrated higher binding to the Prostate cancer cell surface than NPs without bombesin. Furthermore, SPIONs were stacked into the BC-NAHis-GC NPs as a test for MRI, and the results additionally showed the improved tumor amassing in prostate malignant growth
bearing mice, subsequently recommending that such frameworks might be helpful for prostate disease imaging (Lee et al., 2010). PSA, a glycoprotein produced by prostatic epithelial cells, has become a revolutionary in Prostate cancer diagnosis (Azzawi, Seifalian, & Ahmed, 2016; Bharali & Mousa, 2010). Both typical prostate cells and carcinogenic prostate cells will deliver PSA. Although PSA levels can be used as a routine screening tool for Prostate cancer detection, they can also be used as an unambiguous indicator of response to therapy and recurrence in the case of patients who have undergone radical prostatectomy. AuNPs dissipate light at or close to the surface plasmon reverberation (SPR) wavelength locale (Yguerabide & Yguerabide, 1998). AuNPs combined with dynamic light dissipating (DLS) location, a simple NP immunoassay for serum protein biomarker recognition and investigation, has been created. This NP immunoassay can be utilized as a helpful and general apparatus to screen and break down serum proteins like PSA and to find new biomarkers related to malignancy and other human infections (Huo et al., 2011). This bio-barcode system is an ultra-sensitive technology which is based on AuNPs probes decorated with DNA and antibodies (Abs) that can recognize and bind to PSA when present at extremely low levels in the serum sample. This examination proved to be multiple-times more sensitive than economically accessible PSA tests. In order to induce the optical contrast in non-pigmented cancer cells, Viator et al. (2010) connected AuNPs to a prostate disease cell line, empowering the discovery of nonpigmented malignant growth a few sets of size (2.5 3 109). Therefore it can perceive human prostate malignant growth cells at a 50-cell level (Viator et al., 2010). Zheng et al. (2015) reported that the amount of human immunoglobulin G(IgG) in the gold nanoparticle protein corona is found to be increased in Prostate cancer patients compared to non-cancer controls. Prostate cancer biorespository network (PCBN) revealed that this blood test has a 90%
95% explicitness and half affectability in identifying beginning time prostate disease, speaking to a noteworthy improvement over the ebb and flow PSA test. The test might be additionally appropriate for the early identification and hazard evaluation of a wide range of malignancies (Zheng et al., 2015).

11.7.1 Nanotechnologies for fluorescence diagnosis of prostate cancer Diagnosis aids in determining the cancer stage and in helping out in the treatment. Molecular imaging helps in staging, early diagnosis, restaging, and the treatment of cancer. Nanotechnology along with diagnostics aids in attaining improved resolution, high sensitivity, specificity, and also reliability. With the advances in nanotechnology, one can diagnose tumor biomarkers at the molecular level and determine the treatment output in vivo. In order to detect cancer in the early stages, numerous biomarkers were discovered like PSMA, hepsin, PSA (Cheng et al., 2014; Constantinou & Feneley, 2006), and matriptase (Saleem, 2006).

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11.7.2 Targeted prostate-specific antigen nanoprobe for imaging prostate cancer PSA is produced by the prostate gland that is about 33 kDa and is an androgenregulated serine protease. This particular biomarker is used for the diagnosis of prostate cancer and in its detection at an earlier stage. In 2001, Lo¨vgren documented a diagnostic technology that depends on europium (III) NPs and reported the visualization and detection of PSA molecules by utilizing time-resolved microscopy (Ferguson, Yu, Kalyvas, Zammit, & Diamandis, 1996). In 2006, Lee developed a hybrid probe using artificial molecules and by joining peptides and particles that have greater specificity toward PSA (Liu et al., 2008). While, Gao et al. (2005) developed a new design of NP probe and it demonstrated a sensitive detection of PSA. They put forward a new strategy for QD preparation based on NP polymer complexes in a homogenous solution. In 2016, Chen documented the application of a Lu6O5F8:Eu31 nanoprobe for the diagnosis of PSA in clinical studies (Gao et al., 2005). They have developed inorganic lanthanide fluoride nanoparticles based on dissolution enhanced luminescent bioassay technique, leading to amplified signal and improving the detection sensitivity.

11.7.3 Targeted prostate-specific membrane antigen nanoprobes for imaging prostate cancer PSMA was found to express in both prostatic epithelial cells and benign cells as well as in tissues like the liver, kidney, and brain. It is composed of 750 amino acids, is a transmembrane with type 2 glycoprotein, and is expressed normally in human prostate epithelium and overexpressed in prostrate tumor cells. It’s expression is increased in metastatic, less differentiated, hormone refractory carcinomas (O’Keefe, Bacich, & Heston, 2004). A research study stated that the biotinylated anti-PSMA antibody linked to streptavidinlabeled iron oxide NPs could be used as a probe for the diagnosis of prostrate tumor cells (Kasten, Liu, Nedrow-Byers, Benny, & Berkman, 2013). The building of PSMA-targeted AuNPs was done using 5 nm AuNPs covered with streptavidin and heating the PSMA inhibitor, which is biotinylated. The results obtained from the study suggested that the PSMA-targeted AuNPs is found to be better than nonspecificity nontargeted AuNPs, and it was demonstrated that the AuNPs could be utilized for PSMA targeting by providing inhibitors.

11.8 Conclusion In summary, DD systems based on NPs and selective tumor medications are useful and efficient in communicating with particular molecules participating in the development, proliferation, and progression of cancer cells. Formulations based on NPs enhance specificity and promote tumor cell apoptosis (cell death), making them the perfect option for treating prostate cancer. Moreover, a number of challenges and hurdles still have to be resolved to accomplish the effective and desired treatment for specific types of prostate cancer. In contrast to significant studies, variety of NPs have been formulated, and

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are appropriate for treatment for cancer. In addition, new technologies are required for particle rebalancing and acceleration of targeting.

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C H A P T E R

12 Nanomedicine-based multidrug resistance reversal strategies in cancer therapy Rishi Paliwal1,*, Shivani Rai Paliwal2,* and Rameshroo Kenwat1 1

Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India 2SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur, India

12.1 Introduction The clinical efficacy of chemotherapy of cancer cells is limited due to many factors, including the undesired distribution of cytotoxic drugs to healthy vital cells, low bioavailability in the tumor microenvironment, and the development of multidrug resistance (MDR). Biedler and Riehm (1970) reported the concept of MDR in chemotherapy way back in the 1970s. Briefly, MDR in cancer cells can be defined as the resistance of cells to any anticancer agent accompanied by other chemotherapeutic drugs, which possess different structures and functional moieties, or it can also be defined as a condition of resilience against structurally and functionally dissimilar drugs (Harris & Hochhauser, 1992). The MDR phenomenon is a consequence of multiple factors, including p-glycoprotein pump mediation, the upregulation of adenosine triphosphate (ATP)-binding cassette (ABC) transporter proteins, hypoxia, xenobiotics factors, and p53 gene mutation, etc. MDR can be classified into various groups according to the associated mechanisms such as increased drug efflux by efflux pumps, decreased influx, and increased concentration of metabolizing enzymes such as cytochrome p450 that rapidly metabolize and inactivate internalized chemotherapeutic agents, increased DNA repair, and the termination of the

*Equal contributions to the chapter.

Nano Drug Delivery Strategies for the Treatment of Cancers DOI: https://doi.org/10.1016/B978-0-12-819793-6.00013-8

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apoptotic process. In spite of the different mechanisms, MDR is a consequence of a synergistic combination of multiple factors (Tekchandani, Kurmi, & Paliwal, 2017). Drug resistance can be a key obstacle in therapy due to either intrinsic insensitiveness from the beginning or an acquired resistance that develops after continuous exposure of a similar drug. Successful cancer chemotherapy requires MDR reversal or making cells sensitive toward the uptake of drugs and, therefore, to their therapeutic action. The published/ reported literature advocates for using nanoparticles loaded with cytotoxic drugs with or without MDR reversal agents (Ahmad et al., 2016). The exploitation of smart nanosized architectures for MDR reversal provides an opportunity for the fulfillment of the expectation of chemotherapy (Brigger, Dubernet, & Couvreur, 2012). These carriers include polymeric nanoparticles, lipid nanoparticles, multifunctional micelles, dendrimers, gold nanoparticles, quantum dots, and many more. A few of them like gold nanoparticles, quantum dots, and magnetic nanoparticles have been utilized for the detection of cancer cells in theragnostics (Gupta et al., 2016). This chapter summarizes the MDR mechanisms in cancer, methods for MDR reversal for cancer therapy, and reports/strategies of the utilization of nanoparticles for MDR reversal in cancer therapy.

12.2 Multidrug resistance in cancer therapy: a brief account A significant amount of chemotherapy cases (nearly half of all cases) encounter MDR during the course of therapy, and most of them result in clinical failure, leading to major deaths during therapy. Cancerous cells, including lung, breast, ovarian, and colon cancer cells, develop resistance to chemotherapeutics involving mechanisms of MDR. Tumor progression is also a result of the growth of drug-resistant cells; which develop during previous exposure to a drug. The failure of chemotherapy due to MDR is a combined result of the continuous exposure of patients to similar drugs, the tendency of cancer cells to develop MDR, and the individual host as well.

12.3 Mechanisms of multidrug resistance in cancer cells Numerous known mechanisms are responsible for MDR, that is, the overexpression of the P-glycoprotein (P-gp) efflux protein, consideration of drugs as xenobiotics by the cells, mutation in tumor suppressor gene p53, and the hypoxic tumor microenvironment of the tumor region. Fig. 12.1 represents various features of an MDR cancer cell in comparison to a normal cell. Different MDR mechanisms were discussed here in brief for the benefit of the reader.

12.3.1 Overexpression of P-glycoprotein efflux proteins Generally, P-gp efflux pumps are ATP-dependent cellular transporter proteins that work for the elimination of xenobiotic compounds, specifically from intracellular sites to extracellular locations across the cell membrane (Lowrence, Subramaniapillai, Ulaganathan, &

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12.3 Mechanisms of multidrug resistance in cancer cells

FIGURE 12.1

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Schematic presentation of key mechanisms of multidrug resistant cancer cells in comparison to

normal cells.

Nagarajan, 2019). The overexpression of these proteins and the resulting low concentration of cytotoxic drugs remain the major mechanisms of MDR in cancer cells. They are also known as the ABC transporter super family. Some of the active members of this family are ABCB1 (known as MDR1) and ABCC1 (known as the MDR-associated protein MRP-1) (Domenichini, Adamska, & Falasca, 2019). Apart from pumping out from intracellular site, P-gp protein overexpression also participates in other mechanisms of resistance. For example, P-gp presents resistance to complement mediated toxicity due to delayed deposition of complement on the plasma membrane.

12.3.2 Xenobiotics Xenobiotic-induced transcriptional regulation of enzymes and transporters is established. The nuclear receptor like pregnane X receptor (PXR), after binding with structurally unrelated xenobiotics, upregulates the transcription of metabolizing enzymes (CYP450s) and efflux transporters (P-gp). The PXR plays a crucial role in MDR in cancer cells because of the upregulation of its expression in different cancer cells. Further, it has a wide flexibility in recognizing structurally diverse compounds.

12.3.3 Tumor suppressor genes Tumor suppressor gene, p53, restrains the production of abnormal cells and acts as a cell cycle regulator (Moon et al., 2019). A number of human tumors are associated with p53 gene mutation and loss of its activity, resulting in the formation of defective DNA. This DNA replicates continuously and becomes drug resistant. Thus p53 is also responsible for MDR in many tumors.

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12.3.4 Hypoxia The tumor extracellular environment has a restricted solute distribution and reduced levels of oxygen, resulting in a hypoxic state inside the tumor. The success of chemotherapy is influenced by hypoxia as most anticancer agents act by free radicals production (Minassian, Cotechini, Huitema, & Graham, 2019). The hypoxic state also reduces cell proliferation, resulting in the failure of drugs that kill rapidly growing cells. Hypoxiaresponsive element, which is activated by hypoxia-induced transcriptional factor 1α, regulates the MDR1 gene. The upregulation of the MDR1 gene is also responsible for MDR to chemotherapeutic drugs. Tumor cells utilize glucose as an energy source for growth and proliferation. Glycolysis is associated with the accumulation of lactic acid and decreases in tumor pH. This is why basic drugs ionize in acidic environments and fail to cross intracellular barriers, resulting in the failure of chemotherapy.

12.3.5 Autophagy Autophagy is usually a self-degradation process of the cells that maintains intracellular homeostasis. In fact, this process is involved in the degradation of damaged proteins and cellular organelles, recycling their parts and components for the regeneration of metabolic precursors (Galluzzi, Bravo-San Pedro, Demaria, Formenti, & Kroemer, 2017). Preventing this process of cellular damage and, therefore, protecting cancerous cells from apoptosis results in chemoresistance. Although chemo-induced autophagy also activates apoptosis signaling pathways, resulting in MDR reversal, a productive autophagy mechanism protects cancer cells from cytotoxic drugs, leading to the development of drug resistance and refractory cancer cases.

12.4 Novel strategies to combat multidrug resistance in cancer therapy Novel strategies are exploited to combat MDR in cancer therapy. The first strategy is to try to reverse the MDR through the inhibition of drug efflux inhibitors, the downregulation of MDR-related proteins, and p53 gene therapy. An alternative option is the prevention of the emergence of MDR at the onset of chemotherapy treatment. MDR is a complex phenomenon and chances are low that any one strategy may be capable of generating the desired outcomes. Different generations of efflux inhibitors are reported in the literature. These molecules have been investigated routinely for sensitizing MDR cells toward chemotherapy. Various generations of P-gp efflux modulators are shown in Fig. 12.2. Detailed discussion of these approaches is beyond the scope of this chapter.

12.5 Nanomedicine-based multidrug resistance reversal strategies Cancer nanomedicines have become popular for the treatment of cancers as they have unique size and surface characteristics that aid them in dealing with barriers in reaching target locations. Their submicron and even nanosize range (below 100 nm) make them suitable for the cells internally and traffic them at intracellular locations due to the well-known mechanism of enhanced permeability and retention. The most common approaches Nano Drug Delivery Strategies for the Treatment of Cancers

12.6 Multidrug resistance in cancer therapy: the case of doxorubicin

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FIGURE 12.2 Different generations of P-gp efflux pump inhibitors.

for developing such nanomedicines include the encapsulation of a cytotoxic drug in a nanocarrier, the conjugation of these molecules with polymers/lipids to make them selfassembling amphiphilic molecules, and the incorporation of a cell-specific drug-targeting ligand on the surface of the carrier (Paliwal, Paliwal, Mishra, Mehta, & Vyas, 2010). A nanomedicine not only protects drug molecules from off targets distribution but also delivers them safely by protecting from harsh biological micro-events encountered during enrouting of the molecules in blood pool before reaching to the actual target cells (Paliwal, Babu, & Palakurthi, 2014). Nanomedicine also provides significant solubilization to poorly water-soluble cytotoxic molecules. The coencapsulation of an MDR reversal agent along with a cytotoxic drug in the same nanocarrier makes them further appropriate for the reversal of MDR during cancer therapy. Examples of some of the more well-known nanocarriers that have been exploited for MDR reversal include polymeric/lipid nanoparticles, vesicular systems like liposomes, self-assembling micelles, theragnostics like gold or magnetic nanoparticles or quantum dots, etc. Fig. 12.3 outlines nanoparticle-mediated MDR reversal mechanisms at various cellular levels.

12.6 Multidrug resistance in cancer therapy: the case of doxorubicin Doxorubicin (DOX), an anthracycline that is a broad-spectrum cytotoxic drug, is used for cancer therapy and is one of the most effective chemotherapeutics. DOX-loaded nanomedicines have been developed, marketed successfully, and are clinically effective too. Nano Drug Delivery Strategies for the Treatment of Cancers

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FIGURE 12.3 Overview of nanoparticle-mediated multidrug resistance reversal mechanism at different cellular and intracellular levels. (A) Cell membrane: modulation of the membrane fluidity and the drug internalization pathway, increase of the drug diffusion through membrane perturbation, creation of an inward drug diffusion gradient, inhibition of the efflux transporters. (B) Cytoplasm: enabling endo-lysosomal escapes, modulation of the cytoplasmic pH, mitochondrial and nuclear targeting. Adapted with permission from Singh et al., 2017.

However, the development of resistance to DOX treatment results in poor patient diagnosis and, therefore, survival as well. Several mechanisms are proposed as causes of DOX resistance. The induction of proliferation, cell cycle progression, and inhibition of apoptosis may be results of the interaction of DOX with signaling pathways like mitogen-activated protein kinase/extracellular-signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, etc. It is also known that DOX treatment generates reactive oxygen species (ROS), which activate c-jun N-terminal kinase pathways and p38 pathways. Another mechanism of DOX resistance proposed is the activation of tumor suppressor gene p53. This gene regulates the transcription of other genes, that is, p21 and p16, which are involved in the events of cell cycle control, DNA repair, and apoptosis. A defect in these genes results in the failure of

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DOX action to induce cell cycle arrest required for its cytotoxic action and hence develop insensitivity for DOX by these treated tumor cells.

12.7 Multidrug resistance reversal of doxorubicin-loaded nanomedicines Anticancer drug- or multidrug-loaded nanoparticles such as nanomicelles, liposomes, nanostructured lipid carriers, nanoprobes, and solid lipid nanoparticles, etc., have been developed to overcome the MDR of tumor cells, and these have been tested in both in vivo and in vitro studies (Paliwal, Paliwal, Agrawal, & Vyas, 2011; Paliwal, Paliwal, Agrawal, & Vyas, 2016; Paliwal, Paliwal, Pal, et al., 2011; Rai et al., 2008; Vyas et al., 2008). Verapamil, folic acid, metformin, indomethacin, and celecoxib have been incorporated in nanoformulations to act as P-glycoprotein inhibitors; whereas in some cases, miR-375 and small interfering RNA (siRNA) have been incorporated to reduce the overexpression of P-glycoprotein. Numerous studies have been reported that particularly focus on DOX and combinational drugs developed as nanomedicine for cancer therapy and MDR cancer treatment (Table 12.1).

12.7.1 Nanomedicine coloaded with small interfering RNA and doxorubicin The resensitization of DOX-resistant cancerous cells using siRNA coencapsulated with DOX in nanocarriers is an emerging approach for cancer therapy. As discussed previously, MDR may be caused by the overexpression of P-gp and/or MRP-1 protein encoded by MDR1 and MDR2 genes respectively. RNA interference
mediated inhibition of such sequence, which expresses either P-gp or MDR1 via mRNA, is an effective approach to reverse the overexpression of these proteins into such cancerous cells and resensitize them toward DOX treatments. MDR1-siRNA and DOX-coloaded nanoparticles in a cationic polymeric system have been reported (Misra et al., 2014). The authors reported that the synergistic effect of these combinational nanoformulations reduced the MDR in MCF-7/ MDR cells and this may be an effective therapy for drug-resistant breast cancer. Apart from the codelivery of siRNA and DOX, it is also important that codelivered nucleic acid should target similar cellular pathways to increase the sensitivity of the loaded drug. This will not only synergize the effect, but also minimize the dose of DOX and, hence, the related side effects as well. Further, the codelivery of both siRNA and DOX to intracellular locations of the same cell has been advocated for obtaining significant added advantages in MDR reversal. Keeping this view in mind, Tang et al. (2014) synthesized a new amphiphilic pH-sensitive poly(β-amino ester), poly[(1,4-butanediol)-diacrylate-β-5-polyethylenimine]-block-poly[(1,4-butanediol)-diacrylate-β-5-hydroxy amylamine] (PDP-PDHA) polymer and coloaded it with DOX and survivin-targeting siRNA to develop nanomicelles. The authors reported that the pH-sensitive nanoparticles improved both the cytotoxicity of DOX and the transfection efficiency with a higher DOX accumulation. Authors reported that inhibition of survivin expression was about 57.7% and this induced nearly 80.8% cell apoptosis on MCF-7/MDR cell. This combination of DOX and RNA

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TABLE 12.1 Different doxorubicin nanosystems used for multidrug resistant cancer therapy. S. Type of no nanosystem

Drug/molecules coloaded with DOX

Biomaterials/mechanism

MDR cell line in vitro/in vivo

1

Nanoparticle

siRNA

PLGA

MCF-7/ADR

2

Nanoparticle

Verapamil

Acrylamide,2-carboxyethyl acrylate NCI/ADR-RES

Qin et al. (2014)

3

Nanoparticle

shRNA

Poly(β-amino ester), poly[(1,4butanediol)-diacrylate-β-5polyethylenimine]-block-poly[(1,4butanediol)-diacrylate-β-5-hydroxy amylamine] (PDP-PDHA)

MCF-7/ADR

Tang et al. (2014)

4

Solid lipid nanoparticles

Doxorubicin alone

Cholesterol-PEG

MCF-7/ADR

Chen et al. (2015)

5

Nanomicelles siRNA

Folic acid
decorated PEG-b-(PCLg-PEI)-b-PCL

MCF-7/ADR

Wu et al. (2016)

6

Nanoparticles Doxorubicin alone

Sulfhydryl and amino silica, hyaluronic acid

MCF-7/ADR

Yang et al. (2016)

7

Nanoparticles Buthionine sulfoximine/ celecoxib and biotin-heparin/ heparin

Calcium carbonate/calcium phosphate

MCF-7/ADR

Wu et al. (2017)

8

Nanoparticles miR-375

Silica

HepG2/ADR

Xue et al. (2017)

9

Nanoparticles Verapamil

Zeolitic imidazolate framework ZIF-8, methoxy poly(ethylene glycol)-folate (PEG-FA)

MCF-7 (MCF-7/ Zhang et al. A), mice (2017) bearing B16F10 melanoma

10 Nanoparticles siRNA

Tetraethyl orthosilicate (TEOS), triethanolamine (TEA),

MCF-7/ADR

Sun et al. (2017)

11 Nanomicelles Rhein

PEG, TPGS

SKOV3

Han et al. (2018)

12 Nanoparticles Doxorubicin alone

Bovine serum albumin

MOLT-4, MESSA/DX-5

Kayani et al. (2018)

13 Nanoparticles Doxorubicin alone

Hyaluronic acid, triphenylphosphonium

MCF-7/ADR

Liu et al. (2018)

14 Liposome

PLGA, chitosan

MDA-MB-231 and A-549

Rejinold et al. (2018)

Poly(ethylene glycol)-block-poly(2 (methacryloyloxy)ethyl 5-(1,2dithiolan-3-yl)pentanoate) diblock copolymers (PEG-b-PLAHEMA)

MDA-MB-231

Maiti et al. (2018)

Paclitaxel (PTX) and silybin

15 Nanomicelles Doxorubicin alone

References Misra, Das, Sahoo, and Sahoo, (2014)

(Continued)

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TABLE 12.1 S. Type of no nanosystem

(Continued) Drug/molecules coloaded with DOX

Biomaterials/mechanism

MDR cell line in vitro/in vivo

References

16 Nanoparticles Curcumin

Polyethylene glycol (PEG)

NCI-H460 (MDR-ve) and HCT-8 (MDR 1 ve)

Lou et al. (2018)

17 Nanoparticles Doxorubicin and metformin

PLGA and TPGS

MCF-7/DOX

Shafiei-Irannejad et al. (2018)

MCF-7/ADR

Wu et al. (2018)

18 Nanoparticles Vorinostat (SAHA) Self-assembling complex 19 Nanoparticles Doxorubicin alone

β-Cyclodextrin (β-CD) and TPGS

MCF-7/ADR

Yang et al. (2018)

20 Nanoparticles Doxorubicin alone

Silica and TPGS

MCF-7/ADR

Zhao et al. (2018)

21 Nanomicelles Doxorubicin alone

Poly(β-aminoester)s polymers (PHP)

MCF-7/ADR

Zhou et al. (2018)

22 Nanoparticles Doxorubicin alone

Poly(ethylene glycol)-poly(Lhistidine)-D-α-vitamin E succinate (MPEG-PLH-VES)

MCF-7/ADR

Li et al. (2018)

23 Nanoparticles Indocyanine green

Poly(γ-glutamic acid)-g-poly(lacticco-glycolic acid) (γ-PGA-g-PLGA), cholesterol-PEG

MCF-7/MDR

Chen, Ledan Wang, et al. (2019); Chen, Lu, et al. (2019)

24 Nanoparticles Pyrrolidine dithiocarbamate (PDTC)

Poly(ortho ester urethanes)

MCF-7/MDR

Cheng et al. (2019)

25 Nanoparticles Fucoidan

Poly(vinylpyrrolidone)

MCF-7/MDR

Kang et al. (2019)

26 Nanoparticles Doxorubicin alone

Prussian blue

MCF-7/MDR

Li, Dang, Liang, and Yin, (2019)

27 Nanoparticles siRNA (siMDR-1)

Polyamidoamine, polyethylene glycol

A2780 ADR and Pan et al. (2019) MCF-7/MDR

28 Nanoparticles Quercetin

Methoxy polyethylene glycol amine HCT-8/TAX (mPEG-NH2), polydopamine, silica

Wang et al. (2019)

29 Nanoparticles Indomethacin (IND)

Acid-labile ortho-ester monomer

MCF-7 and MCF-7/ADR

Wang et al. (2019)

30 Nanoprobe

Folic acid-poly(ethylene glycol)carboxy succinimidyl ester, silica

Bel-7402/ADR

Wei et al. (2019)

31 Nanoparticles Bcl-2-converting peptide

Polyamidoamine, silica

HepG2 and H292

Xie et al. (2019)

32 Nanoparticles Psoralen

PLGA, DSPE-PEG2000

HepG2/ADR

Yuan et al. (2019)

33 Nanoparticles siRNA

(3-aminopropyl) triethoxysilane (APTES), tetraethyl orthosilicate (TEOS)

MCF-7/MDR

Chen, Ledan Wang, et al. (2019); Chen, Lu, et al. (2019)

DOX alone

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interference produced a synergistic effect, overcoming MDR and providing effective drug delivery (Fig. 12.4). Wu et al. (2016) reported that the codelivery of chemotherapeutic drug DOX and siRNA could produce a synergistic effect of anticancer activity of DOX by different mechanisms that are capable of the reversal of MDR. The authors prepared multifunctional tumor-targeted P-gp siRNA and DOX-loaded nanomicelles constructed with folic acid (FA) and polyethyleneglycol-b-(polycaprolactone-g-polyethylenimine)-b-polycaprolactone (PEG-b-(PCL-g-PEI)-b-PCL) triblock copolymers. The authors reported that these FAfunctionalized nanomicelles could effectively convey the P-gp siRNA, thus, decreasing both the P-gp articulation levels and the IC50 estimation of the DOX on MCF-7/MDR cells. Further, the codelivery of DOX and siRNA in tumor-targeting nanomicelles produced a

FIGURE 12.4 Biodistribution of PDNs. (A) Biodistribution of DOX in MCF-7/ADR tumor bearing mice at 2 h after intravenous administration of DOX, PDP-PDHA/DOX micelles (PDMs), and PDNs at a dose of 5 mg/kg. (C) Biodistribution of shSur in MCF-7/ADR bearing mice at 2 h after intravenous administration of BMs/shSur complex nanoparticles (PNs) and PDNs at a dose of 2 mg/kg. (B, D) Quantitative analysis for the biodistribution of DOX or shRNA-expressing plasmid DNA targeting the survivin gene (shSur). Data was given as mean 6 SD (n 5 3) (*P , .001) PDN 5 doxorubicin and survivin-targeting shRNA coloaded nanoparticles; DM 5 PDP-PDHA/ DOX micelles. Adapted with permission from Tang, S., Yin, Q., Zhang, Z., Gu, W., Chen, L., Yu, H., . . . Li, Y. (2014). Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer. Biomaterials, 35(23), 6047
6059.

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synergistic effect for gene therapy and chemotherapy for the reversal of MDR cancer and to destroy cancer cells. Micro-RNA, that is, miR-375, is a useful gene therapeutic material that particularly suppresses the yes-associated protein and astrocyte elevated gene-1 (AEG-1) and impedes hepatocellular carcinoma (HCC) progression. These genes are responsible for the development of chemoresistance in a variety of cancers like HCC, breast cancer, and neuroblastoma. To synergize the DOX sensitivity toward HegG2/ADR cells, miR-375 was coencapsulated in lipid-coated hollow mesoporous silica nanoparticles (Xue et al., 2017). The authors suggested that the formulation produced a synergistic antitumor effect to enhance apoptosis, and the system was suitable for MDR therapy in HCC. A strategy of sequential release of siRNA and DOX using spherical core
shell hierarchical mesosilica nanoparticles was reported (Sun et al., 2017). These carriers had both large and small mesopores presented in separate parts of the matrix of the nanoparticles to release both siRNA and DOX separately. The small mesopores provided space for loading DOX and served as a reservoir for these small molecules. Whereas the larger mesopores had disulfide bonds for the encapsulation of the siRNA molecules. The objective of developing such a nanocarrier was to first release the siRNA into the tumor microenvironment and to reverse the MDR by suppressing P-gp expression, after which DOX is released from the core to exert its cytotoxicity. Chen, Ledan Wang, et al. (2019) and Chen, Lu, et al. (2019) developed codelivery systems of siRNA and DOX for potentially synergistic cancer treatment to overcome MDR cancer. These systems were first prepared as a stable complex consisting of DOX bound to siRNA via intercalation followed by interaction with (3-minopropyl)triethoxysilane electrostatically and tetraethyl orthosilicate cocondensed. The authors claimed that these systems were easy to control and of a nearly uniform size. The entire fabrication process of these nanosystems was quick and only took about 10 min. The high inhibition of the P-gp protein encoded by the MDR1 gene and the synergistic anticancer efficacy of DOX in MCF-7/ MDR cells after treatment with these “two in one” nanocarriers were achieved.

12.7.2 Nanomedicine coloaded with P-gp efflux inhibitors and doxorubicin As described previously, P-gp efflux inhibitors have been incorporated to downregulate their activity. These inhibitors act by any one of several mechanisms. First, they can block drug-binding sites (competitively, noncompetitively, or allosterically). The second mechanism involves the interference of the ATP hydrolysis process. The third mechanism may be the alteration of the cell membrane lipid integrity. DOX encapsulated with such inhibitors in the core of nanoparticles have been well taken up by cancerous cells. Qin, Lee, Ray, and Kopelman (2014) prepared DOX- and verapamil-loaded hydrogel nanoparticles using the copolymerization of acrylamide and 2-carboxyethyl acrylate. The authors reported that the DOX- and verapamil-loaded nanoparticles increased the intracellular accumulation of DOX as well as the enhanced cell killing ability of DOX on NCI/ADR-RES cells in vitro. One mechanism of MDR in cancer cells is elevated glutathione (GSH) levels within the cells. GSH plays an important role in tissue protection from oxidative damage and its level is higher in drug-resistant cells than in nonresistant cells. Sometimes, the coencapsulation

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of two different molecules in a nanomedicine along with DOX may be a better approach for targeting two different mechanisms of MDR reversal to obtain a therapy that is more effective in practice. Two different drug resistance inhibitors, that is,. celecoxib (to downregulate P-gp expression) and buthionine sulfoximine (to inhibit GSH synthesis), coloaded with DOX in a single nanocarrier has been reported (Wu, Gong, Liu, Zhuo, & Cheng, 2017). The authors developed pH-sensitive tumor-targeting biotin-heparin/heparin/ calcium carbonate/calcium phosphate nanoparticles as a drug delivery system for MDR. The formulations were capable of reversing MDR on MCF-7/ADR cells followed by treatment of DOX-loaded nanoparticles. A pH-responsive biocompatible metal organic framework
based pegylated FAanchored targeted drug delivery system coloaded with verapamil hydrochloride and DOX has been reported (Zhang et al., 2017). Verapamil acts as a P-gp inhibitor and provides synergistic anticancer effects too. Epigenetics, that is, changing the gene expression without changing the DNA sequencing, is associated with MDR against cytotoxic drugs in cancer therapy. A major epigenetic modification is the modification of histones, resulting in the poor efficacy of anticancer drugs. The use of histone deacetylase inhibitors (HDAC) for the upregulation of the degree of histone acetylation can lead to an improved response toward anticancer therapy and the reversal of MDR. However, monotherapy with HDAC is poor in quantification. Therefore it has been reported that the use of combination therapy, that is, an HDAC inhibitor like vorinostat in conjunction with DOX, may be an effective approach against MDR cells to get a synergistic effect by exploring different mechanisms. Wu et al. (2018) developed nano-twin drug, namely DOX and vorinostat (SAHA), loaded nanoparticles for the reversal of MDR cancer efficiently. In a self-assembling nanocarrier, both the drugs were encapsulated and were found to be stable. Because of supramolecular interactions, the developed nanoparticles achieved a spherical shape. The DOX
SAHA nano-twin drug could enter drug-resistant MCF-7/ADR cancer cells and effectively inhibited their proliferation in vitro in comparison to a single DOX treatment and they showed a higher antitumor efficacy accompanied with less side effects. Further, a higher antitumor efficacy was achieved in an animal model when these drugs were encapsulated in nanoparticles compared to the use of the DOX/SAHA mixture. This clearly demonstrates that nanomedicine could enhance the potential of MDR therapeutic regimes. Cationic fourth-generation polyamidoamine (G4 PAMAM) dendrimers are appropriate nonviral nanocarriers for effective intracellular delivery of anionic siRNA, forming dendriplexes. A codelivery system of G4 PAMAM dendrimers conjugated with polyethylene glycol-2000-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (PEG2K
DOPE) (a triblock copolymer having space for a hydrophobic moiety) is suitable for both siRNA and DOX and is useful in MDR reversal and effective chemotherapy. Pegylation provides shielding to the cationic charge of dendrimers and, hence, homogenizes the structure of the developed nanovector. This balance between the required cellular interaction and cytotoxicity is useful in drug carrier design for MDR reversal chemotherapy as well. Pan et al. (2019) prepared multifunctional nanomicelles by conjugating a dendrimer, G4 PAMAM, with a PEG phospholipid copolymer. After these formulations were coloaded with siRNA and DOX, they were tested for cytotoxicity against MDR cancer cells such as human ovarian carcinoma (A2780 ADR) and breast cancer (MCF-7 ADR) cells. The authors reported that the

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combined nanomicelle preparation potentiated the downregulation of P-gp in MDR cancer cells and reversed the resistance toward DOX. Wang et al. (2019) developed an indomethacin (IND) dimer
based nanodrug delivery system for the codelivery of DOX against various drug-resistant tumors. These nanoformulations were prepared using a single emulsion method. The authors found that these nanoparticles had stability along with quick degradation to release the drugs in the lowpH tumor bioenvironment. The degradation of ortho ester linkages resulted in a higher intracellular DOX concentration; whereas the codelivered IND blocked P-gp efflux. Animal studies further established that the IND- and DOX-loaded nanoformulation improved the synergetic antitumor efficacy as compared to free DOX or IND-C12/DOX.

12.7.3 Nanomedicine coloaded with D-α-tocopherol polyethylene glycol 1000 succinate and doxorubicin D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) is an amphiphilic watersoluble natural derivative of vitamin E. TPGS can act as an MDR reversal agent. Furthermore, this molecule possesses anticancer activity via the induction of apoptogenic activity against many cancers. TPGS can target the mitochondria of cancer cells and leads to their destabilization by activating mitochondrial apoptosis mediators. This anticancer activity has been shown against cancerous cells only and does not affect healthy cells. TPGS has been explored in combination therapy with many anticancer drugs, including DOX-loaded nanocarriers. β-Cyclodextrin (β-CD)- and TPGS-loaded DOX nanoparticles to overcome MDR in cancer cells were reported (Yang et al., 2018). The authors demonstrated that the prepared nanoparticles had good biocompatibility and could potentiate DOX uptake in both drugsensitive and drug-resistant cancer cells. The pH-sensitive release of DOX may be beneficial for improved cytotoxicity (Paliwal, Paliwal, & Vyas, 2015; Paliwal, Paliwal, Pal, et al., 2011; Paliwal, Paliwal, Agrawal, et al., 2011). To explore this, Zhao et al. (2018) prepared a TPGS and DOX-coloaded pH-sensitive nanodrug carrier composed of mesoporous silica nanoparticles (MSNs) for a drug-resistant breast cancer cell line (MCF-7/ADR) (Fig. 12.5) (Zhao et al., 2018). A 10-fold enhanced cell killing ability of these systems was reported in comparison to free DOX. The authors suggested that the developed DOX
TPGS coloaded MSNs were better for overcoming drug resistance in tumor treatments. Since TPGS possesses a small PEG chain (i.e., only 1000 Da), it has lower stealth characteristics than is desired to completely avoid opsonization by the macrophages. This low degree of stealth of TPGS results in their poor perseverance in the blood after administration. The use of a higher PEG polymer chain in place of PEG1000 in the vitamin E analogs such as TPGS2000 or TPGS3350 or their combinations has been advocated. Li et al. (2018) prepared nanoparticles composed of methoxy poly(ethylene glycol)-poly(L-histidine)-Dα-vitamin E succinate (MPEG-PLH-VES) copolymers for the delivery of DOX toward MDR in breast cancer treatment. Modified MPEG-PLH-VES copolymers reduced the level of P-gp expression on MCF-7/ADR cells. These MPEG-PLH-VES nanoparticles were subsequently functionalized with biotin for targeted drug delivery. A high drug encapsulation efficiency (approximate 90%), nanosize formulation (i.e.,130 nm), and pH-responsive drug

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FIGURE 12.5 Schematic illustration of preparation of doxorubicin-loaded mesoporous silica nanoparticles
anchored with TPGS over the surface of the nanoparticles. Adopted with permission from Zhao, P., Li, L., Zhou, S., Qiu, L., Qian, Z., Liu, X., . . . Zhang, H. (2018). TPGS functionalized mesoporous silica nanoparticles for anticancer drug delivery to overcome multidrug resistance. Materials Science and Engineering: C, 84, 108
117.

release in an acidic medium were reported by the authors. Conclusively, the multifunctional MPEG-PLH-VES/B nanoparticulate system exerted an efficient delivery of DOX into MCF-7/ADR cancerous cells and the reversal of MDR. A TPGS-derived biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) nanoparticles loaded with DOX and metformin (Met) for MDR cancer treatment was reported (Shafiei-Irannejad et al., 2018). The authors reported that the nanoparticles were spherical shaped with a size range of below 100 nm and encapsulation efficiencies of 42.26% 6 2.14% for DOX and 7.04% 6 0.52% for Met respectively. Both drug-loaded nanoparticles showed higher cytotoxicity and apoptosis in MCF-7/DOX cells than the free drugs. A novel micelle
based carrier based on DSPE-PEG2000 and TPGS1000 loaded with DOX and rhein may be capable of MDR reversal in ovarian cancer cells (Han, Li, Tao, & Zhou, 2018). Both the drugs were coloaded into these polymeric micelles to enhance the therapeutic action of DOX. The authors reported that an in vitro study showed the controlled release of DOX and an enhanced cytotoxicity and high apoptosis-inducing activities in SKOV3/DOX cells.

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12.7.4 Miscellaneous approaches Some plant-based molecules have been coencapsulated with DOX in nanocarriers to enhance its activity against MDR cells. Rejinold, Yoo, Jon, and Kim (2018) prepared DOX nanoparticles having curcumin coated with PEG in an effective therapeutic strategy against MDR cancer cells. These nanoparticles showed good localization within resistant cells and induced apoptosis as identified by flow-cytometry and DNA fragmentation assays. In vivo studies done on HCT-8/DOX-resistant tumor cells using the nanoparticles produced showed an enhanced bioavailability of DOX as well as tumor growth suppression activity. In another study, a naturally occurring coumarin compound, psoralen, was coencapsulated with DOX in nanoparticles as it has antitumor, estrogen-like, and MDR modulation properties. In another study, poly(γ-glutamic acid)-g-poly(lactic-co-glycolic acid) (γ-PGA-g-PLGA) nanoparticles loaded with DOX and indocyanine green (ICG) and coated with cholesterol-PEG (C-PEG) were reported to overcome the low therapeutic efficacy of chemotherapy against MDR breast cancer (Chen, Ledan Wang, et al., 2019; Chen, Lu, et al., 2019). The authors reported that the DOX/ICG-loaded nanoparticles significantly inhibited P-gp activity because of the C-PEG and γ-PGA receptor-mediated endocytosis. These carriers, after photoirradiation, exhibited a synergistic effect of combination therapy. Such therapy broadens the possibilities of dual modality therapy systems (i.e., chemo/photo therapy) in MDR cancer cases. Multifunctional theragnostics along with MDR reversal capabilities may provide simultaneous detection and inhibition of P-gp. This concept was used in the fabrication of a nanoprobe, that is, elacridar-modified quantum dots (QDs-Ela) loaded with DOX and FA-decorated MSNs (Wang et al., 2019). The authors reported the targeted uptake of DOX by MDR cancer cells, Bel-7402/ADR, in an acidic medium, and found that the fabricated QDs-Ela could be removed from the nanoprobe following DOX release. The authors claimed that the isolated QDs-Ela could be combined with P-gp in the cancer cell membrane and inhibit its active sites, which prevents the efflux of intracellular DOX and increases the retention of DOX. In vitro and in vivo experiments showed that the nanoprobe had a 10-fold better curative effect than free DOX and could successfully overcome MDR. From this discussion, it is clear that various strategies have been explored for the reversal of MDR, including the codelivery of MDR inhibitors and the development of novel drug delivery systems, which simultaneously encapsulate or are coated with MDR reversal agents. Although these methods improve the tumor localization, pharmacokinetics, and biodistribution of anticancer drugs, the insufficient intracellular drug level is still a rate-limiting factor for successful chemotherapy. In the case of MDR tumor cells, a sitespecific or time-specific drug release profile is required to reach a drug concentration that is a sufficiently high intracellular level as drugs/drug carriers are eliminated quickly from the cells (Rawat et al., 2007). The efficacy of drugs in MDR cells can be improved using environmental stimuli-responsive delivery systems that exploit diseaserelated changes in pH, redox potential, enzyme level, and external factors like temperature, light, ultrasound, electric current, and magnetic field. Here, some reports that have employed stimuli-responsive characteristics to overcome MDR are discussed.

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A multistimuli-responsive drug delivery system based on sulfhydryl and amino cofunctionalized MSNs (SH/NH2-MSNs) was reported, in which multifunctional hyaluronic acid (HA) subordinates were joined onto the SH/NH2-MSNs by disulfide bonds (Yang et al., 2016). This system was intended for targeted drug delivery, to balance drug release, and to overcome MDR. Interestingly, the DOX-loaded HA-modified MSNs were enzymeand redox-sensitive and could prevent drug leakage before reaching the tumor cell and responded to the intracellular stimuli of hyaluronidase (HAase) and GSH. Preclinical studies confirmed the induction of a strong apoptosis and cytotoxicity in MCF-7/ADR cells. In another study, Shao et al. (2019) prepared polydopamine (PDA)-coated hollow pH-responsive MSNs coloaded with DOX and quercetin (QUR). The formulation was developed with the intention of reversing MDR and potentiating the anticancer effects on taxol (TAX) and DOX double resistant human colorectal cancer cell line HCT-8 (HCT-8/TAX cells). The authors suggested that QUR- and DOX-loaded nanoparticles displayed a notable aptitude to overcome MDR compared with free DOX and DOXloaded nanoparticles. In a similar study, an approach related to DOX-loaded, redox-responsive, and corecrosslinked polymeric nanomicelles for their effective delivery toward drug-sensitive MDA-MB-231 and drug-resistant MDA-MB-231 (231 R) cancer cells was reported (Maiti et al., 2018) A diblock copolymer was first synthesized by reversible additionfragmentation chain transfer polymerization technique. The authors reported an improved anticancer activity of DOX using these core-crosslinked block copolymer micelles (GSHresponsive in nature) toward both the drug-sensitive and drug-resistant cancer cell lines. It was reported that these carriers were reduction-sensitive, biocompatible, had tunable swelling properties and, therefore, were suitable to overcome MDR in cancer cells. Photothermal therapy combined with chemotherapy for MDR cells has been reported in the literature. Fucoidan, a sulfated, polysaccharide-structured, therapeutic biopolymer, has potential anticancer activity and can exert a combinational synergistic effect with DOX in drug-resistant breast cancer cells. Kang et al. (2019) developed fucoidan- and DOX-loaded photothermal (Pt) nanoparticles to overcome MDR cancer. The authors reported that this biological-thermo-chemo trimodal combination treatment showed excellent therapeutic efficiency against MDR breast cancer cell line MCF-7 ADR both in vitro and in vivo. It was also suggested that this approach may be applicable for MDR modulating/anticancer natural products from nanoparticle synthesis to theranostics potentials. Using poly(ortho ester urethane) copolymers, pH-sensitive polymeric nanoparticles were developed for the codelivery of DOX and pyrrolidine dithiocarbamate (PDTC) to overcome MDR cancer (Cheng et al., 2019). Based on both monolayer cultured cell (2D) and multicellular spheroid (3D) experiments, the authors reported that PDTC could reverse the MDR of DOX. A higher DOX-induced cytotoxicity and apoptosis in MCF-7 and MCF-7/ADR cells were achieved due to improved intracellular DOX accumulation with enhanced tumor penetration by downregulating the expression of P-gp. Liu et al. (2018) prepared DOX nanoparticles by using the conjugating agent, triphenylphosphonium (TPP), and then this formulation was linked with HA to form a nanocarrier (HA-ionic-TPP-DOX). The authors obtained spherical shape nanoparticles sensitive to acidic pH, which showed a better drug release as well as cellular uptake than free DOX nanoparticles. When tested on MCF-7/ADR cell lines, it was found that these

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nanoparticles were precisely localized in the mitochondria; they increased ROS production and cytotoxicity effect and enhanced tumor-targeting DOX delivery. A multilayered, multidrug-loaded nanoformulation composed of a PLGA core, a liposome second layer, and a chitosan third layer (Ch-MLNPs) loaded with three anticancer drugs, namely DOX, paclitaxel, and silybin was reported (Lou, Zhao, Dezort, Lohneis, & Zhang, 2018). The three drugs encapsulated in these multilayer nanoparticles were released in a controlled and sequential manner. Against MDR breast cancer cells having CD44s receptor, the triple drug-loaded nanoparticle formulation was more cytotoxic than single and dual drug-loaded nanoparticles. Kayani, Firuzi, and Bordbar (2018) developed DOX-loaded doughnut-shaped bovine serum albumin nanoparticles (Kayani et al., 2018). The anticancer activities of these nanoparticles were promising against lymphoblastic leukemia (MOLT-4) and MDR uterine sarcoma (MES-SA/DX-5) cell lines. A formulation based on hybrid nanocomposite MSNs for the codelivery of Bcl-2converting peptide (NuBCP9, N9) alone or together with DOX was reported in the literature (Xie, Xu, Wu, Niu, & Zhang, 2019). The hybrid nanocomposite contained internal large pore sized
MSNs and external highly branched PAMAM dendrimers, into which the N9 peptide and DOX were encapsulated in different subcellular layers. The authors claimed that the dual drug-loaded nanocomposite exerted a good synergistic anticancer effect on Bcl-2positive cancer cells in vitro and in animal models; while possessing few side effects. The tumor inhibition rate of the nanocomposite (89%) was 5-fold the amount of the two drugs.

12.8 Conclusion MDR is a critical issue that creates hurdles in the successful chemotherapy of cancers. Several mechanisms have been known for MDR; thus, multiple strategies to combat MDR issues like the inhibition of P-gp expression using gene therapy, the use of influx inhibitors, and the utilization of plant-based antioxidants, etc., are useful in MDR reversal and to sensitize cancerous cells to chemotherapy. DOX is one of the most widely used chemotherapeutics and, therefore, many studies are related to the coencapsulation of DOX with other MDR modulators. Nanoparticles are useful drug carriers to upload a variety of molecules, that is, siRNA and DOX or DOX with other cytotoxic drugs for MDR treatment. Nanoparticles may be multilayered, mesoporous, theragnostic, pH-sensitive, and/or targeted toward cell receptors using ligands like folic acid, HA, biotin, peptides, etc. The literature supports that multidrug-loaded nanoparticles are more efficacious than nanoparticles carrying DOX alone. Most reports indicate better therapeutic outcomes in the treatment of MDR cancer cells. All these preclinical reports create hope that soon alternatives may be found for clinical practices as well for cancer therapy using nanoparticles for MDR cases too.

12.8.1 Grant support A part of this project is supported by the Department of Biotechnology, Government of India (Grant No. BT/PR26950/NNT/28/1505/2017) to RP and JRF support to one of the

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336

12. Nanomedicine-based multidrug resistance reversal strategies in cancer therapy

authors RK. SRP is grateful to SERB-DST, New Delhi, India for providing financial assistance in the form of young scientist project grant (SB/YS/LS-333/2013, dated 05
08-2014).

Abbreviations ABC AEG-1 DOX EPR FA GSH HA HCC HDAC ICG IND MAPK MDR Met MPEG-PLH-VES MSNs PAMAM PDTC PLGA QDs QUR ROS siRNA TPGS TPP YAP1

ATP-binding cassette Astrocyte elevated gene-1 Doxorubicin Enhance permeability and retention Folic acid Glutathione Hyaluronic acid Hepatocellular carcinoma Histone deacetylase inhibitors Indocyanine green Indomethacin Mitogen-activated protein kinase Multidrug resistance Metformin Poly(ethylene glycol)-poly (L-histidine)-D-α-Vitamin E succinate Mesoporous silica nanoparticles Polyamidoamine Pyrrolidine dithiocarbamate Poly(lactide-co-glycolide) Quantum dots Quercetin Reactive oxygen species Small interfering RNA D-α-Tocopherol poly (ethylene glycol) 1000 succinate Triphenylphosphonium yes-associated protein

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Index Note: Page numbers followed by “f” and “t” refer to figures and tables, respectively.

A ABC. See ATP-binding cassette (ABC) Aberrant DNA methylation, 203 Abraxane, 120
121 Active targeting, 41 Active transport systems, 39 Acute lymphoblastic leukemia, 228 Acute myeloid leukemia (AML), 228 Acyclovir-loaded transferosome, 15 AD. See Adenocarcinoma (AD) ADCC. See Antibody-dependent cellular cytotoxicity (ADCC) Adenocarcinoma (AD), 107 Adenoma
carcinoma sequence, 193, 194f Adenomatous polyposis coli (APC), 199 Adenosine triphosphate (ATP), 148
149 Adhesion molecule-mediated cell interactions, 95 Adjuvant treatment for cancer, 2 Adriamycin resistant, 178 Adsorptive-mediated transport, 43 AE. See Aloe-emodin (AE) AEG-1. See Astrocyte elevated gene-1 (AEG-1) Af. See Antibody fragment (Af) Afatinib, 109t, 229 Aflatoxin, 225 AFM. See Atomic force microscopy (AFM) AgNPs. See Silver nanoparticles (AgNPs) ALA. See 5-Aminolevulinic acid (ALA) Alanine aminotransferase (ALT), 139
140 Albumin albumin-bound system, 286
287 binder, 45 NPs, 114 Alectinib, 109t Allium sativum. See Garlic (Allium sativum) Aloe-emodin (AE), 257 Aloe-vera, 257 ALP- (MIs) n. See Angiopep-2-lipid-poly(metroniadazoles)n (ALP- (MIs) n) Alpha human folate receptor (αHFR), 291
292 α-tocopherol succinate-cisplatin pro-drug (TOSCDDP), 17 α-tocopherol with sodium casein, 18t

ALT. See Alanine aminotransferase (ALT) Alternating magnetic field (AMF), 91
92 Amiloride, 16
17 5-Aminolevulinic acid (ALA), 253, 258 AML. See Acute myeloid leukemia (AML) Amphipathic tail-anchoring peptide (ATAP), 53
55 Amphiphile-DOPA (Amphi-DOPA), 41
42 Amphiphilic nanocarriers, 158 Androgen receptor (AR), 275
276 Anemia, 228 Angiopep-2-lipid-poly-(metroniadazoles)n (ALP- (MIs) n), 57
58 Anti-epidermal growth factor receptor-mAb (AntiEGFR-mAb), 172
173 Anti-human epidermal growth factor receptor-2mAb (Anti-HER2-mAb), 172
173 Anti-survivin siRNA, 121
122 Antibodies (Abs), 301
302 Antibody fragment (Af), 155
157 Antibody-dependent cellular cytotoxicity (ADCC), 258 Antibody
antigen interactions, 86
87 AntiEGFR antibody
conjugated Au NPs, 87 Antiepidermal growth factor receptor, 8
9 Antimetabolites, 229
230, 254
255 Antitumor efficacy in vivo, 126
128 AODN. See ApoB-100/oleic acid-DOX/NLC (AODN) APC. See Adenomatous polyposis coli (APC) Apigenin, 16t ApoB-100/oleic acid-DOX/NLC (AODN), 19 Apoptosis, 7 Aptamer 32 (A32), 48
49 Aptamers (Apt), 277
278 Aquagel. See Hydrogel AR. See Androgen receptor (AR) Area under first moment curve (AUMC), 218 Area under the curve (AUC), 218 Arginyl-glycyl-aspartic acid (RGD), 19 Aroplatin, 88 Arsenic, 225 Artemether, 13t Asbestos, 225 Asn-Gly-Arg ligand (NGR ligand), 52 Aspartate aminotransferase (AST), 139
140

341

342

Index

Astaxanthin, 18t Astrocyte elevated gene-1 (AEG-1), 329 Astrocytic tumors, 38
39 ATAP. See Amphipathic tail-anchoring peptide (ATAP) Atezolizumab, 109t Atomic force microscopy (AFM), 130
131 Atomic particle accelerator, 5 ATP. See Adenosine triphosphate (ATP) ATP-binding cassette (ABC), 319
320 transporters, 39 AUC. See Area under the curve (AUC) AUMC. See Area under first moment curve (AUMC) AuNPs. See Gold nanoparticles (GNPs) Aurochloric acid (HAuCl4), 130
131 Autophagy, 322

B Basal cell carcinoma (BCC), 4, 246
247 Base excision repair (BER), 199 Bauhinia purprea agglutinin (BPA), 8 BAX receptor, 203 BBB. See Blood
brain barrier (BBB) BCC. See Basal cell carcinoma (BCC) BCECs. See Brain capillary endothelial cells (BCECs) BCS. See Biopharmaceutics classification system (BCS) Beam of electromagnetic radiation energy, 5 BER. See Base excision repair (BER) β-Cyclodextrin (β-CD), 331 β-papillomaviruses, 250 Bevacizumab monoclonal antibody, 10t BG. See O6-benzylguanine (BG) Bilayer phospholipid vesicles, 155
157 “Bio-standardized tag” framework, 301
302 Biodegradability, 234
235 Biodegradable polymers, 175
177 Biological barriers, 237 Biomarkers, 194
203 diagnostic biomarkers, 195
198 NPs in detection of GC using, 173 predictive biomarkers, 198
199 Biomaterials as NPs, 113
114 Biomedical applications, 64
65 Biopharmaceutics classification system (BCS), 128 Biopsy techniques, 251 Bioreduction responsive delivery strategy, 122 Bisphosphonates, 229
230 Bleomycin, 76, 255 Blood cancer, 225
228 challenges and remedies in treatment of leukemia, 237
239 diagnosis of, 239
241 recent and ongoing clinical trials, 240
241 theranostic approach, 239
240

nanotechnology in treatment of cancer, 231
237, 232f CNTs, 235 dendrimeric NPs, 235 drug
protein conjugation, 234 gold NPs, 236 liposomes, 234 mesoporous silica NPs, 236 metal NPs, 235
236 NPs, 233
234 polymeric NPs, 234
235 properties of nanocarriers, 236
237 quantum dots, 235 silver NPs, 236 pathophysiology, 228
229 regulation aspects of nanotechnology-based tools, 241 therapies for, 229
231 advancements in blood cancer treatment, 231 chemotherapy, 229
230 gene therapy, 229 immunotherapy, 230 radiation therapy, 230
231 types, 228 Blood markers, 147
148 Blood
brain barrier (BBB), 37
38, 237 mechanistic pathways by NPs to cross, 41
43 adsorptive-mediated transport, 43 CMT, 41
42 RMT, 42
43 Body mass index (BMI), 192 Bone marrow, 7, 228 Bovine lactoferrin
loaded transferosomal vesicles, 15 BPA. See Bauhinia purprea agglutinin (BPA) Brachytherapy, 284 B-Raf proto-oncogene serine/threonine kinase (BRAF), 198 Brain cancer, 37 using combinatorial approach, 60
64 combination of magnetic resonance imaging and therapy, 61
63 combination of multimodal imaging and therapy, 63
64 combination of optical imaging and therapy, 63 global statistics, 38
39 nanomedicine for diagnosis, 43
50 magnetic resonance imaging, 44
45 NPs as carriers of fluorescent dyes for imaging tumors, 45
48 NPs as fluorescent agents for tumor imaging, 48
50 Raman scattering and CT imaging, 45 nanomedicine for treatment, 51
60

Index

dendrimers, 60 liposomes, 56
58 metal nanoparticles, 51
56 polymeric NPs, 58
60 NPs for treatment, 40
41 active targeting, 41 passive targeting, 40
41 physical properties, 40 Brain capillary endothelial cells (BCECs), 52 Brain metastases, 37 Brain tumors, drawbacks and circumstances in, 39
40 Brigatinib, 109t Brust
Schiffrin method, 130
131

C C-PEG. See Cholesterol-PEG (C-PEG) C&E. See Curettage and electrodesiccation (C&E) C6 glioma cells, 56
57 CA. See Cancer antigen (CA); Contrast agents (CA) Cabazitaxel (CBX), 286 Cadmium telluride quantum dots, 235 CAFs. See Cancer including fibroblasts (CAFs) Camptothecin (CPT), 150 Cancer, 165, 191
192, 225, 275. See also Chemotherapy; Radiation therapy cancer stem-like cell targeting, 91
92 conventional therapies for, 2
8 MDR in cancer therapy, 320 novel approaches for cancer treatment characteristics of transferosomes, 15 ethosomal drug delivery systems, 12
14 lipid-based nanomedicines, 8
20 miscellaneous nanocarriers, 25
27 NLCs, 19 polymer-based nanomedicines, 20
25 statistics, 226 cancer deaths by age, 227f cancer-associated deaths worldwide, 227f treatment, 1
2 natural compound delivery, 97 Cancer antigen (CA), 192 Cancer immunotherapy (CIT), 96 Cancer including fibroblasts (CAFs), 145
146 Cancer nanomedicine, 120
121 Cancer stem cells (CSCs), 77 Cannabis sativa, 115 CAR T therapy. See Chimeric antigen receptors therapy (CAR T therapy) Carbon dioxide (CO2), 226
228 Carbon nanodots, 53, 54f Carbon nanofibers (CNFs), 289 Carbon nanomaterials, 132
133

343

Carbon nanotubes (CNTs), 20
21, 156t, 157, 178
179, 217
218, 235, 289 Carbon-based system, 289 Carbopol hydrogel formulation, 12
14 Carcinoembryonic antigen (CEA), 147
148, 172
173, 192 Carcinoma nasopharyngeal, 91 Carr’s index, 17
19 Carrier-mediated transport (CMT), 41
42 Carvedilol, 16t Cationic lipid, 122 Cationic lipid NPs by entrapping miR-660 (CCL660), 113
114 CBTRUS. See Central Brain Tumor Registry of United States (CBTRUS) CBX. See Cabazitaxel (CBX) CD receptors. See Cluster differentiation receptors (CD receptors) CD13. See Cluster of differentiation 13 (CD13) CD44 receptor, 149
150 CDF. See 3,4-Difluorobenzyl curcumin (CDF) Ce6. See Chlorin e6 (Ce6) CEA. See Carcinoembryonic antigen (CEA) Celecoxib (CEL), 254, 259 Cell adhesion
mediated drug resistance, 77
78 Cell autonomous genetic disease, 6 Cell engulfment. See Phagocytosis process Cell targeting with NPs, 88
91 Cell-membrane coating nanotechnologies, 92 Cell penetrating peptides (CPP), 41 Cell-surface-associated mucin, 147
148 CellSearch, 173
174 Cellular uptake in vitro, 124
126 Central Brain Tumor Registry of United States (CBTRUS), 38
39 Central nervous system, 37, 52 Ceritinib, 109t Cerium oxide
based NPs, 179 Cervical cancer, 4 cells, 24 Cetuximab, 8
9, 113, 204
206, 229 CGA. See Comprehensive geriatric assessment (CGA) Chemobrain, 229 Chemoprevention, 297 Chemoresistance, 1
2 mediated by receptor
ligand interactions, 78 Chemotaxis chamber assays, 215 Chimeric antigen receptors therapy (CAR T therapy), 96, 230
231 Chemotherapy, 1
2, 88, 108
110, 147
148, 192
193, 204, 229
230, 296
297. See also Cancer role in cancer treatment, 6
8 indications for chemotherapy, 7
8

344 Chemotherapy (Continued) principles of cancer treatment by chemotherapy, 6
7 Chitosan (CS), 111 NPs, 174
175 Chlorin e6 (Ce6), 18t, 179 Chlorpromazine, 16
17 Cholesterol-PEG (C-PEG), 333 Chromosomal instability (CIN), 195
196 Chronic myelogenous leukemia (CML), 228 CIMP. See CpG island methylator phenotype (CIMP) CIN. See Chromosomal instability (CIN) Circulating tumor cells (CTCs), 165 Circulating tumor cells detection in GC, 173
174 Cis-diamminedichloroplatinum, 76 Cisplatin (CST), 76, 88, 155
157, 255 CIT. See Cancer immunotherapy (CIT) Classical drug delivery systems, 119
120 Cluster differentiation receptors (CD receptors), 149
150 Cluster of differentiation 13 (CD13), 52 CM. See Curcumin (CUR) CML. See Chronic myelogenous leukemia (CML) CMT. See Carrier-mediated transport (CMT) CNFs. See Carbon nanofibers (CNFs) CNTs. See Carbon nanotubes (CNTs) Cobalt, 5 Collagen, 145
146 Colloidal drug carrier system, 120 Colon cancer, 191
192 chemotherapeutic/cytotoxic bioactives, 205t molecular biology, 193
203 adenoma
carcinoma sequence, 193, 194f biomarkers, 194
203 genetic mutations, 194 nanoparticles, 206
218 treatment options, 203
206 chemotherapy, 204 immunotherapy, 206 radiation therapy, 204 surgical resection, 203 targeted therapy, 204
206 Combidex. See Ferumoxtran-10 Comprehensive geriatric assessment (CGA), 203 Computed tomography (CT), 39
40, 45, 167, 192 Confocal laser scanning microscope, 125 Contralateral breast cancer BRCA1 mutation, 3 Contrast agents (CA), 79
83 Conventional therapies for cancer treatment, 2
8 cisplatin, 76 5-FU, 76 for oral cancers management, 75
76

Index

paclitaxel/docetaxel, 76
77 Cowpea mosaic virus (CPMV), 114 CPD. See Cyclobutane pyrimidine dimers (CPD) CpG island methylator phenotype (CIMP), 203 CPMV. See Cowpea mosaic virus (CPMV) CPP. See Cell penetrating peptides (CPP) CPT. See Camptothecin (CPT) Creatinine (CREA), 139
140 Cryosurgery, 4 Cryotherapy, 251
253 CS. See Chitosan (CS) CSCs. See Cancer stem cells (CSCs) CST. See Cisplatin (CST) CT. See Computed tomography (CT) CTCs. See Circulating tumor cells (CTCs) CTLA-4. See Cytotoxic T-lymphocyte antigen 4 (CTLA4) Curative surgery, 2
3 Curcumin (CUR), 13t, 14t, 111, 256, 285
286 Curcumin-docetaxel, 21t Curcumin-loaded polymeric NPs (NanoCurc), 151 Curettage and electrodesiccation (C&E), 251 2-Cyano-6-aminobenzothiazole, 55
56 Cyclobutane pyrimidine dimers (CPD), 249 Cysteamine (Cys), 85 Cytochalasin D, 16
17 Cytokines, 230 Cytotoxic chemotherapeutic agents, 6
7 Cytotoxic T-lymphocyte antigen 4 (CTLA-4), 95
96

D DA. See Dithiodipropionic acid (DA) Dabrafenib, 109t DAC. See Decitabine (DAC) Dacomitinib, 109t DAS. See Diallyl sulfide (DAS) Daunorubicin, 10t Daunorubicin plus honokiol, 10t DCC. See Deleted in colon cancer (DCC) DCs. See Dendritic cells (DCs) DCT. See Docetaxel (DCT) DD. See Drug delivery (DD) Death receptor, 149 Debulking surgery, 4 Decitabine (DAC), 18t Deleted in colon cancer (DCC), 201
202 Delivering gene therapy, 233 Dendrimer-polyethlyeneimine (Den-PEI), 112 Dendrimeric NPs, 235 Dendrimers, 22, 23t, 60, 156t, 157
158, 289
290 Dendritic cells (DCs), 95
97, 148
149 Dermal drug delivery system, 12 Dermoscopy, 250

Index

Dextran, 293
294 Dextran CD44-coated SPIONPs functionalized with hyaluronan (HA-DESPIONs), 91
92 DGC. See N-deoxycholic acid glycol chitosan (DGC) DHAuNCs. See DOX-loaded and HA-grafted AuNCs (DHAuNCs) DHTPAuNCs, 133
134, 138 Diagnostic biomarkers, 195
198 Diagnostic surgery, 3
4 Diallyl sulfide (DAS), 257 1,2-Diaminocyclohexane-platinum(II), 158 Diaryl heterocycle. See Celecoxib (CEL) Differential scanning calorimetry (DSC), 52 3,4-Difluorobenzyl curcumin (CDF), 149
150 L-3,4-Dihydroxyphenylalanine (L-DOPA), 41
42 Dimericine. See T4 endonuclease V 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT assay), 138, 177 1,10 -Dioctadecyl-3,3,30 ,30 -tetramethyl indotricarbo cyanine iodide (DiR), 9 Dioscin, 10t Disulfide-containing crosslinked polyethylenimine (PEI-SS-CLs), 122 Disulfidecontaining poly(amidoethyl enamine)s (SSPAEIs), 122 Disulfiram (DSF), 112 Dithiodipropionic acid (DA), 114 DLS. See Dynamic light scattering (DLS) DNA, 108 base excision repair genes, 199 DNA-repair enzyme inhibitors, 229
230 repair enzymes, 259 Docetaxel (DCT), 18t, 174
175, 286 L-DOPA. See L-3,4-Dihydroxyphenylalanine (L-DOPA) DOX. See Doxorubicin (DOX) DOX-loaded and HA-grafted AuNCs (DHAuNCs), 133
134 DOX-loaded AuNC, 133
134 DOX-LOV-liposomes, 130 DOX-LOV-Lips, 130 DOX/PJAD-PEG-siRNA. See Poly[juglanin dithiodipropionic acid]-b-poly (ethylene glycol)siRNA Kras with doxorubicin (DOX/PJADPEG-siRNA) dox@PVP-AuNPs. See Doxorubicin on surface of AuNPs with polyvinylpyrrolidone (dox@PVPAuNPs) Doxil, 120
121 Doxorubicin (DOX), 10t, 13t, 14t, 25, 52, 113
115, 120
121, 128
130, 165
166, 254, 323
325 doxorubicin and lovastatin co-delivery liposomes, 128
130 anticancer activity, 129
130

345

histological analysis, 130 doxorubicin-loaded nanoemulsions, 16
17 doxorubicin-loaded nanomedicines, 325
335 hybrid nanocomposite, 335 multistimuli-responsive drug delivery system, 334 with P-gp efflux inhibitors, 329
331 plant-based molecules, 333 with small interfering RNA, 325
329 with TPGS, 331
332 doxorubicin-loaded self-assembled niosomes, 9
12 Doxorubicin on surface of AuNPs with polyvinylpyrrolidone (dox@PVP-AuNPs), 113 nanosystems, 326t Drug delivery (DD), 20
21, 110, 179, 277
281 in head and neck tumors, 77
78 to liver with nanoparticles, 120
124 using NPs for cancer stem-like cell targeting, 91
92 Drug
protein conjugation, 234 DSC. See Differential scanning calorimetry (DSC) DSF. See Disulfiram (DSF) DU145 solid cancer
bearing mice, 8 Durvalumab, 109t Dynamic light scattering (DLS), 44
45, 301
302

E EBRT. See External beam radiation therapy (EBRT) EC. See (2)-Epicatechin (EC) ECM. See Extracellular matrix (ECM) EGC. See (2)-Epigallocatechin (EGC) EGCG. See Epigallocatechin 3-gallate (EGCG) EGF. See Epidermal growth factor (EGF) EGFR. See Epidermal growth factor receptor (EGFR) EHT. See Exogenous heating sources (EHT) EIS. See Electrical impedance spectroscopy (EIS) Elacridar-modified quantum dots (QDs-Ela), 333 Electrical impedance spectroscopy (EIS), 252t Electron acceptors, 63 Electron donor, 63 Electrosurgery, 4 ELG-NPs. See Eugenol-entrapped ethosome nanoparticles (ELG-NPs) ELISA. See Enzyme-linked immunosorbent assay (ELISA) Embelin, 16t Emulsifier, 19 Encapsulated antitumor drugs in NPs, 92 Endocytic pathways, 148
149 Endocytosis, 148
149 Endoscopy, NPs in early detection of GC via, 172
173 Enhanced permeability and retention (EPR), 40
41, 151
155, 233
234 effect, 120
121 Enzyme-linked immunosorbent assay (ELISA), 173

346

Index

Enzymes, 234 (2)-Epicatechin (EC), 256 Epidermal growth factor (EGF), 131
132, 290 Epidermal growth factor receptor (EGFR), 8
9, 83
84, 108, 149, 202 EGFRvIII, 48
49 Epigallocatechin 3-gallate (EGCG), 19, 57
58, 256, 297 (2)-Epigallocatechin (EGC), 256 Epigenetics, 330 Epirubicin, 23t Epoxy-activated tetraiodothyroacetic acid, 159 EPR. See Enhanced permeability and retention (EPR) ERCC1. See Excision repair cross-completing-1 (ERCC1) Erlotinib, 17
19 Erlotinib-loaded SLNs, 17
19 ERT-HSA-HA NPs. See HA and human serum albumin modified erlotinib NPs (ERT-HSA-HA NPs) Ethosomal drug delivery systems, 12
14, 14t Ethosome, 12
14 ethosomal drug delivery systems, 12
14 Eugenol-entrapped ethosome nanoparticles (ELG-NPs), 14 European network for Health Technology Assessment (EUnetHTA), 241 Excision repair cross-completing-1 (ERCC1), 199 Exfoliative cytology, 87 Exocytosis, 55
56, 148
149 Exogenous heating sources (EHT), 53
55 External beam radiation therapy (EBRT), 5 Extracellular matrix (ECM), 77, 145
146 Ezrin, 199

F FA. See Folic acid (FA) FAM-siRNA, 124
125 Familial adenomatous polyposis (FAP), 192 FDA. See Food and Drug Administration (FDA) Fecal immunochemical test (FIT), 192 Fenestration, 110 Ferrous chlorophyllin, 14t Ferumoxtran-10, 170, 295 FI. See Fluorescence imaging (FI) Fibronectin, 145
146 Fisetin, 14t FIT. See Fecal immunochemical test (FIT) FLT3 gene, 231 Fluorescence imaging (FI), 159, 170 Fluorescent/fluorescence agents for tumor imaging, 48
50 diagnosis, 302 dyes, 49 for imaging tumors, 45
48

emission, 53 fluorescence-based nanosensors, 173 5-Fluorouracil (5-FU), 8
9, 10t, 16t, 75
76, 254
255, 293
294 Folate receptor (FR), 149
150 Folate receptor alpha (FRA), 112 Folic acid (FA), 85 folic acid
conjugated silica-capped gold nanoclusters, 178 Food and Drug Administration (FDA), 167 Fourier transformation infrared spectroscopy (FT-IR), 52 FR. See Folate receptor (FR) FRA. See Folate receptor alpha (FRA) FT-IR. See Fourier transformation infrared spectroscopy (FT-IR) 5-FU. See 5-Fluorouracil (5-FU)

G GA. See Gambogic acid (GA); Gum arabic (GA) GA-NPs. See Gambogic acid-loaded NPs (GA-NPs) 68Ga-PRGD2. See Gallium-BNOTA-PRGD2 (68GaPRGD2) Gadolinium (Gd), 44
45, 113 Gadolinium-doped zinc oxide NPs (Gd-doped ZnO NPs), 113 Gallium-BNOTA-PRGD2 (68Ga-PRGD2), 45 Gambogic acid (GA), 177 Gambogic acid-loaded NPs (GA-NPs), 177 Garlic (Allium sativum), 257 Gastric cancer (GC), 165, 166f NPs in circulating tumor cells detection, 173
174 NPs in early detection, 172
173 NPs in GC detection, 173 NPs in imaging, 166
172, 168t NPs-based therapy, 174
179 Gastrointestinal tract (GIT), 172, 201 enzymes, 12 GBM. See Glioblastoma multiforme (GBM) GC. See Gastric cancer (GC) Gd-doped ZnO NPs. See Gadolinium-doped zinc oxide NPs (Gd-doped ZnO NPs) Gd31 complexed with diethyl triamine-pentaacetic acid (Gd-DTPA), 79
83 Gefitinib (GEF), 91 Gelatinase-sensitive peptide, 172 GEM. See Gemcitabine (GEM) GEM-entrapped magnetic multiwalled carbon nanotubes (mMWNTs-GEM), 157 GEM-loaded magnetic-activated carbon particles (mACs-GEm), 157 Gemcitabine (GEM), 21t, 233 GEM-loaded chitosan, 151
155 Gene

Index

delivery, 298
300 therapy, 229 strategies, 122 Genetic mutations, 194 Genetic susceptibility, 108 Genistein BIO 300, 21t Genome stability genes, 6 Genomic instability, 195
197, 195f gFOBT. See Guaiac-based fecal occult blood test (gFOBT) GIT. See Gastrointestinal tract (GIT) Glioblastoma, 38
39, 43
44 Glioblastoma multiforme (GBM), 37, 55f Gliomas, nanomedicine for treatment and diagnosis of, 43 Global statistics of brain cancers, 38
39 Glottic cancer, 4 Glucose transporter, 12 Glucose-regulated protein 78 (GRP78), 178 GRP78 binding peptide (GRP78BP), 167
170 Glutathione (GSH), 329
330 Glycans, 258 Glycogen synthase kinase (GSK), 199 Glycolysis, 322 GNPs. See Gold nanoparticles (GNPs) Gold (Au), 51, 235
236 Gold nanocages (AuNCs), 132
133 Gold nanohybrids (Au nanohybrids), 84 Gold nanoparticles (GNPs), 41
42, 55
56, 113, 130
139, 174, 178, 236 antitumor effect in vivo, 138
139 gold nanoparticulate system, 290
292 mechanism, 134
138 microscopy electron imaging of biopsies, 57f thermal therapy, 132
134 toxicity of nanocomposites, 139
140 Gold NPs conjugated with resveratrol (Res-AuNPs), 151
155 GPD acid. See GX1-PEG-deoxycholic acid (GPD acid) Graphene, 20 GRP78. See Glucose-regulated protein 78 (GRP78) GSH. See Glutathione (GSH) GSK. See Glycogen synthase kinase (GSK) Guaiac-based fecal occult blood test (gFOBT), 192 Gum arabic (GA), 151
155 GX1-PEG-deoxycholic acid (GPD acid), 174
175 Gynecological cancer, 4

H HA. See Hyaluronic acid (HA) HA and human serum albumin modified erlotinib NPs (ERT-HSA-HA NPs), 113
114 HA-conjugated nanomicelles of styrene-maleic acid (HA-SMA), 149
150

347

HA-DESPIONs. See Dextran CD44-coated SPIONPs functionalized with hyaluronan (HADESPIONs) HA-SMA. See HA-conjugated nanomicelles of styrenemaleic acid (HA-SMA) HAase. See Hyaluronidases (Hyals) Hausner ratio, 17
19 HCC. See Hepatocellular carcinoma (HCC) HCDDs. See Highly crystalline carbon nanodots (HCDDs) HDAC. See Histone deacetylase inhibitors (HDAC) HDL. See High-density lipoprotein (HDL) Head and neck cancer (HNC), 77 nanotechnology in HNC detection and diagnosis, 78
97 nanotechnology-based drug delivery systems for treatment, 88
97 NPs in HNC immunotherapy, 95
97 Head and neck squamous cell (HNSC), 75 Head and neck squamous cell carcinomas (HNSCC), 75, 78
79 Head and neck tumors, 77
78 Heat shock proteins, 147
148 Hedgehog pathway inhibitors, 253
254 Hedgehog signaling (Hh signaling), 253
254 Hematological cancer, 225
226 Hepatocellular carcinoma (HCC), 119
120, 329 HepG2 cells, 124
125 HER2-positive early breast cancer, 2 Herceptin, 167, 178 Hereditary nonpolyposis colon cancer (HNPCC), 192, 196
197 Hh signaling. See Hedgehog signaling (Hh signaling) HIF-1. See Hypoxiainducible factor 1 (HIF-1) High-density lipoprotein (HDL), 114 High-frequency ultrasound, 252t Highly crystalline carbon nanodots (HCDDs), 53 Histone deacetylase inhibitors (HDAC), 229
230, 330 HMG-coA. See 3-Hydroxy-3-methylglutaric coenzyme A (HMG-coA) HNC. See Head and neck cancer (HNC) HNPCC. See Hereditary nonpolyposis colon cancer (HNPCC) HNSC. See Head and neck squamous cell (HNSC) HNSCC. See Head and neck squamous cell carcinomas (HNSCC) Hodgkin disease, 230 Hodgkin lymphoma, 225
226, 228 Homing peptides, 132
133 Hot melt encapsulation process, 57
58 HPV. See Human papillomavirus (HPV) Human glioma cell line, 48
49 Human neuroblastoma cells, 53
55 Human papillomavirus (HPV), 15, 75, 246
247, 250

348

Index

Human umbilical vein endothelial cells (HUVEC), 174
175 Hyaluronic acid (HA), 21t, 111, 132
133, 145
146, 170, 334 Hyaluronidases (Hyals), 132
133, 334 Hydrogel, 216
217 Hydrogen atoms, 79
83 Hydrogen peroxide (H2O2), 157 Hydrophilic surface, 63, 110 Hydrophobicity, 234
235 3-Hydroxy-3-methylglutaric coenzyme A (HMG-coA), 128 10-Hydroxycamptothecin, 23t Hyper vascularized lymphatic system, 40
41 Hypomethylating agents, 229
230 Hypopharynx, 75 Hypoxia, 78, 322 Hypoxiainducible factor 1 (HIF-1), 78

I ICG. See Indocyanine green (ICG) IFNɣ. See Interferon-gamma (IFNɣ) IGFBP2. See Insulin-like growth factor binding protein 2 (IGFBP2) IGS. See Image-guided surgery (IGS) IL. See Interleukins (IL) Image-guided surgery (IGS), 170 Image-guided thermal ablation of HNC, 84
85 Imaging tumors autocatalytic delivery strategy of ABTT nanoparticles, 48f NPs as carriers of fluorescent dyes for, 45
48 Imatinib, 145 Imiquimod, 255
256 Immune quiescent, 145 Immunomodulators, 229
230 Immunosuppression, 249
250 Immunotherapy, 1
2, 108, 206, 230, 300
301 In situ solid-state transformation, 63
64 Indocyanine green (ICG), 16t, 63, 170, 333 Indomethacin (IND), 331 Inflammatory bowel disease, 192 Infrared spectroscopy (IR), 44
45 Inherited gene mutations, 192 Inorganic NPs, 51 for lung cancer, 112
113 Insulin, 42
43 Insulin-like growth factor binding protein 2 (IGFBP2), 197 Intensity-modulated radiation therapy, 5 Intensity-modulated radiotherapy, 230
231 Interferon, 230 Interferon-gamma (IFNɣ), 95
96

Interleukins (IL), 149, 230 IL-13, 44
45 Intraprostatic route, 283
284 Ionizing radiation, 5 Iontophoresis, 8
9 Ipsilateral breast cancer BRCA1 mutation, 3 IR. See Infrared spectroscopy (IR) Iron, 44
45 Iron oxide NPs, 295

J Juglanin (Jug), 114 Juglans mandshurica, 114

K Kirstein rat sarcoma (K-RAS), 198
199

L Lactoferrin, 15, 42
43 Lactosome, 171 Laminin, 145
146 Large amino acid transporter-1 (LAT1), 41
42 Large-cell carcinoma, 107 Larynx, 75 Laser surgery, 4 LAT1. See Large amino acid transporter-1 (LAT1) Lawsone and Hinna extract, 13t LDL. See Low-density lipoprotein (LDL) Leukapheresis, 231 Leukemia, 225
226, 228 treatment biological barriers, 237 challenges, 237 remedies, 238
239 renal system, 238 RES, 237
238 Ligand
receptor interactions, 42
43 Lipid-based nanomedicines. See also Polymer-based nanomedicines ethosome, 12
14 liposomes, 8
9 nanoemulsion, 15
17 nanostructured lipid carriers, 19 niosomes, 9
12 solid lipid nanoparticles, 17
19 transferosome, 14
15 Lipidoids, 120
121 Lipid nanoparticles, 262
264 Lipid-based drug delivery systems, 17 Lipid-based nanocarriers, 8 Lipoplatin, 88 Liposomal/liposomes, 8
9, 45
48, 56
58, 83, 120
121, 155
157, 156t, 208
209, 234, 285

Index

daunorubicin, 120
121 formulations for cancer treatment, 9, 10t irinotecan, 120
121 liposome-coated fluorescent MNPs, 167 nanoparticles, 285
286 transferrin-functionalized nanoparticles, 61f vincristine, 120
121 in vivo efficacy in C6-GFP-Luci glioma mouse model, 59f Liquid biopsy, 173
174 Liver cancer, nanoparticles and antitumor efficacy in vivo, 126
128 cellular uptake in vitro, 124
126 doxorubicin and lovastatin co-delivery liposomes, 128
130 anticancer activity, 129
130 histological analysis, 130 drug delivery to liver with nanoparticles, 120
124 gold nanoparticles, 130
139 theranostic nanomedicines, 120f Localized surface plasmon resonance (LSPR), 132
133 Locoregional imaging, NPs in, 170
171 Locoregional metastasis, 165 Locoregional route, 283
285 LOH. See Loss of heterozygosity (LOH) Lorlatinib, 109t Loss of heterozygosity (LOH), 200
201 Lovastatin (LOV), 128 lovastatin co-delivery liposomes, 128
130 Low-density lipoprotein (LDL), 19 Low-temperature-sensitive liposomes (LTSL), 209 LSPR. See Localized surface plasmon resonance (LSPR) LTSL. See Low-temperature-sensitive liposomes (LTSL) Luffin, 258 Lung cancer, 107 cause, molecular target, 107
108 nanotechnology and, 110
115 shortcomings with existing treatments, 109
110 traditional therapies for treatment, 108 US FDA-approved drugs for treatment of lung cancer, 109t Lung-specific X protein (LUNX), 114
115 Lymphatic system, 145
146 Lymphoblastic cell leukemia, 228 Lymphocytes, 225
226 Lymphocytic cell leukemia, 228 Lymphoid cell, 228 Lynch syndrome. See Hereditary nonpolyposis colon cancer (HNPCC) Lysosomes, 148
149

M mAbs. See Monoclonal antibodies (mAbs)

349

mACs-GEm. See GEM-loaded magnetic-activated carbon particles (mACs-GEm) “Magic bullet”, 279 Magnetic core
shell nanoparticles (MCNPs), 53
55 Magnetic hyperthermia (MHT), 53
55, 114
115 Magnetic iron oxide, 156t Magnetic nanoparticles (MNPs), 51, 53
55, 167, 178, 214
215 Magnetic particle imaging (MPI), 42
43 Magnetic quantum dot nanobead system (MQBs system), 290 Magnetic resonance imaging (MRI), 39
40, 44
45, 46f, 79
85, 167, 214
215 and therapy, 61
63 Magnetism-based nanosensors, 173 MAL. See Methyl aminolevulinate (MAL) 3-Maleimidopropionic acid hydrazide (BMPH), 115 Malignant gliomas, 37 Malignant melanoma, 248 MAN. See p-aminophenyl-α-D-manno-pyranoside (MAN) Manganese, 44
45, 79
83 MAPS. See Molecularly activated plasmonic nanosensors (MAPS) Matrix metalloproteinases (MMPs), 93
94 MMP2, 60 MCNPs. See Magnetic core
shell nanoparticles (MCNPs) MDR. See Multidrug resistance (MDR) Mechanotransduction, 77
78 Median survival time (MST), 209 Medulloblastoma, 38
39 Melanocytes, 246, 248 Melanoma, 248 Mesenchymal stem cells (MSC), 114 Mesoporous silica nanoparticles (MSNs), 52, 84, 113, 150, 236, 331 Metal NPs, 51
56, 213
214, 235
236, 262, 292
295. See also Polymeric nanoparticles carbon nanodots, 53 gold NPs, 55
56 magnetic NPs, 53
55 silica NPs, 52 TiO NPs, 52 Metastasis, 107 Metformin (Met), 332 Methotrexate, 76 Methoxy poly(ethylene glycol) (mPEG), 111 Methyl aminolevulinate (MAL), 253 MGMT. See O6-methylguanine
DNA methyltransferase (MGMT) MHT. See Magnetic hyperthermia (MHT) Micelles, 156t, 158

350

Index

Micro-RNA (miRNA), 2, 113
114, 329 Microorganisms, 131 Microsatellite instability (MSI), 195
196 Microsatellites, 196 Microscopically controlled surgery, 4 Microspheres, 165
166 Microtubule-stabilizing drug, 76 miRNA. See Micro-RNA (miRNA) Miscellaneous nanocarriers, 25
27 quantum dots, 25
27, 26f Mismatch repair (MMR), 196 Mitogen-activated protein kinases (MAPK), 198 Mitomycin C (MMC), 289 Mitosis, 229
230 Mitoxantrone, 255 MKN45 xenograft tumor model, 167 MMC. See Mitomycin C (MMC) MMPs. See Matrix metalloproteinases (MMPs) MMR. See Mismatch repair (MMR) mMWNTs-GEM. See GEM-entrapped magnetic multiwalled carbon nanotubes (mMWNTsGEM) MNPs. See Magnetic nanoparticles (MNPs) Molecular target, 107
108 Molecular weight (MW), 132
133 Molecularly activated plasmonic nanosensors (MAPS), 86 Monoclonal antibodies (mAbs), 167, 202, 229
231 Mononuclear phagocyte system. See Reticuloendothelial system (RES) mPEG. See Methoxy poly(ethylene glycol) (mPEG) MPI. See Magnetic particle imaging (MPI) MQBs system. See Magnetic quantum dot nanobead system (MQBs system) MRI. See Magnetic resonance imaging (MRI) MSC. See Mesenchymal stem cells (MSC) MSDSLA. See Multispectral digital skin lesion analysis (MSDSLA) MSI. See Microsatellite instability (MSI) MSNs. See Mesoporous silica nanoparticles (MSNs) MST. See Median survival time (MST) MTT assay. See 3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide assay (MTT assay) Mucous membranes, 7 Multidrug resistance (MDR), 319 in cancer therapy, 320 doxorubicin, 323
325 mechanisms in cancer cells, 320
322, 321f autophagy, 322 hypoxia, 322 P-glycoprotein efflux proteins, 320
321 tumor suppressor genes, 321 xenobiotics, 321

nanomedicine-based multidrug resistance reversal strategies, 322
323 novel strategies, 322 reversal of doxorubicin-loaded nanomedicines, 325
335 Multimodal imaging and therapy, 63
64 Multiphoton tomography, 252t Multiple myeloma, 225
226, 228 Multispectral digital skin lesion analysis (MSDSLA), 252t Multiwalled carbon nanotubes (MWCNTs), 21t, 218 MW. See Molecular weight (MW) MWCNTs. See Multiwalled carbon nanotubes (MWCNTs) Myelogenous leukemia, 228 Myeloid cell, 228

N Nano drug delivery strategies nanotechnology in HNC detection and diagnosis, 78
97 oral and throat cancers, 75
77 transport barriers to drug delivery in HNC tumors, 77
78 Nano-based molecular imaging, 79
88 MRI, 79
85 OCT, 85 PAI, 85
86 QDs imaging and biomarkers, 88 SERS, 87
88 surface plasmon resonance scattering, 86
87 Nano-chemotherapeutics to target chemical environment, 94
95 targeting metastasis, 95 in targeting tumor vasculature, 92
94 Nano-roughened structures, 173
174 Nanocapsules, 210
211, 261, 287
288 Nanocarriers, 20, 24
25, 259
264 properties, 236
237 in treatment of PC, 151
159, 154f CNTs, 157 dendrimer, 157
158 liposomes, 155
157 micelles, 158 nanogel, 158
159 NPs, 151
155 QDs, 159 Nanochemoprevention of prostate cancer, 297
298 Nanocolloidal, 295 NanoCurc. See Curcumin-loaded polymeric NPs (NanoCurc) Nanoemulsion, 15
17, 18t

Index

Nanoencapsulated tocopheryl succinate (a-TOS), 93
94 Nanofibers, 173
174 Nanogel, 156t, 158
159 Nanoliposomes, 56
57 Nanomaterials, 119
120 Nanomedicine, 119
120, 151
155, 165, 231
233, 237, 241, 277
278 for brain cancer, 60
64 for diagnosis of brain cancers, 43
50 drawbacks and circumstances in brain tumors, 39
40 future perspectives and challenges, 64
65 global statistics of brain cancers, 38
39 nanomedicine-based multidrug resistance reversal strategies, 322
323 strategy for natural compound delivery for cancer treatment, 97 for treatment of brain cancer, 51
60 and diagnosis of gliomas, 43 Nanoparticles (NPs), 40, 51t, 62t, 83, 110, 110f, 148
149, 151
155, 154f, 156t, 165
166, 175f, 176t, 206
218, 231, 233
234, 245
246, 259
264, 278, 280f carbon nanotubes, 217
218 as carriers of fluorescent dyes for imaging tumors, 45
48 characterization techniques, 151, 152t, 153t in detection of tumors, 172
174 drug delivery to liver with, 120
124 functionalization, 131
132 in HNC immunotherapy, 95
97 hydrogel, 216
217 in imaging of GC, 166
172, 168t in locoregional imaging, 170
171 in systemic imaging, 167
170 in theranostics, 171
172 ways of imaging, 170
172 lipid, 262
264 liposomes, 208
209 in locoregional imaging, 170
171 magnetic, 214
215 mechanistic pathways employed by NPs to cross BBB, 41
43 metallic, 213
214, 262 nanoparticle-treated mice, 57
58 natural or biomaterials as, 113
114 NP-based drug-delivery systems for PC therapy, 156t NP-based theranostic modalities, 171 NPs-based therapy of GC, 174
179 AgNPs, 177

351

AuNPs, 178 carbon nanotubes, 178
179 chitosan NPs, 174
175 miscellaneous, 179 MNPs, 178 PDT, 179 polymeric NPs, 175
177 pH-responsive nanoparticles, 207
208 polymeric, 209
212, 259
261 micelles, 216 polymerosomes, 217 release modulators, 45
48 SLNs, 213 strategy for treatment of brain cancers, 40
41 for treatment of brain cancers, 40
41 active targeting, 41 passive targeting, 40
41 physical properties, 40 uptake mechanism in PC, 148
149 viral nanoparticles, 215 Nanopharmaceuticals, 88 Nanoplatin, 88 Nanoscale drug delivery system, 233 MRI, 83 Nanosized semiconductor crystals, 159 Nanospheres, 22
24, 156t, 211
212, 260 Nanosponges, 260
261 Nanostructured lipid carriers (NLCs), 19, 91, 262
264 nanosuspension, 20 Nanosuspension, 20, 21t Nanotechnology, 38
40, 110
115, 120
121, 145, 147
148, 165, 174, 245, 278 in HNC detection and diagnosis, 78
97, 80t nano-based molecular imaging, 79
88 nanotechnology-based drug delivery systems, 88
97 inorganic NPs for lung cancer, 112
113 nanotechnology-based tools, 241 natural or biomaterials as NPs, 113
114 novel NPs systems for lung cancer, 114
115 organic NPs for lung cancer, 111
112 and prostate cancer, 301
303 for fluorescence diagnosis, 302 targeted prostate-specific antigen nanoprobe, 303 targeted prostate-specific membrane antigen nanoprobes, 303 in treatment of cancer, 231
237, 232f types of nanomaterials, 111f NanoVelcro Chips, 173
174 NAR. See Naringenin (NAR) Naringenin (NAR), 21t Natural compound delivery for cancer treatment, 97

352

Index

Natural-origin bioactives, 256
258 N-deoxycholic acid glycol chitosan (DGC), 174
175 Near infrared fluorescence (NIRF), 167 Near-infrared (NIR), 41
42, 85
86, 132
133 Neoadjuvant treatment for cancer, 2 Neovascularization, 92
93 Next-generation impactor, 17
19 NGR ligand. See Asn-Gly-Arg ligand (NGR ligand) Niosomes, 9
12, 13t NIR. See Near-infrared (NIR) NIRF. See Near infrared fluorescence (NIRF) Nivolumab, 109t N-lauryl glucosamine
anchored doxorubicin niosomal formulation, 12 NLCs. See Nanostructured lipid carriers (NLCs) NMSC. See Nonmelanoma skin cancer (NMSC) Non-small-cell cancer drugs, 109
110 Nonbiologics, 254 Noncancerous fibroblast cells, 145
146 NonHodgkin lymphoma, 225
226, 228 Nonmalignant cells, 77 Nonmelanoma skin cancer (NMSC), 248 NonPEGylated liposomal DOX, 120
121 Nonsmall cell lung cancer (NSCLC), 17
19, 107 Nonsolid tumor, 239
240 Novel NPs systems for lung cancer, 114
115 NPs. See Nanoparticles (NPs) NSCLC. See Nonsmall cell lung cancer (NSCLC) Nucleic acid nanoconstructs, 240 Nucleic acid-based tumor antigens, 97 Nystatin, 16
17

O O6-benzylguanine (BG), 61
63 O6-methylguanine
DNA methyltransferase (MGMT), 61
63 Oat-cell cancer, 107 OCT. See Optical coherence tomography (OCT) Oncogenes, 6 Opsonin, 237 OPSS. See Ortho pyridyl disulfide (OPSS) Optical coherence tomography (OCT), 85, 252t Optical imaging and therapy, 63 in vivo PTT of mice bearing subcutaneous U87 xenograft tumors, 64f Optical-based nanosensors, 173 Oral cancers, 75
77 conventional therapies for management of, 75
76 Organ transplant recipients, 249
250 Organic NPs for lung cancer, 111
112 Oropharynx, 75 Ortho pyridyl disulfide (OPSS), 134 Orthotopical glioblastoma mice model, 41
42

Osimertinib, 109t Osmium, 5 Ova, 23t Oxaliplatin, 178 Oxaliplatin-Au-Fe3O4-herceptin, 178

P P53. See Tumor protein-53 (P53) PAAs. See Poly(amidoamine)s (PAAs) Paclitaxel (PTX), 10t, 14t, 17, 23t, 61
63, 111, 233 Paclitaxel-betulinic acid, 21t Paclitaxel-loaded poly(ethylene oxide)-co-poly(D, Llactide) (PTX-PEG-PLDA), 148
149 Paclitaxel-loaded polymeric nanoparticles, 24 Paclitaxel/docetaxel, 76
77 PAI. See Photoacoustic imaging (PAI) Palladium, 235
236 Palliative chemotherapy, 7 Palliative treatment, 2 Palliative with supportive surgery, 4 PAMAM. See Poly(amidoamine)s (PAAs) p-aminophenyl-α-D-manno-pyranoside (MAN), 57
58 Pancreatic cancer (PC), 145 characterization techniques, 151, 152t, 153t current scenario and epidemiology, 146 microenvironment, 147f nanocarrier systems in treatment, 151
159 nanoparticle uptake in, 148
149 physiology, 145
146 receptor for targeting PC, 149
151 CD44 receptor, 149
150 EGFR, 149 FR, 150 Tfr, 150 VEGF, 150
151 treatment, 147
148 Panitumumab, 204
206 Panobinostat, 18t Passive targeting, 40
41 Pathogenesis of skin cancer, 248
250 PC. See Pancreatic cancer (PC) PCL. See Polycaprolactone (PCL) PDA. See Polydopamine (PDA) PDL-1. See Programmed cell death-ligand 1 (PDL-1) PDT. See Photodynamic therapy (PDT) PDTC. See Pyrrolidine dithiocarbamate (PDTC) PEG. See Polyethylene glycol (PEG) PEGylation, 131
132 PEI. See Polyethylenimine (PEI) PEI-SS-CLs. See Disulfide-containing crosslinked polyethylenimine (PEI-SS-CLs) Pembrolizumab, 109t Peptide antigens, 97

Index

Perfluoro-hexane, 18t Perfluorocarbon, 18t PET. See Positron emission tomography (PET) PEtOz-SS-PCL. See Poly(2-ethyl-2-oxazoline)-b-poly (ε-caprolactone) (PEtOz-SS-PCL) PGA. See Poly(glycolic acid) (PGA) P-glycoprotein (P-gp), 320
321 efflux inhibitors, 329
331 pH-responsive nanoparticles, 156t, 207
208 Phagocytosis process, 148
149 Phagolysosomes, 148
149 Phagosomes, 148
149 Phosphatase and tensin homolog protein (PTEN), 199 Phosphatidyl choline, 14
15 Phospholipids, 12 Photoacoustic imaging (PAI), 63, 85
86 Photoacoustic signal, 86 Photocatalyzed TiO2 NPs, 112 Photodynamic therapy (PDT), 94, 112, 131, 179, 247, 253 Photolyase, 259 Photosensitizers, 258 Photothermal therapy (PTT), 53, 131
133 Phthalocyanine, 16t, 258 Pinocytosis, 148
149 PKM2. See Pyruvate kinase M2 (PKM2) PLA. See Poly (lactic acid) (PLA) Plasma, 226
228 Plasmonic nanobubbles (PNBs), 291
292 Platelet cells, 226
228 Platinum, 5, 235
236 Platinum drug delivery nanoforms, 113 PLG. See Poly(lactide-co-glycolide) (PLG) PLGA. See Poly(lactic-co-glycolic acid) (PLGA) PNBs. See Plasmonic nanobubbles (PNBs) Polipoproteins, 237 Poly (lactic acid) (PLA), 24, 58
60, 111, 287
288 Poly-L-lysine coated poly(lactic-co-glycolic acid) NPs (PPNPs), 151
155 Poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) (PEtOz-SS-PCL), 58
60 Poly(amidoamine)s (PAAs), 122, 287
288 Poly(ethylene oxide)-co-poly(L-lactide) (PTX-PEGPLLA), 148
149 Poly(glycolic acid) (PGA), 58
60 Poly(lactic-co-glycolic acid) (PLGA), 45
48, 84, 111, 151
155, 171
172, 245
246, 287
288 PLGA encapsulating letrozole inhibitor, 58
60 Poly(lactide-co-glycolide) (PLG), 283
284 Poly(N,N-diethyl acrylamide)-functionalized graphene QD hydrogels, 26
27 Poly[juglanin dithiodipropionic acid]-b-poly (ethylene glycol)-siRNA Kras with doxorubicin (DOX/ PJAD-PEG-siRNA), 114 Polyacrylates, 22
24

353

Polycaprolactone (PCL), 22
24, 171
172, 287
288 Polydopamine (PDA), 52, 177 Polyelectrolyte, 111 Polyethylene glycol (PEG), 114, 120
121, 151
155, 170 Polyethylenimine (PEI), 115, 121
122, 171
172 PEI-SS-OA-based lipid vector system, 124
125 Polylactide, 22
24, 177 Polylactide
polyglycolide copolymers, 22
24 Polymer-based fluorescent NPs, 115 Polymer-based magnetic NPs, 84 Polymer-based nanomedicines. See also Lipid-based nanomedicines CNTs, 20
21 dendrimers, 22 polymeric micelles, 24
25 polymeric nanoparticles, 22
24 Polymeric micelles, 24
25, 156t, 216 Polymeric nanoparticles, 22
24, 58
60, 175
177, 209
212, 233
235, 259
261. See also Metal NPs for cancer treatment, 287
289 Polymerosomes, 217 Polyp
carcinoma sequence, 193 PorphyrinHDL, 114 Positron emission tomography (PET), 43
44, 167 PPNPs. See Poly-L-lysine coated poly(lactic-co-glycolic acid) NPs (PPNPs) Predictive biomarkers, 198
199 Preventive surgery for cancer, 3 Primary treatment for cancer, 2 Prognostic biomarkers, 199 Programmed cell death-ligand 1 (PDL-1), 95
96, 108 Prostate cancer, 4, 275
278 drug delivery, 279
281 active and passive targeting, 280
281 locoregional route, 283
285 routes to prostate, 281
285, 281f systemic route, 281
283 toward tumor cells, 280 nanoparticle system classification for, 285
295 albumin-bound system, 286
287 carbon-based system, 289 dendrimers, 289
290 gold nanoparticulate system, 290
292 liposomal nanoparticles in, 285
286 metallic nanoparticle, 292
295 nanocolloidal, 295 polymeric nanoparticle systems, 287
289 QDs, 290 nanotechnology approach and, 301
303 treatment for, 295
301 via cancer immunotherapy, 300
301 via gene delivery, 298
300 nanochemoprevention of, 297
298 Prostate gland, 275
278, 276f, 279f Prostate malignant growth, 275
276

354 Prostate-specific antigen (PSA), 275 Protooncogenes, 6
7 PSA. See Prostate-specific antigen (PSA) PTEN. See Phosphatase and tensin homolog protein (PTEN) PTT. See Photothermal therapy (PTT) PTX. See Paclitaxel (PTX) PTX-loaded bovine serum albumin (PTX
BSA), 155
157 PTX-PEG-PLDA. See Paclitaxel-loaded poly(ethylene oxide)-co-poly(D, L-lactide) (PTX-PEG-PLDA) PTX
BSA. See PTX-loaded bovine serum albumin (PTX
BSA) Pyrrolidine dithiocarbamate (PDTC), 334 Pyruvate kinase M2 (PKM2), 197

Q QDs-Ela. See Elacridar-modified quantum dots (QDsEla) Quantum dots (QDs), 25
27, 26f, 48
49, 88, 151, 159, 235, 290 imaging and biomarkers, 88 Quercetin (QUR), 13t, 18t, 334

R Radiation therapy, 1
2, 109
110, 204, 230
231, 253 principles, 5, 6f types, 5 Radioactive substances, 5 Radiosensitization property, 55
56 Radiotherapy, 76 principles, 5 role for cancer treatment, 5 types, 5 Raman spectroscopy, 45, 252t RCM. See Reflectance confocal microscopy (RCM) Reactive oxygen species (ROS), 16, 195, 253, 323
325 Receptor-mediated endocytosis (RME), 131
132, 148
149 Receptor-mediated transport (RMT), 42
43 Recombinant single chain fragment variable (rscfv), 215 Red blood cells, 226
228 Redox-responsive NPs (RR-NPs), 112 Reflectance confocal microscopy (RCM), 252t Relative tumor volume (RTV), 138
139 Renal system, 238 RES. See Reticuloendothelial system (RES) Res-AuNPs. See Gold NPs conjugated with resveratrol (Res-AuNPs) Restorative surgery, 4 Reticuloendothelial system (RES), 122, 236
238 RGD. See Arginyl-glycyl-aspartic acid (RGD)

Index

RGD-modified PTX and cisplatin loaded LPNs (RGDss-PTX/CDDP LPNs), 111 RISC. See RNA-induced silencing complex (RISC) RME. See Receptor-mediated endocytosis (RME) RMT. See Receptor-mediated transport (RMT) RNA interference (RNAi), 10t, 121, 298
300 RNA-induced silencing complex (RISC), 121 RNAi. See RNA interference (RNAi) ROS. See Reactive oxygen species (ROS) RR-NPs. See Redox-responsive NPs (RR-NPs) rscfv. See Recombinant single chain fragment variable (rscfv) RTV. See Relative tumor volume (RTV)

S SBRT. See Stereotactic body radiation therapy (SBRT) SC. See Stratum corneum (SC) sc-RIP. See Single-stranded ribosome-inactivating protein (sc-RIP) Scavenger receptor class B type I (SR-BI), 114 SCC. See Squamous cell carcinoma (SCC) Selenium NPs (SeNPs), 113 SERS. See Surface-enhanced Raman spectroscopy (SERS) Shh. See Sonic Hh (Shh) Short tandem repeats (STRs). See Microsatellites SIL. See Silibinin (SIL) Silibinin (SIL), 13t, 286 Silver (Ag), 87, 235
236 Silver nanoparticles (AgNPs), 52, 112
113, 177, 236 Single-photon emission CT, 167 Single-stranded ribosome-inactivating protein (sc-RIP), 258 Single-walled carbon nanotubes (SWCNTs), 157, 178
179 siRNA. See Small interfering ribonucleic acid (siRNA) Skin, 246 epidermis and dermis, 247f lymph node metastasis, 2
3 Skin cancer, 4, 246
247 classification, 247
248 detection, 250
251, 252t induction, 249f nanocarriers, 259
264 pathogenesis, 248
250 HPVs, 250 immunosuppression, 249
250 organ transplant recipients, 249
250 UV radiation, 248
249 treatment modalities, 251
259 biologics, 259 C&E, 251 cryotherapy, 251
253

Index

hedgehog pathway inhibitors, 253
254 miscellaneous products, 259 natural-origin bioactives, 256
258 nonbiologics, 254 PDT, 253 photosensitizers, 258 radiation therapy, 253 synthetic chemotherapeutic agents, 254
256 SLNs. See Solid lipid nanoparticles (SLNs) SMAD4, 202 Small interfering ribonucleic acid (siRNA), 10t, 13t, 18t, 23t, 120
121, 151, 171
172, 325 nanomedicine coloaded with, 325
329 Small-cell lung cancer, 107 Smart drug-delivery vehicle, 147
148 SMMC cells, 124
125 Sodium alginate
coated iron oxide particles, 238
239 Sodium silicate, 236 Solid lipid nanoparticles (SLNs), 17
19, 42
43, 213, 245
246, 262
263 Sonic Hh (Shh), 253 SP-A. See Surfactant protein-A (SP-A) Spherical lipid bilayer systems, 234 SPIO. See Superparamagnetic iron oxide (SPIO) SPIONPs. See Superparamagnetic iron oxide NPs (SPIONPs) sPOLP, 123, 125
126 SPR. See Surface plasmon resonance (SPR) sPssOLP, 123
126 Squamous cell carcinoma (SCC), 8
9, 107, 246
247 Squamous cell lung cancer, 107 SR-BI. See Scavenger receptor class B type I (SR-BI) Src-activated signaling cascades, 95 SS-PAEIs. See Disulfidecontaining poly(amidoethyl enamine)s (SS-PAEIs) Staging surgery, 4 Stereotactic ablative body radiotherapy, 5 Stereotactic body radiation therapy (SBRT), 5 Stool-based tests, 192 sTPssOLP, 123
126 Stratum corneum (SC), 246 Structural tests. See Visual tests Structured lipid
polymer hybrid NP, 91 Superparamagnetic iron oxide (SPIO), 61
63, 167 SPIO
Au NS, 84
85 Superparamagnetic iron oxide NPs (SPIONPs), 91
92, 213 Surface plasmon resonance (SPR), 131
132, 301
302 scattering, 86
87 Surface plasmon reverberation. See Surface plasmon resonance (SPR) Surface-enhanced Raman spectroscopy (SERS), 87
88, 172

355

Surfactant protein-A (SP-A), 114
115 Surgery, 1
2, 109
110 role for cancer treatment, 2
5 risk and side effects in cancer treatment, 5 of surgery, 2
4, 3f Surgical resection, 203 Surgical therapy, 39
40 Survivin, 121
122 Swarna Bhasma, 151
155 SWCNTs. See Single-walled carbon nanotubes (SWCNTs) Synergistic anticancer effect, 25 Synthesized nanoparticles, 45
48 Synthetic chemotherapeutic agents, 254
256 Synthetic polymers, 22
24 Systemic imaging, NPs in, 167
170 Systemic route, 281
283

T T4 endonuclease V, 259 TAA. See Tumor-associated antigens (TAA) Tamoxifen, 9
12, 13t Target chemical environment, nano-chemotherapeutics to, 94
95 Targeted drug delivery, 149 Targeted prostate-specific antigen nanoprobe, 303 Targeted prostate-specific membrane antigen nanoprobes, 303 Targeted therapy, 204
206 Targeting tumor vasculature, 92
94 TAT. See Transactivator of transcription (TAT); Transcriptional activator (TAT) Taxane, 76 Tea polyphenols, 256
257 Telomerase, 197
198 TEM. See Transmission electron microscopy (TEM) Temoporfin, 258 19-Tert-butyldiphenylsilyl-8,17-epoxy andrographolide, 21t Tetraiodothyroacetic-conjugated pegylated QDs, 159 Tfr. See Transferrin receptor (Tfr) TGA. See Thermogravimetric analysis (TGA) Theranostic nanomedicine, 119
120 Theranostics, 119
120, 165
166, 239
240 action, 231
233 NPs in, 166, 171
172 Thermogravimetric analysis (TGA), 52 Thermoresponsive lipid nanoparticles (TLNs), 57
58 Thiophenyl sulfonated zinc, 16t Three-dimensional conformal radiation therapy (3DCRT), 108, 296 Throat cancers, 75
77 Thymoquinone, 13t

356 Thyroid cancer, 4 Titanium dioxide (TiO2), 112 Titanium oxide (TiO), 52 NPs, 52 TLNs. See Thermoresponsive lipid nanoparticles (TLNs) TNF-α. See Tumor necrosis factor-α (TNF-α) TNM. See Tumor, nodule, and metastasis (TNM) Tobacco smoke, 225 D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), 331
332 Topoisomerase-2, 254 TOS-CDDP. See α-tocopherol succinate-cisplatin prodrug (TOS-CDDP) Toxicity of nanocomposites, 139
140 TPGS. See D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) TR3 siRNA, 23t Tracheobronchial amyloidosis, 5 Trametinib, 109t Transactivator of transcription (TAT), 55
56 Transcriptional activator (TAT), 17 Transcytosis, 43 Transdermal drug delivery system, 12 Transferosome, 14
15, 16t characteristics of, 15 Transferrin, 42
43 Transferrin receptor (Tfr), 149
150 Transferring iron-bound protein, 150 Transferring receptors, 41 Transmembrane glycoprotein
containing family members, 149 Transmission electron microscopy (TEM), 130
131 Transport barriers to drug delivery in head and neck tumors, 77
78 Transrectal, 284
285 Trastuzumab, 167, 229 Trehalose, 257 Tretinoin, 259 TSA. See Tumor-specific antigens (TSA) Tumor, nodule, and metastasis (TNM), 75
76 Tumor imaging, NPs as fluorescent agents for, 48
50, 50f Tumor microenvironment targeted nanotherapy, 92
97, 93f nano-chemotherapeutics to target chemical environment, 94
95 targeting metastasis, 95 in targeting tumor vasculature, 92
94 nanomedicine as strategy for natural compound delivery, 97 potential of NPs in HNC immunotherapy, 95
97 Tumor necrosis factor-α (TNF-α), 139
140 Tumor protein-53 (P53), 200
201

Index

Tumor-associated antigens (TAA), 96
97 Tumor-specific antigens (TSA), 96
97 Tumor(s), 107, 191
192, 225 angiogenesis, 92
93 cells, 280 NPs in detection, 172
174 detection of circulating tumor cells, 173
174 detection of GC using biomarkers, 173 early detection of GC via endoscopy, 172
173 proliferating cells, 77 quiescent cells, 77 suppressor genes, 6, 321 targeting agents, 39 Tyrosine kinases, 108 inhibitors, 229
230

U UA. See Ursolic acids (UA) Ultrafine dispersion, 15
16 Ultrasmall superparamagnetic iron oxide NPs (USPIO), 84
85 Ultrasound-responsive nanoemulsion, 156t Ultraviolet A (UVA), 52 Ultraviolet radiation (UV radiation), 248
249 Urokinase plasminogen activator receptor (UPAR), 149 Ursolic acids (UA), 57
58 USPIO. See Ultrasmall superparamagnetic iron oxide NPs (USPIO) UV radiation. See Ultraviolet radiation (UV radiation) UVA. See Ultraviolet A (UVA)

V Vas deferens, 284 Vascular endothelial growth factor (VEGF), 93
94, 150
151, 202 Vincristine liposome, 234 Viral nanoparticles, 215 Visual tests, 192

W Warburg effect, 78 Water-based vehicles, 9 White blood cells, 226
228, 239 World health organization (WHO), 1
2, 37, 75, 107, 226

X X-ray photoelectron spectroscopy (XPS), 44
45 Xenobiotics, 321

Z Zinc phthalocyanine, 258 Zinnia elegans, 48
49