Nanomedicine in Treatment of Diseases (Learning Materials in Biosciences) 9819976251, 9789819976256

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Learning Materials in Biosciences

Bushra Akhtar Faqir Muhammad Ali Sharif   Editors

Nanomedicine in Treatment of Diseases

Learning Materials in Biosciences Series Editors Anja K. Bosserhoff, Friedrich-Alexander University Erlangen Erlangen, Germany Aydin Berenjian, The University of Waikato Hamilton, Waikato, New Zealand Pablo Carbonell, Universitat Politècnica de València Valencia, Spain Mia Levite, School of Pharmacy, Faculty of Medicine The Hebrew University, Jerusalem, Israel Joan Roig, Molecular Biology Institute of Barcelona Barcelona, Spain Kursad Turksen, University of Ottawa Ottawa, ON, Canada

Learning Materials in Biosciences textbooks compactly and concisely discuss a specific biological, biomedical, biochemical, bioengineering or cell biologic topic. The textbooks in this series are based on lectures for upper-level undergraduates, master’s and graduate students, presented and written by authoritative figures in the field at leading universities around the globe. The titles are organized to guide the reader to a deeper understanding of the concepts covered. Each textbook provides readers with fundamental insights into the subject and prepares them to independently pursue further thinking and research on the topic. Colored figures, step-by-step protocols and take-home messages offer an accessible approach to learning and understanding. In addition to being designed to benefit students, Learning Materials textbooks represent a valuable tool for lecturers and teachers, helping them to prepare their own respective coursework.

Bushra Akhtar • Faqir Muhammad • Ali Sharif Editors

Nanomedicine in Treatment of Diseases

Editors Bushra Akhtar Department of Pharmacy University of Agriculture Faisalabad, Pakistan

Faqir Muhammad Department of Biosciences Bahauddin Zakariya University Multan, Pakistan

Ali Sharif Department of Pharmacology, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences Lahore College for Women University Lahore, Pakistan

ISSN 2509-6125     ISSN 2509-6133 (electronic) Learning Materials in Biosciences ISBN 978-981-99-7625-6    ISBN 978-981-99-7626-3 (eBook) https://doi.org/10.1007/978-981-99-7626-3 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Paper in this product is recyclable.

We dedicate this book to our parents and daughters (Aroosh Ali and Ayesha Ali) for loving and supporting us at every stage. Dr. Bushra Akhtar Dr. Ali Sharif

Preface

In the ever-evolving field of medicine, advancements in technology continue to ­revolutionize the way we approach treatments and patient care. One of the most exciting and promising developments in recent years has been the advent of nanomedicine. This emerging interdisciplinary field harnesses the power of nanotechnology to address the numerous challenges that conventional therapies often struggle to overcome. In this book, we embark on an illuminating journey through the awe-inspiring field of nanomedicine and its extraordinary impact on revolutionizing medical treatments. From conquering bacterial and viral diseases to treating cancer and metabolic, fungal, skin, gastrointestinal, and cardiovascular disorders, nanomedicine has emerged as a cutting-edge force in the quest for improved healthcare. This book is divided into three parts. Part I encompasses the introduction to nanomedicine in two chapters. The first chapter provides an overview of nanomedicine, discussing its fundamental concepts, principles, and techniques. The remarkable potential of nanotechnology in medicine is explored, and how it has paved the way for innovative therapies and diagnostic tools is elaborated. While nanomedicine has immense potential, it also faces numerous challenges and limitations. This chapter addresses the latest nanotechnology techniques such as microfluidics, nanorobotics, microchips, and gene/drug delivery devices. The future directions and emerging trends in nanomedicine are explored. The latest developments in this field and the potential impact they may have on medicine and patient care are discussed. The second chapter discusses the advantages of nanomedicine over conventional therapies. Conventional therapies have long been the cornerstone of medical treatments. However, as we delve further into the realm of nanomedicine, it becomes evident that it holds several advantages over traditional approaches. This chapter discusses the specific advantages that nanomedicine offers, including enhanced drug delivery, increased therapeutic efficacy, and reduced side effects with the use of different nanocarrier devices. Part II gives an elaborated review of nanomedicine in the treatment of various diseases in Chaps. 3–11. Chapter 3 is about the use of nanomedicine in the treatment of bacterial diseases. Bacterial infections, formidable adversaries to human health, have long posed challenges for medical professionals. However, nanomedicine provides a novel approach vii

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for combating bacterial diseases. The readers will learn how nanoscale materials and devices are ingeniously revolutionizing the treatment of bacterial infections. The mechanisms through which nanomedicine effectively targets, neutralizes, and eradicates bacterial pathogens have been explored, paving the way for future advancements in antibiotic therapies. Chapter 4 highlights nanomedicine in the treatment of viral diseases. Viral infections, notorious for their capacity to evolve rapidly and cause widespread harm, necessitate innovative medical interventions. This chapter explores how nanomedicine equips us with powerful tools to combat viral diseases. The intricacies of nano-based platforms and therapies are explored, which target and suppress viral replication. Various nanocarrier systems have been discussed for the delivery of antiviral drugs. By gaining insights into the forefront of nanotechnology in virology, the immense potential of nanomedicine in defeating viral adversaries has been uncovered. Disorders of the nervous system, such as Alzheimer’s, Parkinson’s, epilepsy, and spinal cord injuries, present unique challenges in treatment due to the complexity of the human brain and spinal cord, which are discussed in Chap. 5. This chapter explores how nanomedicine offers revolutionary solutions for these ailments. Breakthroughs in nanotechnology are examined that enable targeted drug delivery, crossing the blood-brain barrier, and development of neuroprotective strategies. Through these advances, nanomedicine provides hope for millions affected by nervous system disorders. Cancer, one of the most formidable diseases of our time, demands innovative approaches for effective treatment. Chapter 6 delves into the remarkable strides made by nanomedicine in the battle against cancer. How nanotechnology facilitates the development of targeted drug delivery systems is explored, enabling precise and personalized cancer therapeutics. By examining cutting-edge research, efforts are witnessed in how nanomedicine is transforming cancer treatment and offering improved outcomes for patients. Nanomedicine in the treatment of metabolic diseases, fungal diseases, skin diseases, gastrointestinal diseases, and cardiovascular diseases is reviewed in Chaps. 7–11. In successive chapters, we explore how nanomedicine is revolutionizing the treatment of a range of ailments. From metabolic diseases to fungal infections, skin disorders, gastrointestinal ailments, and cardiovascular diseases, the innovative applications of nanomedicine in each domain are elaborated in detail. The applications of nanomedicine against important diseases such as obesity, diabetes, dermatosis, stroke, atherosclerosis, inflammatory bowel disease, and ringworm infections are discussed in detail. By uncovering breakthroughs and advancements, a comprehensive understanding of how nanomedicine is transforming diverse areas of medical practice is gained. Part III covers the current status of nanomedicine in clinical practice. This final chapter presents and explores the current status of nanomedicine in clinical setup. The real-world applications, ongoing clinical trials, and challenges and opportunities that lie ahead are examined in detail. FDA-approved nanomedicines in different phases of development for cancer, HIVs, hepatitis, fungal infections, iron-deficiency anemia, and joint diseases are discussed in detail. By exploring the successes and hurdles faced by nanomedicine, valuable insights into the future of this game-changing field are gained.

Preface

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As we journey through the chapters, we aim to provide a comprehensive understanding of the potential of nanomedicine in transforming medical treatments and improving patient outcomes. Join us in this thrilling exploration of nanomedicine as we uncover the cutting-­ edge breakthroughs that are changing the landscape of healthcare. We hope that this book serves as a valuable resource for readers seeking a comprehensive understanding of nanomedicine, its present perspectives, and the future challenges it presents. By keeping in view the advantages nanomedicine offers over conventional therapies, we aim to inspire further research and innovative approaches that can revolutionize the field of medicine for the betterment of lives. Faisalabad, Pakistan Multan, Pakistan  Lahore, Pakistan 

Bushra Akhtar Faqir Muhammad Ali Sharif

Contents

Part I Introduction to Nanomedicine 1 N  anomedicine: Present Perspectives and Future Challenges��������������������������   3 Sajid Ali, Aatika Sadia, and Imran Tariq 2 A  dvantages of Nanomedicine Over Conventional Therapeutics ��������������������  45 Adeel Masood Butt, Nabiha Abdullah, Amna Sattar, Talib Hussain, Manisha Pandey, Tarun Kumar, Unnati Garg, Jatin Rathee, Neha Jain, and Muhammad Mustafa Abeer Part II Nanomedicine in Treatment of Diseases 3 N  anomedicines for the Treatment of Bacterial Diseases����������������������������������  89 Rida Siddique, Ammara Saleem, Faqir Muhammad, Muhammad Furqan Akhtar, Bushra Akhtar, and Ali Sharif 4 N  anomedicine in the Treatment of Viral Diseases�������������������������������������������� 123 Ammara Akhtar, Muhammad Ijaz, Fatima Batool, and Javeria Pervaiz 5 N  anomedicines in the Treatment of Nervous System Disorders���������������������� 151 Zakiah Zeb, Ali Sharif, Mohamed M. Abdel-Daim, Syed Muhammad Muneeb Anjum, Atif Ali Khan Khalil, Muhammad Furqan Akhtar, Ammara Saleem, and Muhammad Imran Khan 6 N  anomedicines in Treatment of Cancer������������������������������������������������������������ 183 Bushra Akhtar, Ayesha Tanveer, Ali Sharif, Fozia Anjum, Muhammad Shahid, and Saadiya Zia 7 N  anomedicine in the Treatment of Metabolic Diseases������������������������������������ 213 Sairah Hafeez Kamran 8 N  anomedicines in the Treatment of Fungal Diseases���������������������������������������� 257 Anam Ahsan, Qurat-ul-ain Aslam, and Clive A. Prestidge

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9 N  anomedicines in the Treatment of Skin Diseases�������������������������������������������� 285 Majid Anwar, Faqir Muhammad, Bushra Akhtar, Sana Fatima, Hassnain Khan, and Chi-Chung Chou 10 N  anomedicines in the Treatment of Gastrointestinal Disorders���������������������� 307 Muhammad Ayaz, Assad Usman, Ali Talha Khalil, Abdul Sadiq, Farhat Ullah, Osama F. Mosa, and Muhammad Arif Khan 11 N  anomedicines in Treatment of Cardiovascular Diseases�������������������������������� 335 Ayesha Tanveer, Bushra Akhtar, Ali Sharif, Muhammad Irfan Anwar, Haroon Khan, Sultan Mehtap Buyuker, Mian Muhammad Zeeshan Javaid, Kanwal Akhtar, and Hafiz Muhammad Zubair Part III Current Status of Nanomedicine in Clinical Applications 12 C  urrent Status of Nanomedicines in Clinical Practice ������������������������������������ 369 Syeda Asloob Fatima, Zartashia Kanwal, Bushra Akhtar, Muhammad Imran Akhtar, Madiha Liaquat, Safwan Muhammad, Ali Sharif, and Muhammad Salman Index������������������������������������������������������������������������������������������������������������������������������ 387

Editors and Contributors

About the Editors Bushra Akhtar  earned her Doctor of Philosophy (Pharmacology) degree from the University of Agriculture, Faisalabad, Pakistan. She studied Master of Philosophy (Pharmacology and Toxicology) from the University of Veterinary and Animal Sciences, Lahore, Pakistan. She did PharmD from Bahauddin Zakariya University, Multan, Pakistan. She is working as a lecturer in the Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan. She has published 60 peer-reviewed articles with an impact factor of around 160. She has one national patent to her credit. Dr. Bushra Akhtar has produced around 20 postgraduate students as the major supervisor. She is the editorial board member of 02 impact factor journals.  Faqir Muhammad  earned his Doctor of Philosophy degree in 2004 from North Carolina State University, USA, and MSc (Hons.) and DVM degrees from the University of Agriculture, Faisalabad. Dr. Faqir Muhammad is working as Professor and Chairman, Department of Biosciences, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan. He has the experience of working as Research Assistant Professor at Kansas State University, USA, for 2 years. He is a full member of the Society of Toxicology. He has been awarded the Star Award 2005, the Millennium Lifetime Award 2008, and Research Productivity Award 2012. He has contributed a number of book chapters in international books. He has published more than 150 peer-reviewed articles with an impact factor of 255 and has more than 3500 citations to his credit. Dr. Faqir Muhammad has won various research projects from national funding agencies worth more than Rs. 14 million. 

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Editors and Contributors Ali  Sharif  is currently serving as an Assistant Professor and In Charge at the Department of Pharmacology, Institute of Pharmacy, Lahore College for Women University, Lahore. He received his PhD in Pharmacology and Toxicology in 2016, University of Veterinary and Animal Sciences, Lahore. He studied Master of Philosophy (Pharmaceutics) and BPharm from Bahauddin Zakariya University, Multan, Pakistan. He has a teaching experience of more than 13 years. He has produced more than 25 MPhil and PhD students as the major supervisor. He is the author of more than 65 research papers and book chapters with a cumulative impact factor of 150. He is the editorial board member of 03 impact factor journals.

Contributors Mohamed M. Abdel-Daim  Department of Pharmaceutical sciences, Pharmacy Program Batterjee Medical College, Jeddah, Saudi Arabia Pharmacology Department, Faculty of Veterinary Medicine, Suez Cana University, Ismaililia, Egypt Nabiha  Abdullah  Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan Muhammad Mustafa Abeer  CSIRO Agriculture and Food, Werribee, VIC, Australia Anam  Ahsan  Clinical and Health Science, University of South Australia North Tce, Adelaide, SA, Australia Ammara  Akhtar  Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan Bushra Akhtar  Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan Kanwal  Akhtar  Department of Physics, Government College for Women University, Faisalabad, Pakistan Muhammad  Furqan  Akhtar  Riphah Institute of Pharmaceutical Sciences, Riphah International University Lahore Campus, Lahore, Pakistan Muhammad  Imran  Akhtar  Radiology Department, Allied Hospital, Faisalabad, Pakistan Sajid  Ali  Department of Chemistry–Ångström Laboratory, Uppsala University, Uppsala, Sweden Fozia  Anjum  Department of Chemistry, Government College University, Faisalabad, Pakistan

Editors and Contributors

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Syed Muhammad Muneeb Anjum  Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan

Majid  Anwar  Department of Pharmacology, Riphah International University, Lahore, Pakistan Muhammad  Irfan  Anwar  Department of Pathobiology, Bahauddin Zakariyya University, Multan, Pakistan Qurat-ul-ain Aslam  Drug Testing Laboratory, Faisalabad, Punjab, Pakistan Muhammad Ayaz  Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, Pakistan Fatima Batool  Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan Adeel Masood Butt  Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan Sultan  Mehtap  Buyuker  Department of Pharmacy Services, Uskudar University, Istanbul, Turkey Chi-Chung  Chou  Department of Veterinary Medicine, CVM, National Chung-Hsing University, Taichung, Taiwan Sana  Fatima  Department of Botany, The Govt Sadiq College Women University, Bahawalpur, Pakistan Syeda  Asloob  Fatima  Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan Unnati  Garg  Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, UP, India Talib Hussain  Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan Muhammad Ijaz  Department of Pharmacy, COMSATS University Islamabad, Lahore, Pakistan Neha Jain  Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, UP, India Mian  Muhammad  Zeeshan  Javaid  Department of Pharmacy, Faculty of Health and Medical Sciences, Mirpur University of Science and Technology, Azad Kashmir, Pakistan Sairah  Hafeez  Kamran  Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Punjab, Pakistan

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Editors and Contributors

Zartashia Kanwal  Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan Ali  Talha  Khalil  Department of Pathology, Lady Reading Hospital Medical Teaching Institution, Peshawar, Pakistan Atif  Ali  Khan  Khalil  College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea Haroon Khan  Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan Hassnain  Khan  Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan Muhammad  Arif  Khan  Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, Pakistan Muhammad  Imran  Khan  Riphah Institute of Pharmaceutical Sciences, Riphah International University Lahore Campus, Lahore, Pakistan Tarun Kumar  Department of Pharmaceutical Sciences, Central University of Haryana, Mahendragarh, Haryana, India Madiha Liaquat  Anesthesia Department, DHQ Hospital, Faisalabad, Pakistan Osama F. Mosa  Health Sciences College at Al-Leith, Umm Al-Qura University, Mecca, Saudi Arabia Faqir Muhammad  Department of Bioscience, Bahauddin Zakaryia University, Multan, Pakistan Safwan Muhammad  Sahiwal Medical College, University of Health Sciences, Lahore, Pakistan Manisha  Pandey  Department of Pharmaceutical Sciences, Central University of Haryana, Mahendragarh, Haryana, India Javeria  Pervaiz  Institute of Molecular Biology, Medical University of Innsbruck, Innsbruck, Austria Clive  A.  Prestidge  Clinical and Health Science, University of South Australia, North Tce, Adelaide, SA, Australia Jatin  Rathee  Department of Pharmaceutics, Amity Institute of Pharmacy, Amity University, Noida, UP, India Aatika Sadia  Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, Norrköping Campus, Linköping, Sweden Abdul  Sadiq  Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, Pakistan

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Ammara  Saleem  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan Muhammad Salman  Department of Pharmacy Practice, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan Amna Sattar  Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan Muhammad Shahid  Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan Ali Sharif  Department of Pharmacology, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan Rida  Siddique  Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan Ayesha  Tanveer  Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan Imran Tariq  Punjab University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan Farhat  Ullah  Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, Pakistan Assad Usman  Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, Pakistan Zakiah  Zeb  Department of Pharmacology, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan Saadiya Zia  Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan Hafiz  Muhammad  Zubair Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan

Abbreviations

AAA Abdominal Aortic Aneurysms AAS Acute Aortic Syndrome ACA American Cardiac Association ACAT Acyl-Coenzyme A cholesterol acyltransferase AD Atopic dermatitis AD Aortic dissection ADCH Amiodarone Hydrochloride ADHF Acutely Decompensated Heart Failure AF Atrial Fibrillation AF Atrial Fibrillation AgNPs Silver Nanoparticles AgNPs Silver nanoparticles AgNS Silver nanostructure AHA American heart Association AHF Acute Heart Failure AI Active ingredients AIDS Acquired Immunodeficiency Syndrome ALX Alloxan AMPK AMP activated protein kinase APCs Antigen-presenting cells apoB 100 Apolipoprotein-B 100 ARF Acute Rheumatic Fever ARN Acute Retinal Necrosis ART Antiretroviral Therapy AS Ankylosing spondylitis AUC Area under curve AUC Area under curve AuNPs Gold nanoparticles AZT Zidovudine or Azidothymidine Aβ amyloid beta xix

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BBB Blood Brain Barrier BBB Blood brain barrier bFGF Basic fibroblast growth factor BUN Blood urea nitrogen C1A1P Chloroaluminum phthalocyanine CAD Coronary Artery Disease CAGR Compound annual growth rate CAMs Cell Adhesion Molecules CChG Cross-linked chitosan biguanide CCR2 C-C chemokine receptor type 2 C-dots Carbon Dots CDs Cyclodextrins CH Cholesterol CHD Coronary heart disease, CHIAmB Amphotericin B containing chitosan CID Chronic iron deficiency Cmax Mmaximum concentration CMV Cytomegalovirus CNS Central nervous system COVID-19 Corona Virus Disease Of 2019 cRGD Cyclic Arginine-Glycine-Aspartic Acid CST Chair standing test CuO copper oxide CVD Cardiovascular disease (CVD), CVRDs Cardiovascular and associated disorders DAS Disease activity score DENV-1 Dengue Virus Type 1 DENV-2 Dengue Virus Type 2 DES Drug-Eluting Stent DES Drug-Eluting Stents DM Diabetes mellitus DMSA Dimercaptosuccinic acid DNA Deoxyribonucleic Acid DOD Dodecyl gallate DODAB Dimethyldioctadecylammonium bromide DOX Doxorubicin DVT Deep Vein Thrombosis ECM Extracellular Matrix EMA European Medicines Agency eNOS Nitric Oxide Synthase FBG Fasting blood glucose FDA Food and Drug Administration

Abbreviations

Abbreviations

FDA Food and Drug Administration Fe Iron oxide G6pase Glucose-6-phosphatase GA Glycyrrhizic acid GAS Group A streptococcal GIT Gastrointestinal Tract GLUT-4 Glucose transporter-4 GOF Gain-Of-Function GP Glycoproteins (GP) GQDs Graphene Quantum Dots GSK-3β Glycogen synthase kinase-3β H1n1 Strain of Influenza Virus H5N1 Strain of Avian Influenza A Virus HBeAg Hepatitis B e-Antigen HBsAg Hepatitis B s Antigen HBV-DNA Hepatitis B Virus DNA HCV Hepatitis C virus HDL High density lipoproteins HIV Human Immunodeficiency Virus HSV Herpes Simplex Virus HSV-1 Herpes Simplex Virus Type 1 HZV Herpes Zoster Virus iNOS Inducible nitric oxide synthase IBD Inflammatory bowel disease IDF International Diabetes Association IFN Interferon’s IFN-g Interferon gamma IL Interleukin IL-1β Interleukin -1β IL-6 Interleukin-6 IMH Intramural Hematoma i.p Intraperitoneal IRS-1 Insulin receptor substrate-1 ITZ Itraconazole LDL Low density lipoproteins LDL Low-density lipoprotein LDL Low-Density Lipoproteins LOF Loss-Of-Function mAB Monoclonal antibody MAPK Mitogen activated protein kinase erk MAPK Mitogen-activated protein kinase/extracellular-regulated kinase MDA Malondialdehyde

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MERS-CoV Middle Respiratory Syndrome-Coronavirus MIC Minimum inhibitory concentration MNP Magnetic nanoparticles MTP Microsomal triglyceride transfer protein (NF)-B Nuclear Factor NA Nucleic acid NASH Non-alcoholic steatohepatitis NAT Natamycin nCoV Novel Corona Virus NFLAD Non-alcoholic fatty liver disease NLC Nanolipid Structured Carrier NLC Nano Lipid Carrier NLCs Nanostructure Liquid Carriers NLCs Nanostructured lipid carriers NPs Nanoparticles OA Osteoarthritis P/SOM Primary/secondary outcomes measures PAD Peripheral Arterial Disease PAH Pulmonary Arterial Hypertension PAU Piercing Aortic Ulcer PBCA Polybutylcyanoacrylate PC Plasma concentration PCAs Polyacrylates PCLs Polycaprolactones PCM Paracoccidioidomycosis PE Pulmonary Embolism PEG Polyethylene glycol PEPCK Phosphoenolpyruvate carboxykinase Phyto-AuNPs Phytochemical-decorated gold nanoparticles PI3K Phosphoinositide-3-kinase PK Pharmacokinetics PLA Polylactic acid PLAs Polylactides PLGA Poly (Lactic-Co-Glycolic Acid) PLGA NPs Poly (Lactic-Co-Glycolic Acid) Nanoparticles PLL Poly-L-Lysine Dendrimers PMA Polymethacrylic acid PP1 Plaque-Targeted Peptides (PP1) PPI Poly-Propylene Imine PR Pulse Rate p-tau Phosphorylated tau PUFAs Polyunsaturated Fatty Acids

Abbreviations

Abbreviations

PVD Peripheral Vascular Disease RA Rheumatoid arthritis RABV-G Rabies Virus-Gene RCT Randomized Control Trial RGD Glycyl-Aspartic Acid RHD Rheumatic heart disease rHDL Reconstituted HDL RNA Ribonucleic Acid ROS Reactive oxygen species ROS Reactive oxygen species RSV-F Respiratory Syncytial Virus- Type 1 Fusion Protein RT-PCR Real Time Polymerase Chain Reaction RVSP Right Ventricular Systolic Pressure RyR2 Ryanodine-Receptor, Gain-Of-Function s.c. subcutaneous SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 scFv Variable single-chain fragments SDCS Sodium deoxycholate sulfate SEDDS Self-Nanoemulsifying Drug Delivery Systems SGF Simulated Gastric Fluid SGLT1 Sodium-glucose-linked-transporter protein 1 SIF Simulated intestinal fluid SIRS Systemic inflammatory response syndrome SLE Systemic lupus erythematosus SLN Solid Lipid Nanoparticles SLN Solid lipid nanoparticles SLN Solid Lipid Nanoparticles SLNs Solid lipid nanoparticles SPIONs Superparamagnetic iron oxide nanoparticles STDs Sexually Transmitted Diseases STZ Streptozotocin SVR Sustained viral response T1DM Type1 Diabetes mellitus T2DM Type 2 Diabetes mellitus TAA Thoracic Aortic Aneurysms TF Tissue Factor TG Triglycerides TG Triglycerides Th1 T helper cells 1 Th2 T helper cells 2 TiO2 Titanium dioxide TiO2 Titanium dioxide

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TNF-α Tumor necrosis factor-α tPA Tissue-Type Plasminogen Activator tRES-HESP Trans-resveratrol and hespertin UC Ulcerative colitis ULP Ulcer-Like Projection UV Ultraviolet VAS Visual analog score VEGF Vascular Endothelial Growth Factor VIP Vasoactive intestinal peptide VLDL Very low-density lipoproteins VLDL Very-Low-Density Lipoproteins VSMc Vascular Smooth Muscle Cells VTE Venous Thromboembolic Disease VZV Varicella-Zoster Virus WHO World Health Organization WHO World Health Organization ZnO Zinc oxide

Abbreviations

Part I Introduction to Nanomedicine

1

Nanomedicine: Present Perspectives and Future Challenges Sajid Ali, Aatika Sadia, and Imran Tariq

Contents 1.1  Introduction  1.2  Chronology of Nanomaterial to Nanomedicine  1.2.1  Early Records  1.2.2  Advances in Microscopy  1.2.3  Employment of Nanomaterial in Medicine  1.3  Nanomaterial Composition and Morphology  1.4  Lipid-based Nanoparticles  1.4.1  Liposomes  1.4.2  Lipodiscs  1.5  Polymer-based Nanoparticles  1.5.1  Natural Polymer-based Nanoparticles  1.5.2  Synthetic Polymer-based Nanoparticles  1.6  Surface Morphology of Nanoparticles  1.7  Lab-on-a-Chip  1.7.1  Organ-on-a-Chip  1.7.2  Brain-on-a-Chip 

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S. Ali (*) Department of Chemistry–Ångström Laboratory, Uppsala University, Uppsala, Sweden e-mail: [email protected] A. Sadia Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, Norrköping Campus, Linköping, Sweden e-mail: [email protected] I. Tariq Punjab University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_1

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S. Ali et al.

1.7.3  Gut-on-a-Chip  1.7.4  Lung-on-a-Chip  1.7.5  Human-on-a-Chip  1.7.6  Replacing Animal Testing  1.8  Nanobots  1.8.1  Nucleic Acid Robots  1.8.2  Nanolithography Chips  1.8.3  Biohybrid Systems  1.8.4  Bacteria-Based Chips  1.9  Intricate Nanocarriers  1.10  Drug Delivery  1.11  Gene Delivery  1.12  Peptide Delivery  1.13  Stimuli-Responsive Delivery Systems  1.14  Photodynamic Therapy  1.15  Acoustically Sensitive Nanocarriers  1.16  pH-Sensitive Nanomaterial  1.17  Disease Prophylaxis  1.18  Covid-19 Vaccine: A Gift of Nanomedicine  1.19  Tissue Engineering, Regeneration, and Repair  1.19.1  Bone Tissue Engineering  1.19.2  Cornea Tissue Engineering  1.19.3  Tissue Regeneration in Nervous System  1.19.4  Cell Repair  1.20  Precision Medicine  1.20.1  Nanosensors; Diagnostic Nanomaterials  1.21  Assembling of Nanosensors  1.21.1  Descending Order  1.21.2  Lithography  1.21.3  Chemical Etching  1.21.4  Ascending Order  1.21.5  Self-Assembly  1.22  Imaging Quantum Dots  1.22.1  Theranostics with Nanomaterial  1.22.2  Administration, Absorption, and Bioavailability of Nanomedicine  1.23  Challenges and Perspectives  References 

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What You Will Learn from This Chapter

In this chapter, a concise and comprehensive introduction of nanomedicine is conveyed. The timeline of nanomaterials leading to nanomedicine are described with progress in development of microscopes through the history. The prototypical and distinguishing details of nanomaterial regarding their physical dimensions and chemical basis are described. The elaborately explained medicinal applications of nanomaterial are aimed to enlighten the readers with the state-of-the-art treatment strategies based on nanomedicine.

1  Nanomedicine: Present Perspectives and Future Challenges

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1.1 Introduction With persistently skyrocketing technologies, the previously insurmountable has become just about customary. Through the nanotechnology-based application of medicine, the nanomedicine, remarkable milestones in healthcare have been met in the past couple of years. The term nanomedicine was first used by Robert A. Freitas Jr. in the year 1999. Many advancements in terms of prophylaxis, diagnosis, and treatment are now routinely practiced that could only be imagined a decade ago. One such example is the development of vaccine for Covid-19 within a year of its global outbreak. If it weren’t for nanomedicine, such a revolutionary resuscitation of the everyday human life would simply be impossible. Many similar applications of the nanotechnology such as drug and gene delivery systems, nanosensors, and quantum dots have become indispensable tools in various medical procedures [1]. Many natural organic (e.g., viral capsids, bone matrix, corals, paper, and cotton, etc.) and inorganic substances (e.g., photonic crystals, clays, opals, etc.) are classified as nanomaterials based on their physicochemical properties [2]. Aside from natural sources, certain engineered nanomaterials are exclusively designed to possess specificity with respect to their physicochemical properties. The engineered medicinal nanomaterial is harvested using the interdisciplinary approach from health and natural sciences especially medicine, pharmacology, biochemistry, and nanotechnology. Nanomedicine, therefore, deals with the designing of highly sophisticated nanomaterials for the prevention, diagnosis, and treatment of the diseases [3]. Earlier in the 1990s, the nanomedicine was particularly focused on the treatment of only critical diseases like cancer due to the heavy cost of research and pharmaceutical production. However, the quality enhancement in general research practices and the limelight of precision treatments have attracted the researchers to use nanomedicine-based approach for several other diseases. Today, nanomedicine is in the first row to deal with many acute and chronic diseases such as cancer, infections, cardiopathies, and asthma, etc. Apart from the treatments, the astonishing and peculiar characteristics of certain nanomaterials channel them in the diagnostic and theranostic applications. As the time advances, new and more challenging diseases erupt while some existing diseases also exhibit aggravation. Therefore, more and more sophisticated approach is required in terms of investigations and treatment. Such approach is significantly and effectively managed with nanotechnology and nanomedicine as these rather interdisciplinary research domains have predominantly focused the investigative and therapeutic potentials of the nanomaterial.

1.2 Chronology of Nanomaterial to Nanomedicine 1.2.1 Early Records The nanomaterial has been astonishing the world since early times. The earliest known accounts of the use of nanoparticles were about the Lycurgus Cup of Rome which dates to the 300s CE. The cup was made of a dichroic glass and changed its color from olive

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green to ruby red as the light incidence was changed from outside to the inside. This phenomenon occurred due to the use of colloidal gold and silver nanoparticles at the surface of the glass in the antique cup [4]. Later in the late medieval era, a significant emphasis was given to the churches in some cultures. On that account, the churches were constructed such that their windows become distinctive with a luminous shine. To achieve this purpose, the silver and gold nanoparticles were fused with the glass which resulted in the eye catching and lustrous red and yellow shine in the church windows [5]. Another account of the use of nanomaterial in history about the swords made in Damascus. The tensile strength of steel of Damascus was famous since the 800s CE Al-Kindi (800  CE–873  CE) and Al-Bairuni (973  CE–1048  CE) mentioned the steel of Damascus and the swords made up of steel as “Damascene.” Later in the 2000s, some researchers demonstrated that the coating of the carbon nanotubes and cementite nanowires on the seventeenth century Damascene Swords could be a reason of their demonstrated tensile strength and elasticity [6].

1.2.2 Advances in Microscopy Since the prehistoric times, certain objects have been observed to aid the human eye in seeing the smaller substances that are unable to be seen with the naked eye. Some accounts on lens-like objects and water-infused spheres date back to fifth century BC. The quest to see the invisibly small particles led to the progressive development in the fields of microscopy. The earliest prototype compound microscope was invented around 1620s, nonetheless the inventor of this prototype microscope is not known. A compound microscope was designed such that it would use the power of light with the help of two lenses. The use of compound microscope for exploration in the field of microbiology led to the discovery of cell in 1665 by Robert Hooke. Around 1670s, Antonie van Leeuwenhoek assembled a compound microscope of his own design. He used his microscope to visualize the cells as reported by Hooke, and performed experiments with the microbes known at that time. While the nucleus of cell had been discussed in earlier nineteenth century, the discovery of nucleus in 1831 by Robert Brown was also made through a compound microscope. The nanomaterial made its way to medicine in the nineteenth century when the ceramic and porcelain filters such as the Pasteur-Chamberland filters were developed. These filters eventually led to the discovery of the “tobacco mosaic virus” by Dmitri Ivanovsky in 1892 [7]. At that time, the compound microscopes were not able to visualize the nanomaterials; however, the scientists were convinced about their existence. Max Plank and Albert Einstein theoretically proved the existence of nanomaterial in around 1900. Shortly after, in 1904 Richard Zsigmondy and Henry Siedentopf made a breakthrough discovery of structures 100 nm so as to carry higher drug loads. Use of nanocarries in drug delivery is attractive owing to their desirable properties such as the increased surface area available for contact with the body and the ability to carry or encapsulate drugs [3]. Traditionally, nanocarriers usually consist of minimum of two components, an active ingredient or the drug load and the material employed for the formation of nanoscale carrier [4]. However, it is not necessary to have a specific material to form the nano sized carriers as various strategies can be employed to form nanocarriers of drugs itself [5].

2.3 Characteristics of an Ideal Nanocarrier for Drug Delivery An ideal nanocarrier should have following characteristics [3]. • • • •

Reduce the toxicity of the payload and enhance or maintain therapeutics effect Safe and biocompatible Compatible for easy development with a broad range of medicines Provides targeted drug delivery and targeting

2.4 Types of Nanocarriers There are a number of types of nanocarriers, and the types and number are increasing as newer technologies and advances in science are happening. Some main types are liposomes, nanoparticles, micelles, dendrimers, quantum dots, and carbon nanotubes. Nanocarriers can be categorized according to the composition of materials they are produced from, e.g., Polymers, lipids and graphene, some types are discussed later in this chapter.

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2.4.1 Nanocarriers Based on Polymers Polymeric nanoparticles generally have a size range varying from 10 to 200 nm and are biodegradable. They offer control over pharmacokinetic parameters, ease of surface modification, and capability of delivering a wide range of chemotherapeutic drugs.

2.4.2 Polymer-Drug Conjugates There is a type of nanoparticles that can be chemically modified to attach a variety of drug molecules; these consist of different organic or synthetic polymers like albumin, chitosan, and polyethylene glycol (PEG). The drug molecules may also be adsorbed or encapsulated on these nanoparticle structures, and are released through desorption, diffusion, or erosion of the nanoparticles. Abraxane nanoparticles (paclitaxel coupled to albumin) were recently used to treat metastatic breast cancer. The most widely utilized synthetic polymers that are not biodegradable are PEG and HPMA. Among these, PEG has been used to coat PLGA (polylactic-co-glycolic acid) nanoparticles to make them invisible to the immune system while also improving their stability. It was reported that these coated nanoparticles were nontoxic, nonthrombogenic, nonimmunogenic, and did not have proinflammatory effects, did not stimulate neutrophils, and had no effect on the reticuloendothelial system. As compared to conventional uncoated and free drugs, PLGA-conjugated drugs have shown encouraging results in terms of reducing adverse effects and improving efficacy in clinics, in vitro, and in vivo.

2.4.3 Polymeric Micelles Polymeric micelles are nanostructures that are formed when amphiphilic copolymers, such as poly (ethylene oxide)-poly (-benzyl-Laspartate) and poly (N-isopropylacrylamide) polystyrene are put in aqueous environment and undergo self-assembly. The hydrophobic core area, which acts as a drug reservoir, is stabilized by the outer shell, making the polymers water soluble. Micelles can be easily modified with small functional groups to improve their ability to target certain organs or receptors or any other stimuli. Moreover, their small size is thought to be the cause of their specific accumulation in pathological tissues. Although external stimuli like pH, temperature, and ultrasound can be used to trigger drug release, we must take into consideration the locus of drugs, which is generally the core. Lastly, micelles suffer from limitations such as poor targeting ability if unmodified, low drug-loading capacity, and low drug-loading efficiency.

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2.4.4 Dendrimers Dendrimers are synthetic polymers with highly branched structures that emerge radially from a central core. These polymers have the advantage of ease of modification and can be tailored to provide desired activity, pharmacokinetics, stability, and biocompatibility. As with other nanoscale entities, dendrimers also have promising applications in medicine, which is dependent on the ability of modification of their size and surface functionality. Dendrimers have huge potential for solubilization of hydrophobic drugs. Moreover, as mentioned earlier, dendrimers have easily modifiable surfaces and can be simultaneously conjugated with drugs and many other compounds, including targeting ligands, and/or imaging contrast agents, for the creation of a dendrimers-based multifunctional drug delivery system.

2.5 Advantages of Nanomedicine Over Conventional Therapeutics Nanoparticles can be constituted from different materials including metals such as silver nanoparticles. Doxorubicin and alendronate were loaded in silver nanoparticles for treating cancer and showed better efficacy toward cancerous cell as compared to doxorubicin or alendronate alone [6]. The conventional chemotherapy approaches have various issues like induction of toxicity, drug penetration issues, poor biodistribution, and damage to normal tissues. Doxorubicin loaded in nanoparticles has been shown to inhibit the growth of tumors and can prolong the survival of patients by providing targeting to tumor site as compared to conventional doxorubicin formulation [7]. The main application of nanotechnology is to carry and deliver drugs to their site of action to achieve desired therapeutic effects. Challenges such as oral bioavailability of some drugs and delivery of drugs to brain with the aim of bypassing BBB can also be achieved through nanotechnology [8].

2.6 Reduced Toxicity of Drugs Drugs often are associated with side effects that limit their application in several diseases. For example, doxorubicin, which is a routinely used drug in cancer chemotherapy, is associated with dose-dependent cardiotoxicity. Despite being effective at high doses, we can not exceed doxorubicin dose beyond a certain limit as cardiotoxicity starts to weight over the benefits of doxorubicin. As mentioned earlier, nanoparticles offer a way to deliver drugs at target sites and organs or even at cellular level, and thus can be used to reduce this toxicity. When administered via nanoparticles or as a nanomedicine formulation, toxicity of doxorubicin can be reduced [9]. Similarly, PEGylated and non-PEGylated liposomes have also shown reduced cardiotoxicity. Moreover, the entrapment of drugs such as doxorubicin in biocompatible polymers can prevent their degradation and reduce their side effects [10].

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2.7 Overcoming Resistance in Cancer Cells One major problem associated with the dose escalation of anticancer drugs is that cancer cells develop resistance which has been extensively studied. This makes it even harder for clinicians to increase the doses of anticancer drugs such as doxorubicin and paclitaxel. Butt et al. found that when doxorubicin is incorporated in chitosan nanoplexes or polymeric micelles, it can reduce the resistance and may even overcome the resistance when the nanomedicine formulation contains a mechanism to reduce the resistance such as incorporation of an siRNA that can reduce the expression of genes associated with drug efflux as outlined in Fig. 2.1 [9].

Fig. 2.1  Schematic of the mechanism of improved therapeutic efficacy of doxorubicin (DOX) in MDR cells. After injection into the blood circulation, polyplexes target the tumors and release DOX in tumor microenvironment due to acidic pH and folate receptor targeting. Free DOX is pumped out of the cells by drug efflux pumps. On the other hand, when DOX is delivered by polyplexes, drug efflux pumps are inhibited by downregulation of mdr-1 gene due to siRNA-mediated knockdown and micellar nanocarriers, improving its efficacy in multidrug-resistant cancers. Adapted with permission from Butt et al. Mol. Pharmaceutics 13, 4179–4190. Copyright 2016 American Chemical Society [9]

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2.8 Nanotechnology in Immunotherapy Immunotherapy is a powerful approach in treating cancer along with radiotherapy, surgery, and chemotherapy. Modulation of immune system via various strategies to enhance anticancer effect results in improved survival rate. Despite this progress, the positive response due to immunotherapy has shown low success rate due to the presence of extracellular side effects and unpredictable efficacy. Use of nanotechnology offers vast range of different materials and targeted delivery systems to overcome challenges of immunotherapy [11].

2.9 Nanomedicines for Better Pharmacokinetic Profile Efficacy of anticancer drugs is often limited due to poor pharmacokinetics parameters. Nanoparticles can increase oral bioavailability of drugs. For example, chitosan nanoparticles were found to improve oral bioavailability of anticancer drug doxorubicin by providing sustained release and enhanced cellular uptake [12]. The use of nanotechnology in industries and research has not only been limited to design of nanomedicine but also in diagnostics including biosensors and imaging probes. Moreover, it has also found its use in cosmetics industry for improving production, shelf life, bioavailability, and stability. Zinc nanoparticles show antimicrobial activity and are used in food industry to inhibit the growth and control foodborne bacteria. Nanoparticles are also used as food sensors for the detection of quality of food and safety.

2.10 Topical Application of Nanoparticles Wound infections are considered a major problem due to development of resistance to administered antimicrobials. Silver is known from ancient times for the treatment of infections and if it is administered at very low concentration, its toxicity to local cells can be minimized. Silver nanoparticles can provide the low concentration and have been proven and established as a safe way of use in human tissues/cells. Silver nanoparticles (AgNPs) can provide high-drug concentrations at the site of infection, reduce the penetration problem of drugs, and thus can reduce the resistance issue associated with subtherapeutic levels. Silver nanoparticles can also be used for sterilization of medical devices [13]. Silver nanoparticles have been demonstrated to affect the bacterial DNA replication by releasing silver ions in the cells that interact with thiol groups present on DNA of bacteria and help to stop the oxidative phosphorylation of respiratory chain [14]. There is an interaction between positively charged silver nanoparticles and negatively charged DNA in bacterial cells. As mentioned earlier, AgNPs can provide better penetration and can interact with

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biological macromolecules and enzymes given their small size and properties. The ­possible interactions at cell level (such as binding with functional groups of proteins) can cause DNA to lose its ability of replication primarily owing to cellular protein inactivation and protein denaturation [15]. Given their large surface to volume ratio, AgNPs have high reactivity that plays a vital role in stopping the growth of bacteria. AgNPs are effective against both gram-positive bacteria and gram-negative bacteria [16]. Silver nanoparticles can be biosynthesized and are biocompatible; therefore, these have better acceptability as compared to chemically synthesized compounds (DDS). Silver nanoparticles have a wide range of applications such as antibacterial, anticancer, wound healing, and in catalysis. Nanoparticles can be synthesized from plants, bacteria, fungi, and yeasts. Some applications of nanoparticles in other areas include water treatment sensors, healthcare ­systems, textiles designing and knitting, production of renewable energy, biomedical devices, agricultural tools, and food processing/production [17]. Chitosan-alginate nanofibers were reported to provide high gentamicin concentration at wound sites. These chitosan-based nanofiber scaffolds showed excellent antibacterial performance and wound healing. These scaffolds promoted wound healing and prevented wound infection. When loaded with gentamicin, these nanofibers showed good antibacterial activity. In vivo study of chitosan-­ alginate nanofibers containing 3% gentamicin showed better wound healing at a faster rate [18]. Similarly, gentamicin loaded in PVA/gelatin molecularly imprinted polymer (MIP) nanofibers was found to heal the wounds faster and as compared to free drug [19]. Silver and gold nanoparticles are widely used theranostic agents for diseases like diabetes, hepatitis, arthritis, cardiovascular diseases, tuberculosis, injuries of spinal cords, etc. [20].

2.11 Nanocarriers in Cancer Chemotherapy The main objective of a drug delivery system is to safely delivery the drug at the target site to avoid the side effects as well to enhance the efficacy. In cancer chemotherapy, this is a challenging task as tumors or cancers may be present in one organ or in multiple organs due to which a strategy to target a particular organ cannot be employed. This would reduce the therapeutic potential of chemotherapy. Nanocarriers possess the specific properties desired for the treatment of cancers as their small size gives them access to the tumor via the enhanced permeability and retention effects and this could enhance the drug concentrations inside resulting in increased therapeutic efficacy. Liposomes owing to the lipophilic nature, flexible structure, and small size can cross through the smallest fenestrations making them compatible for the delivery of chemotherapy. Doxorubicin liposomal formulation Doxil was the first nanocarrier-based drug approved by FDA in 1995 [21]. Similarly polymer-based nanoparticles, micelles, and dendrimers have also been used recently for the delivery of anticancer drugs.

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In nanocarrier development for cancer chemotherapy, a major challenge is the poor solubility which is made even more important because most of the new drugs discovered by the high-throughput screening (HTS) are either poorly or complete water insoluble. If the hydrophobic or poor water solube drugs are used as such, it may lead to problems such as poor absorption and in turn low bioavailability [22] . Further, it can also result in complications such as embolism [23] due the aggregation of water insoluble drugs and local toxicity [24]. The hydrophobicity of drugs is intrinsic property [25] as it helps the drug to pass through cell membranes [26] to reach the target sites inside cells [27]. To overcome these issues, using micelle forming surfactants is suggested, making micelles a promising nanocarrier system for pharmaceuticals.

2.12 Nanomedicines for Delivery of Nucleic Acids Biotechnology and bioengineering have helped us in almost every field of life. One of the most encouraging applications recently is drug delivery carriers with the ability to carry RNA designed to knock down particular genes through RNA interference. Making RNA sequences which can silence a particular cancer gene is easier process as compared to delivery of this designed RNA to the specific target. This is only possible if there a good enough delivery carrier for RNA as pure RNA is degraded when given in free form. More recently, nanoengineered drug carriers (or nanoparticles) have found growing interest as delivery vehicles for RNA. However it is not easy to design a nanocarrier for gene silencing medicated by RNA as it has to make all the way inside a cancer cell while evading the destruction throughout the whole process. Most of the nanoparticles would be identified by the immune system as foreign particles and cleared from the system. However, if a particle gets through all the barriers and finds the cancer cells, it will bind to the membrane which then forms an acidic vesicle called the endosome. This presents another major barrier in effective silencing as the RNA could be destroyed inside the endosome. To evade this problem, researchers have designed polymer carriers having a property to absorb the positive charges creating an osmotic pressure that in turn bursts the endosome releasing the entrapped RNA.

2.13 Nanomedicine in Cancer: Advantages Over Traditional Molecular Therapy Cancer cells have mutated genes producing proteins that are not druggable by traditional way of therapy as the traditional molecular therapies work by binding to and disabling proteins. It could be due to following; • Proteins hiding inside cancer cells not reachable for the antibody drugs • Proteins with shapes that provide no foothold for drugs

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In such cases, nanoengineering or properly designed nanocarriers could get through all these defenses, by silencing the particular genes for these proteins instead of targeting the otherwise unreachable and undruggable proteins. Further, if properly designed, simultaneously targeting multiple targets could be possible which would help to enhance the therapeutic efficacy. One common and leading cause of the chemotherapy failure is the multidrug resistance process. This becomes even more important in cases where chemotherapy is the first choice or at least one of the few choices available for the treatment and nanocarriers-based medicine has shown prominence in overcoming MDR.

2.14 Targets for Anticancer Drug Delivery Mildly acidic pH of tumors, lysosomes, endosomal compartment, and inflammatory tissues are some targets that can be considered to design the pH-sensitive micelles. However in general polymeric micelles which are intended for parenteral administrations should be stable at pH  7.4 as destabilization would lead to disassembling of the micelle-forming material and eventually the premature release of the payload. In the recent years, stimuli and environment-sensitive drug delivery have received much attention. It may be toward target tissues or to release the payloads at specific locations (intra/extra cellular) or may be to enhance drug release. Using pH gradients and ligand-mediated receptor targeting are a few approaches used in this regard. Especially the pH-mediated targeting has been involved in a number of delivery systems like hydrogels, liposomes, and most importantly polymeric micelles. pH gradient between physiological and pathological conditions (in particular tumor), has been utilized to achieve a targeted delivery and drug release (of anticancer drugs in this case).

2.15 Barriers in Tumor-Targeted Drug Delivery After overcoming all the hurdles and reaching the target tissues, the nanocarriers have to enter the cells and release the cargo. At cellular level, the pH difference from the outside environment is even more pronounced. The lysosomes and endosomes have a pH of 4.5–6.5 [28] which is far more than the physiological extracellular pH (7.4). Several drugs and nanocarriers reach target sites and are taken up by cells via endocytosis thus ending up in endosomes and lysosomes [29–32]. This process of interanalization via endosomes is called endocytosis. The fate of the drugs or carriers depends upon the proteins which form the vesicles and the way they are taken up. In some instances, the entrapped drugs or carriers are transferred to the lysosomes which is the last step in the endocytic degradation pathway. Lysosomes contain a number of hydrolytic enzymes like proteases and esterases and have an acidic pH (4.5–5.5) which breaks and degrades the materials trafficked as a terminal step.

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For a drug delivery nanocarrier, it is thus important to be able to escape the endosome and lysosome and release the encapsulated cargo unharmed so as to have any therapeutic effects. This has been discussed elsewhere in detail [33].

2.16 Nanocarriers for Overcoming Chemotherapeutic Toxicity To overcome these toxicity issues and to enhance the efficacy drug delivery system, approaches have been used to deliver doxorubicin in a controlled manner which provides clinically relevant concentrations and reduces the toxicity. This could include doxorubicin formulations in liposomes, micelles or drug polymer conjugates. An example of such drug delivery is Doxil which is pegylated liposome formulation of doxorubicin with controlled release and enhanced efficacy. Pegylation prevents the detection by immune system and thus prolongs the blood residence times of drugs [34]. However long-term toxicity and efficacy studies are still being carried out for the liposomal formulations such as Doxil despite the protection from cardiomyopathies as it was shown that a dermatological reaction known as palmar plantar erythrodysesthesia (hand-foot syndrome) was seen in 50% of the patients treated with Doxil [35]. Another approach is to encapsulate doxorubicin in micelles or nanoparticles. If such micelles, nanoparticles or complexes are prepared using cationic polymers such as chitosan, the cellular uptake is enhanced due to the increased interactions with cell membranes. Alakhov and coworkers prepared gels based on pluronic and polyacrylic acid copolymers which are mucoadhesive. They showed that these microgels enhanced the doxorubicin uptake in intestinal caco-2 cells [36]. Songsurang and coworkers used chitosan derivatives for preparation of mucoadhesive delivery system encapsulating doxorubicin for topoisomerase inhibition-based anticancer activity [37]. It was observed that these mucoadhesive nanoparticles enhanced and prolonged the topoisomerase activity of doxorubicin. Some examples of doxorubicin-loaded micelles are presented in Table 2.1.

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Table 2.1  Some examples of doxorubicin-loaded micelles Targeting ligand Polymer None Stearic acid-grafted chitosan oligosaccharide Poly(D,L-lactic-co-glycolic Folic acid acid) and poly(ethylene glycol)

Size 40 nm

Stage/tested in In vitro, SKOV3 cell line 100– In vivo, KB cell 115 nm xenografts in athymic nude mice PEG-PE micelles Monoclonal Less In vitro, antibody than NCI-ADR-RES 15 nm cell line NK911: PEG–poly(aspartic None 40 nm Clinical trials; acid) conjugated to doxorubicin phase III SP1049C: Pluronic L61 and None 30 nm Clinical trials F127 Phase II Poly(L-histidine-co-LFolic acid 150 nm In vivo, in nude phenlyalanine)-PEG mice with Poly(L-lacticacid)-b- PEG-­ doxorubicin-­ folate mixture in 80:20 resistant A2780 cell line xenograft Poly(ethylene glycol)-modified RGD 20– in vitro in BEL stearic acid-grafted chitosan peptide 40 nm 7402 and Hela cell line Octadecylamine & O-(2-­ Biotin 290– In vitro MCF7 aminoethyl) polyethylene 310 nm cell line glycol-grafted Polysuccinimide Poly[2-(dimethylamino) ethyl None 100– In vivo in MCF7 methacrylate] (PDMAEMA) 120 nm xenograft in block poly[N-(3BALB/c nude (methacryloylamino) propyl)mice N,N-dimethyl-N-(3-­ sulfopropyl) ammonium hydroxide] (PMPD) Folic acid 20 nm In vivo in 4T1.2 PEG5K-embelin2 tumor breast cancer models in Balb/c mice

Drug loading References 1.67% [45] 19.6 and 19.2%

[46]

66%

[47]

–

[48]

8.2%

[49]

20% [50] (DLC) 80% EE

More [51] than 90% EE – [52]

5% [53] DLC 27% EE

More than 90%

[54]

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2.17 Development of Resistance to Conventional Chemotherapeutics Resistance to conventional therapeutics is a major issue and limits their benefits, as dose escalation comes with side effects and toxicity. For example, doxorubicin develops resistance mainly due to over expression of ATP-dependent efflux transporter including the P-glycoproteins [38]. It is a common problem and in vitro cell lines have been developed to mimic the multidrug resistance process. These cell lines which are resistant to doxorubicin are typically represented by ADR or AD at the end, e.g., MCF-ADR or A2780/AD. Resistance to doxorubicin is commonly due to overexpression of mdr 1 gene that is normally expressed in a number of tissues such as GIT and kidneys [39]. The expression product of this mdr 1 gene is p-glycoproteins (Pgp) also known as ABCB1 [38, 40]. These are ATP-dependent transporters and physiologically act to get rid of toxins. It has been shown that these transporters also pump out doxorubicin and some other anticancer drugs. However resistance to doxorubicin is not only due to pgp, it may also be due to other transporters such as MDR-associated proteins (MRPs) and breast cancer-related proteins (BCRP & ABCG2). All of these belong to the family of ATP-binding cassette (ABC) family of transporters [41].

2.18 Overcoming Doxorubicin Resistance by Nanocarriers To overcome this resistance problem, various nanotechnology-based approaches have been used [42, 43]. These include the encapsulation of doxorubicin in micelles or other nanoparticles composed of polymers that reduce or inhibit the drug efflux by inhibition one or another mechanism. Another approach is to deliver doxorubicin along with the delivery of siRNA for silencing the genes involved in resistance process. Use of nanocarriers allows for the doxorubicin delivery to target sites in high concentrations as well as avoidance of the side effects. The high concentration and targeting to tumors could be achieved by passive targeting due to nanosize and active targeting by conjugation of carriers with ligands that are overexpressed in cancer as described earlier. In most of the nanocarrier-­based delivery approaches targeting cancer, the outer surface of the particles is coated with PEG which helps them avoid the clearance by RES [44].

2.19 Examples of Nanocarriers for Anticancer Drug Delivery The major nanodrug delivery systems include liposomes [55], polymer-drug conjugates [56], and dendrimers [57]. All of these systems along with micelles have different structures and biological properties.

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2.19.1 Liposomes Liposomes and polymer-drug conjugates by far are the most successful nanocarriers so far in clinical use. For example, Doxil is a liposomal formulation of doxorubicin [58] that was the first nanomedicine to be approved for clinical use. Liposomes, as the name implicates, are lipid-based vesicles of nanosize that are produced from the phospholipids and cholesterol mimicking the cell membrane bilayer structure. These vesicles or nanoparticles have a hydrophilic core compartment as compared to the hydrophobic cores of micelles. This makes them ideal for the delivery of hydrophilic drugs, although the hydrophobic drugs can also be incorporated, albeit at with a low drug-­ loading capacity, in the lipid bilayers [59]. Liposomes may have a coating of PEG on the surface by conjugation, have increased circulation times in blood giving them more time for the passive targeting to the tumors by the EPR effect. However, it has been shown that liposomes are not able to penetrate the tumors efficiently [60]. In order for a nanomedicine to be effective in curing a cancer, it should cross all the barrier and then must release the drug at target sites in a controlled manner; however, release of drugs from liposomal formulations in tumors is limited. Strategies such as triggered release in response to pH and temperature changes have been tried to over this problem [61, 62]. Doxil®: The first approved chemotherapy nanomedicine and need for smart drug delivery approaches. Doxorubicin is an antibiotic of anthracycline class, used to treat a wide range of cancers. Despite its usefulness to treat the cancers, it has severe side effects most important of which is the severe life-threatening myocardial damage. Doxil® was of the first nanomedicine approved in 1995 that helps to reduce the drug out of the heart. Doxil® is a liposome formulation carrying doxorubicin. Doxil®, was designed to take advantage of the leaky vasculature of tumors with a diameter of about 100 nm. However lipids, on which Doxil® is based on, do not allow much engineering control other than self-assembling into liposomes. Doxil consisted of a liposomal core carrying doxorubicin which was then coated with polyethylene glycol (PEG) to evade the immune system. Doxil® was a success story as the incidence of congestive heart failure in patients reduced by one-third as compared to patients receiving conventional doxorubicin. This was considered “a quantum jump in the quality of life” [63]. Getting drug into the right target areas or cancerous tissues is easier than keep them out the wrong places or otherwise healthy tissues. Although the colloidal dimensions help nanomedicine from being excluded out of the healthy tissues; however, they may not get deep into the tumors. This results in clustering of the nanomedicine at the perimeter and reducing the efficacy. Despite the advances made in recent years in drug delivery to tumors, most of the nanomedicine are based on the basic design of a spherical particle coated with an extra protection layer.

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2.19.2 Polymer-Drug Conjugates Maeda and colleagues developed SMANCS, a polymer-drug conjugate, is a conjugate of neocarzinostatin and poly (styerene-co-maleic acid) that has been approved for treatment of liver cancer [64]. These nano-based drug delivery systems afford improved stability as well as show increased mean residence times in plasma resulting in enhanced tumor selectivity and efficacy. Further, these nanocarriers also show the improved antitumor efficacy of encapsulated drugs by EPR effect [65]. Further, there are a number of polymer-drug conjugates that are in phase I, II, and III clinical trials [4].

2.19.3 Dendrimers Dendrimers are still comparatively new in the field of nanoparticle-based delivery systems; however, these show promise for delivery of anticancer drugs in preliminary research. Recently, a dendrimer-based formulation of docetaxel (DEP-docetaxel) has started phase I clinical trials [66]. Molecular-based drugs have shown disappointing results especially in case of cancer therapy owing to heterogeneous nature of cancer tissue [67]. There are multiple mutations in cancer cells and this leads to development of mutant cells which are not hurt by approaches used to target the specific ligands on cancer cells. American Society of Clinical Oncology (ASCO) reports showed that only 4–5% of response rate was achieved by molecular target drugs. This was well below the expectations given their very high cost. Given above circumstances, there is a need for anticancer drug delivery carriers which have a very high selectivity and efficacy as well in clinical trials. The advances in synthetic chemistry and biotechnology have led to fabrication and development of “smart polymeric micelles (SPMs).” The engineering of the core and shell have allowed the scientists to design and develop desired properties to achieve targeting and to integrate environment sensitivity in the micelles. Strongly dedicated and impulsive approach to the development of polymeric micelles as a nanocarrier of future is thus advised.

2.19.4 Lipid Nanocarriers As mentioned earlier, lipid-based nanocarrier systems were among the earliest used systems and offer many advantages. Various types of lipid nanocarriers have been reported including liposomes and solid lipid nanoparticles. The subsequent section summarizes technical considerations in design of these nanocarriers.

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2.20 Technical Considerations for Commercially Viable Lipid Nanocarriers Current conventional medicine system involves using drugs, radiations, and surgery by healthcare professionals to treat diseases and symptoms and vaccination for prophylaxis. The established formulation development workflow and research in broader drug discovery area have together facilitated the pipeline of therapeutics and diagnostics. Advancing technology has impacted how medicines are developed or active pharmaceutical ingredients (APIs) combined with excipients as a formulation. Nanoscale development of therapeutics and diagnostics has changed how scientists and clinician approach molecular targets to deal with health issues. Nanomedicine, once arguably facing the end of its hype probably due to not being able to utilize the claimed potential, has regained momentum due to recent success facing nanoscale lipid technology. The vaccines offered by Moderna and Pfizer in collaboration with Bio “N” Tech have used lipid nanocarriers to help millions of people against coronavirus disease (COVID-19). In a few years preceding pandemic, there were three anticancer nanomedicine candidates approved by the FDA namely Patisiran/ONPATTRO, VYXEOS, and NBTXR3/Hensify. Vyxoes, for instance, targeting acute myeloid leukemia led to improvement in overall survival of 9.6  months over 5.9 months of free drug control [68]. The nanoscale materials have exceptional advantage of being similar in scale to biologic molecules and capable of flexible functionality unlike the biological molecules [69]. Specifically, micro/nanoscale drug carriers can interact with biological systems on the same length scale as cells and cellular processes [3]. The application of nanomedicine is based on tailoring the physical characteristics of nanomaterials for the diagnosis and treatment of diseases at the molecular level. Interesting examples have ranged from processing biological tissues to yield exosomes or even using human blood cells to deal with difficult-to-target diseases. More than 50 formulations are reported to be currently in the market, and the recent approvals have demonstrated that nanomedicine can lead to products which can overcome critical barriers in conventional medicine [70]. Nanomedicine can also enable nanomaterials to deliver therapeutic effects without using encapsulating drugs for the biological effect. This chapter will cover how nanomedicine can prove advantageous over current formulation design and a brief introduction of variety of commercially viable nanomedicine candidates for both small molecule and biologics. Specifically, emphasis will be on the examples of lipid-based nanoparticles (LNPs) from literature, which provides substantial understanding of concepts underlying technical development of recent regulatory approvals. The lipid nanocarriers are composed of natural lipid or phospholipids and are prepared as solid particles or vesicles. These are broadly classified as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) [71] based on the types of physical properties of constituent lipids (Fig. 2.2). There are other varieties based on complexation with cyclodextrin and hybrid formations with polymers. The advantages of the lipid nanocarriers are summarized in the context of bulk versus nanoscale function and how trickling down to nanoscale can change the formulation design altogether. The following descrip-

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Fig. 2.2  Schematic representation of a SLN and a NLC sterically stabilized with a neutral surfactant (gray). The oxygen atoms in the liquid and solid lipids are shown in orange. Drug molecules are not depicted since they may be located inside the lipid core and/or attached to the outer shell. Reproduced from S Scioli Montoto et  al. (2020). Solid Lipid Nanoparticles for Drug Deliver: Pharmacological and Biopharmaceutical Aspects. Front. Mol. Biosci. 7:587997 licensed under CC By 4.0 [72]

tion serves only as a high-level overview of the factors required to develop projects for novel nanomedicine utilizing lipids. Each advantage would describe at least one example of mechanism by which benefit is achieved.

2.21 Advantages of Lipid Nanomedicine Bulk scale active pharmaceutical ingredients are typically packaged into oral, parenteral, and topical dosage forms. Nanoscale development of materials can also be incorporated into traditional dosage forms with added effects. Several issues with bulk scale development of APIs arise that may include poor solubility, poor bioavailability, or poor permeability across biological barriers. Very often, dose-related off-target effects are an issue, and nanomedicine, especially in cancer therapeutics proves beneficial. There are scale-up and parameter optimization limitations with nanomedicine as well, which need to be kept in mind while considering commercial workflow of drug discovery area.

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2.22 Improvement of Poor Solubility More than 90% of the commercially available drugs are small molecules and around 40% of the new chemical entities are poorly soluble in nature. Lipid-based nanocarriers have proven effective in improving solubility issues. Small molecules can be dissolved in organic solvents due to their lipophilicity and solid lipid nanoparticles (SLNs) have been used to incorporate drugs like Paclitaxel. Slow release from the SLNs confirms dispersion of the drug within the matrix rather than adsorbed on the surface, which rather could have led to immediate release. Organic solvent evaporation leads to the paclitaxel dissolution in the stearic acid nanoemulsion [73]. The rapid quenching of the nanoemulsion is thought not to allow the drug to crystallize leading the drug to stay in the matrix. The lipid-based nanocarriers have recently gathered increasing attention in improving solubility of biopharmaceutics classification system (BCS) class II and class IV drugs for oral drug development. Lipophilic drugs face poor absorption due to poor solubility issues, and limit the application of an otherwise compliant route of administration due to noninvasive nature. Apart from SLNs and NLCs, self-nanoemulsifying drug delivery systems also serve the purpose and increase dissolution of drug as well as lymphatic uptake wherever required [74].

2.23 Overcoming Biological Barriers Human intestine, blood–brain barrier, and skin are the most notable membrane barriers which require strategies to overcome poor permeability across them. The barriers are naturally designed to prevent unwanted transport of agents disturbing homeostasis or causing serious health issues upon exposure. Careful design of nanoparticles has led to limited success in overcoming the epithelial barriers, which are particularly relevant for biologics delivery. Pathologies also make some barriers such as delivery to solid tumors is challenging and tumor microenvironment is exclusively studied to enable nanoparticle technology efficient. Use of permeation enhancer has been commercially successful to increase intestinal permeability of peptide therapeutics; however, the use of the permeation enhancer may lead to complications in blood–brain barrier. In contrast to improving solubility, improving lipophilicity is also a virtue of lipid nanocarriers [75]. The lipid nanocarriers have been prepared via hydrophobic ion pairing with freely soluble peptides which have poor permeability such as exenatide, to prepare nanocarriers of the order of 25 nm. Both cationic and anionic lipids were combined with exenatide to have a higher relative oral bioavailability of cationic lipid hydrophobic pair of 27.96 ± 5.24% over 16.29 ± 6.63% of anionic lipid hydrophobic ion pair. Human physiology involves using varying pH, cocktail of salts leading to optimal osmolarity critical to cellular integrity and multiple enzymes. Intracellular drug delivery is another challenge which may either pose the challenge of endosomal escape or degradation of enzyme-prone biologics. Lipid nanocarriers have been utilized and have shown advantage to overcome these issues in individual studies.

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2.24 Improvement in Dosing Regimen The key issue with conventional small molecule therapeutics is that are programmed to do one thing and keep doing it until it is eliminated regardless of the physiological state of the patient [76]. This is free drug problem which requires making them smart enough to read the cues they are encountering in the body. Nanomedicine can afford to make them smart enough as other biomaterials do, but with the added advantage of being at atomic scale and allowing more payload to reach the target and only when required. Lipid nanocarriers have been combined with different polymers imparting smartness, e.g., pH sensitivity. Buprenorphine, an opioid, when trialed to be packaged in lipid nanoparticles with linseed oil as liquid lipid and cetyl palmitate as solid lipid had an improved entrapment efficiency. Oil caused crystalline changes in solid lipid matrix making room for drug to be incorporated and thereby improving entrapment efficiency [77].

2.25 Herbal Medicines Herbal medicines or herbal-based medicines have been in use for long time. Recently, their popularity has seen a multifold rise because of the perception that these have fewer side effects than allopathic medicines; moreover, they comprise multiple constituents which work together at the same time to treat the disease [78–80]. Advantages of Herbal Nanomedicine

• • • • • • • •

Provides site-specific action Allows passive targeting of the product to the diseased organ Reduces dosage and dosing frequency of the drug The small size helps enhance permeation through various barriers and increased retention, as in the case of tumors Improves the pharmacokinetic effect of the drug Enhances the efficacy and stability of the drug Reduces side effects Improves biocompatibility and biodegradability

Although herbal products have multiple advantages, the majority of them have poor aqueous solubility, due to which their bioavailability is very less, and systemic clearance is more which results in the need for frequent administration and increased dosage of the product, thus restricting their clinical application. To overcome these limitations, nanotechnology can be used an approach. As mentioned earlier, nanotechnology can help achieve targeted action, improve effectiveness, reduce first-pass metabolism, and prevent degradation of the product in the liver, thereby reducing dosage and in turn, result in better patient compliance [81, 82].

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2.26 Nanotechnology Approaches Inspired from Nature: Plant-Derived Nanovesicle Over the past few decades, research has confirmed the presence of extracellular vesicles in multiple plants. Extracellular vesicles have a lipid bilayer as the basic structure and contain different active moieties like proteins, nucleic acids, or smaller molecules. These vesicles help in the growth and development of the plant [83]. Zhang et al. showed that vesicles obtained from edible ginger were able to significantly reduce the proinflammatory cytokines, like interleukin-6, IL-1β, and tumor necrosis factor-α in colitis mouse and fasten the healing of intestinal mucosal injuries [84]. Further research by Sundaram et  al. showed that these vesicles derived from edible ginger inhibited the pathogenicity of Porphyromonas gingivalis [85]. The concept and effectivity of formulation are illustrated in Fig. 2.3. Another study performed by Lee et al. showed that the vesicles obtained from the stems and leaves of Dendropanax morbifera inhibited melanin and provided a whitening effect which was better than that produced by the control group arbutin along with no visible toxicity [86]. Along with having good therapeutic potential, these vesicles can also be used as a drug carrier as shown in a study by Wang et al., where they used vesicles obtained from grapefruit for loading methotrexate and found results showing increased therapeutic

Fig. 2.3  Effectivity of ginger exosomes in treatment of chronic periodontitis. Figure adapted with permission from Sundaram et al. [85]

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effects and reduced side effects of the drug [87]. Furthermore, broccoli-derived nanoparticles were investigated to prevent DSS-induced colitis and to target dendritic cells (DCs) [88]. Likewise, SLN from Lycium barbarum (LB) was explored to treat ulcerative colitis. SLN was composed of the fat-soluble component extracted from LB. The fabricated nanocarrier possessed a narrow particle size distributed with negative zeta potential. Additionally, these natural nanoparticles inhibit the secretion of IL-12 and TNF-α, but high uptake by macrophages was observed. Accumulation was shown in inflamed colon tissue during an in vivo experiment [89]. Plant-delivered herbal nanocarriers are found to be beneficial compared to synthetic carriers as they may be associated with toxicity; however, herbal nanocarriers are cytocompatible and considered safe for drug delivery. For instance, Ginseng-derived novel nanoparticles were found to reduce the growth of cancer by inhibiting IEC proliferation and inducing IEC apoptosis [84, 90]. Active and passive targeting at cancer sites is one of the prime criteria for nanoformulation development. It can be achieved by the surface modification of the plant-derived nanoparticles. Wang et al. used a similar approach to fabricate grapefruit-derived nanovectors (GNVs) whose surface was modified with inflammatory-related receptor-enriched plasma membranes (IGNV). The effectiveness for IGNV was proved with a reduction in tumor growth with anti-inflammatory property [91]. In the next research, the surface of grapefruit-derived nanovectors was modified with folic acid to deliver paclitaxel for effective cancer treatment. They found improved targeting efficiency on SW620 or CT26 cells-­ grafted mice [92]. Likewise, miR17-loaded ginger-derived nanovector decorated with FA was explored for treating brain cancer models. The enhanced targeting on brain tumor with folate receptors was reported with delayed tumor growth in mice [93]. The recent pandemic creates a new horizon for developing new drug delivery systems to treat SARS-CoV-2. In coherence with this concept, plant-derived exosome (ENP) loaded with miRNAs was developed to kill SARS-CoV-2. Firstly, the targeting sequence was identified by silico studies and later fabricated with qRT-PCR. Natural resources such as grapefruit, tomato, etc. were used to fabricate ENPs. The accumulation of nanocarrier was observed on lungs which denote the effectivity ENPs against SARS-CoV-2 [94]. These studies conclude the effectivity of herbal-derived nanocarriers in treating different diseases.

2.27 Nanoencapsulation of Herbal Drugs Lipid nanoparticles, nanoemulsions, and polymeric nanocapsules can be used for encapsulating essential oils to widen their scope for clinical applications. Essential oils pose stability problems, and nanoencapsulation can help overcome them. Lipid nanoparticles include a variety of carriers, including nanostructured lipid carriers, and solid lipid nanoparticles. Liposomes are made from amphiphilic lipids; therefore, they can incorporate hydrophilic and hydrophobic molecules. The other two carriers have

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a lipoidal core, so they are suitable for lipophilic molecules like essential oils only [80]. The research was conducted by Valencia-Sullca et al. where they encapsulated essential oil obtained from the leaves of cinnamon and eugenol into liposomes and found that liposomes enhanced the capacity of the water vapor barrier more than the free compound [95]. Another study was done by Montenegro et al. where they loaded rosemary essential oil into NLCs and showed better skin hydration and elasticity than the free compound [96]. In a study by Khadem et  al., they loaded essential oil extracted from the seeds of Ferula asafoetida into SLNs and found that it showed significant apoptotic and antiangiogenic activity [97]. Another study was performed by Azadmanesh et al. where they loaded essential oil of Eucalyptus globulus L. in SLNs and found that there was an increase in the yield and the level of phytoconstituents of the essential oil. It also increased the therapeutic efficacy of the oil [98]. Herbal constituents were also explored for the treatment of cancer which is one of the leading causes of mortality. Currently, the main constraint with drugs used to treat cancer is the development of drug resistance. So, some researchers explored herbal liposomes as an alternative approach to cancer treatment. For instance, Long et al. investigated the effectiveness of PEGylated liposomal quercetin (Lipo-Que) on a cisplatin-­ resistant ovarian cancer cell model. The loaded liposomes were prepared with the solid dispersion method and release of quercetin in a sustained released manner. The cytotoxicity results revealed that Lipo-Que induced apoptosis and inhibited cell proliferation in A2780cp and A2780s cells. Moreover, an in vivo study on nude mice treated with Lipo-­ Que showed a significant reduction in tumor growth compared to the control group. It concludes the therapeutic effectiveness of liposomal quercetin in treating cisplatin-­resistant and cisplatin-sensitive ovarian cancer [99]. Likewise, honokiol-loaded liposomes (Lipo-­ HNK) were also investigated for anticancer activity against cisplatin-resistant and cisplatin-­sensitive ovarian cancer. Significant tumor inhibition was observed in Lipo-­ HNK-­treated mice with prolonged survival. Marked reduction in intratumoral microvessel density and enhanced apoptosis was reported. It suggests the honokiol-loaded liposomes as an effective approach for treatment [100]. On the other hand, resveratrol-loaded liposomes were developed to target mitochondria for cancer treatment. The liposomes were prepared with nanosize and modified with TPP-PEG or DQA-PEG to enhance EPR as well as prolong circulation time. Furthermore, they induce toxicity in cancer cells by reactive oxygen species generation [101]. Besides cancer, the herbal extract is also used to treat depression. As evident from traditional Chinese medicine and Ayurveda, Hibiscus Rosa Sinensis is used as an antidepression. However, poor oral bioavailability and pharmacokinetic variability are the main constraints. So researcher investigated the formulation of Hibiscus rosa Sinensis extract-­ loaded SLN for systemic delivery. The prepared SLN carried a negative charge with a spherical shape and nanosize. The in vivo results revealed that similar pharmacological effects were achieved by a lower dose of SLN compared to the traditional formulation. This concludes that the encapsulation of phytopharmaceuticals into nanocarriers may improve therapeutic efficacy [102].

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These are colloidal dispersions that are amphiphilic and can incorporate both hydrophobic and hydrophilic drugs. They have a distinct self-assembly property. When put in a hydrophilic solvent, the molecules arrange themselves in a manner so that the hydrophilic part is facing outwards and the hydrophobic part is facing the core [103]. Ghalehkhondabi et  al. developed silibinin-loaded nanomicelles and their study results showed sustained release of the drug along with desirable cytotoxicity [104]. In a different study, Azadi et al. loaded berberine into nanomicelles. They found that it showed a significant reduction in the levels of inflammatory factors with lower doses and minimal side effects [105]. Additionally, Kumar et al. loaded root extract of Grewia asiatica into nanoemulsion and microparticles and investigated for its antianthelmintic activity. The results depict the higher activity of nanosuspension compared to microparticle and conventional formulation. Thus, these studies indicate the potential of herbal drugs in treatment of disease conditions as well as to formulate nanocarrier as edible carriers (Tables 2.2 and 2.3). Table 2.2  Summary of herbal nanocarrier nanovesicles in disease treatment Objectives To develop edible ginger-derived nanoparticles and investigate it potential for IBD and colitis-­ associated cancer

Disease Colitis-­ associated cancer Inflammatory bowel disease (IBD)

Development of plant-derived exosomes for the treatment of chronic periodontitis To investigate antimelanogenic effects of plant-derived vesicles extracellular vesicles derived from plant leaves and stems in mouse melanoma cells and human healthy skin

Chronic periodontitis

Formulation type 6-Gingerol and 6-shogaol-­ derived nanoparticle

Animals/ cell lines Intestinal epithelial cells (IECs), mouse

Ginger-­ derived nanoparticle

Mice

Antimelanogenic Extracellular vesicles from Dendropanax morbifera

B16BL6 mouse melanoma cell line Human epidermis model

Outcomes Decreased level of proinflammatory cytokines and enhanced anti-­ inflammatory cytokines Prolonged survival rate Edible ginger inhibited the pathogenicity of porphyromonas gingivalis

References [84]

[85]

Dendropanax [86] morbifera inhibited melanin and provided a whitening effect

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Table 2.2 (continued) Objectives To formulate bioactive nanovesicles from grape fruit to attenuate inflammatory responses To investigate the potential of broccoli-derived nanoparticle for colitis treatment To evaluate the effectiveness of plant derived nanoparticle against colitis

Formulation type Nanovesicles from grape fruit

Animals/ cell lines DSS-­ induced mouse colitis

Colitis

Broccoli-­ derived nanoparticle

Mouse

Colitis

Mice Lycium barbarum derived edible nanoparticles

[89]

Surface-­ modified grapefruit-­ derived nanovectors Grapefruit-­ derived nanovectors decorated with folic acid

[91]

Disease Immunological disease

Cancer To fabricate grapefruit-derived nanovectors to treat cancer To investigate the Cancer effectiveness of folic acid decorated grapefruit-derived nanovectors against cancer Brain cancer To develop miR17-loaded ginger-derived nanovector decorated with FA for treating brain cancer models SARS-CoV-2 To develop miRNAs-loaded plant-derived exosome against SARS-CoV-2

Ginger-­ derived nanovector

Outcomes Enhanced therapeutic effects and reduced side effects of the methotrexate

[88]

Inhibit the secretion of IL-12 and TNF-α, but high uptake by macrophages Mice Reduction in tumor growth with anti-­ inflammatory property SW620 or Improved tumor CT26 targeting efficiency cells-­ grafted mice

Mice

Plant-derived – exosome

References [87]

[92]

[93] Enhanced targeting on brain tumor Delayed tumor growth in mice

Effective accumulation of nanocarrier was observed on lungs against SARS-CoV-2

[94]

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70 Table 2.3  Examples of herbal drugs encapsulated in nanoparticles To develop and evaluate rosemary essential oil-loaded lipid nanoparticles To investigate the efficiency of Ferula asafoetida essential oil-loaded solid lipid nanoparticle (SLN) on embryocarcinoma cells Biological traits and C/MS profiling of SLN loaded with essential oil of Eucalyptus globulus To evaluate efficacy of PEGylated liposomal quercetin on angiogenesis inhibition and apoptosis induction Development of herbal formulation for cisplatin-resistant ovarian cancer treatment

Dryness of skin

Rosemary essential oil-loaded nanocystals Embryocarcinoma Ferula asafoetida essential oil-loaded solid lipid nanoparticle (SLN) – SLN loaded with essential oil of Eucalyptus globulus Cisplatin-resistant PEGylated ovarian cancer liposomal quercetin

Healthy Better skin [96] human hydration and volunteers elasticity than the free compound Human Significant [97] NT-2 apoptotic and cancer antiangiogenic stem cell activity line

–

Increased the [98] therapeutic efficacy of the oil

A2780cp and A2780s cells Nude mice

Release of [99] quercetin in a sustained released manner

Cisplatin-resistant Honokiol-­ ovarian cancer loaded liposomes

Mice

To prepare resveratrol-loaded liposomes for targeting cancer Development of herbal SLN to treat depressant

Cancer

Resveratrol-­ loaded liposomes

B16F10

Depression

Hibiscus rosa sinensis extract-loaded SLN

Male Swiss albino mice

To fabricate folate-targeted herbal nanomicelles for liver cancer treatment

Liver cancer

Silibinin-­ loaded nanomicelles

Human liver cancer cells (HepG2)

Prolonged survival of mice Marked reduction in intratumoral microvessel density and enhanced apoptosis Prolonged circulation time Induce toxicity in cancer cells Similar pharmacological effects were achieved by a lower dose of SLN Sustained release of the drug along with desirable cytotoxicity

[100]

[101]

[102]

[104]

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2  Advantages of Nanomedicine Over Conventional Therapeutics Table 2.3 (continued) To develop berberine Cerebral ischemia Berberine into Wistar rats nanomicelles into nanomicelles and investigate anti-inflammatory efficacy

Significant reduction in the levels of inflammatory factors

[105]

2.28 Nanoadsorption of Herbal Drugs Mesoporous nanomaterials like mesoporous silica nanoparticles and metal-organic frameworks can be useful techniques for delivering hydrophobic herbal drugs due to the adsorption of mesopores. Mesoporous silica nanoparticles are beneficial due to their porous structure, adjustable pore size, chemical stability, biocompatibility, porosity, and low-­ production cost. All these characteristics contribute to the protection of the herbal compound against degradation. Gao and his team performed a study where they loaded paclitaxel and curcumin in mesoporous silica nanoparticles and found that this enhanced the bioavailability and cytotoxicity of both drugs [106]. In another study, Shabana et al. loaded quercetin in mesoporous silica nanoparticles, and they found that it enhanced the cytotoxicity and antibacterial activity of the drug [107]. Metal-organic frameworks are porous crystalline materials having a high-loading capacity for volatile compounds because of their well-organized structure [108, 109]. Wu et  al. formulated thymol-loaded zinc metal-organic framework and their study results showed enhanced stability along with the prolonged release of thymol thereby resulting in better growth inhibition of the cells [110]. Another research was done by Zhang and the team where they loaded curcumol in a porphyrinic metal-organic framework. The results confirmed that the formulation enhanced the targeting ability and retention capability of the drug [111]. In summary, herbs and their extracts have been of therapeutic use since time immemorial and they have numerous benefits. Still, their use has been restricted due to some of their poor physiochemical properties. Nanomedicine is an approach that can solve this problem and can help in utilizing the true potential of herbal drugs. It can not only improve the physiochemical properties of the drug but can also alter the cell membrane structure, metabolism in the body, tumor immunity, and microcirculation. The most recent research and developments are proof to confirm the wonders nanotechnology can do for herbal medicine.

2.29 Issue of Toxicity in Nanomedicine By now, we know that nanoparticles have become immensely popular with their popularity growing every day in medicine, which can be linked to their extraordinary qualities that distinguish them from conventional therapeutics. Due to their properties, these can be used

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in the biomedical field for the administration of medications, diagnostics or imaging, for manufacturing biomaterial substances, and many other [112–114]. As mentioned earlier, nanoparticles are particles of size less than 100 nm [115]. Conventional medications have issues such as limited specificity, lower bioavailability, and significant toxicity. The use of nanoparticle-based medicine delivery systems has the potential to considerably ease these difficulties [116]. Nanoparticles can be used for medicinal reasons in two ways: (1) a drug or (2) a carrier [117, 118]. Because the nanoparticles penetrate the biological system, nanomedicines derived from these interact with various biological processes and macromolecules or enzymes found in living organisms. Whereas nanoparticles’ particular qualities make them attractive for medication administration, the same properties can pose issues if these are not maximized properly [119]. Nanotechnology has great impact on everyday science due to innumerable potential benefits. However, given the possibility of exposure due to its growing use in everyday technologies, there have been many concerns about the risks related to health and environment. For example, potential effects to human health are a major concern due to lack of toxicity data [120]. Due to these concerns, additional scientific disciplines have emerged including nanotoxicology, which deals with the potential side effects of nanoparticles. In the following section, some nanomedicine properties that influence their toxicity in vivo are outlined.

2.30 Characteristics of Nanoparticles that Affect Their Toxicity 2.30.1 Size and Surface Area of Particle When nanoparticles size reduces, their surface area to volume ratio rises, which further enhances their biological and chemical properties [121, 122]. If the nanoparticle size is reduced from 30 nm to 3 nm, number of molecules that are involved increase from 10% to 50% [123]. Nanomaterial cytotoxicity is caused by nanoparticle surfaces interaction with numerous cell components. Thus, even though nanoparticles have similar chemical ­components, their cytotoxicity might vary dramatically which depends on the particle size and surface area. In other words, nanoparticles are more hazardous than larger particles having identical contents. Chao et al. have reported the size-dependent acute toxicity of silver nanoparticles in BALB/c mice. They injected silver nanoparticles of various sized via intraperitoneal route. Histopathological abnormalities such as thymus cortex apoptosis, localized necrosis, mono necrosis, vacuolation and congestion in the liver, and splenic congestion were only identified when 10 nm silver nanoparticles were injected, not 60 or 100 nm silver nanoparticles. Based on their results, they reported that smaller nanoparticles induce higher acute toxicity in mice [124].

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2.30.2 Shape The shape of nanoparticles is a crucial component in affecting their biological reactivity and toxicity. Nanoparticles are commonly shaped as spheres, cylinders, cubes, sheets, or rods. The form of the nanoparticle has a crucial role in its cellular absorption [121]. In zebrafish (Danio rerio) embryos, nanoplates of silver were shown to be more toxic than silver nanospheres [125]. Gold nanorods generate less autophagosome accumulation than gold nanospheres [126]. Using MTT assay, Steckiewicz et al. found that star-shaped gold nanoparticles were the most cytotoxic against human cells among different-shaped particles [127]. Needle-shaped nanoparticles are more dangerous than spherical nanoparticles because they are capable of interrupting endocytic process at different stages, have higher internalization rates, and more efficient adhesion to the surface of the target cell [128–130].

2.30.3 Aspect Ratio A nanoparticle’s aspect ratio is defined as its width-to-height ratio. Higher the aspect ratio of the nanoparticles, more toxic the nanoparticles. In several studies investigating the role of aspect ratio, aspect-ratio-dependent lung injury was discovered [131]. Muller et  al. stated that after being given directly into the trachea, carbon nanotubes with a high aspect ratio induced significantly high pulmonary toxicity in rats. Carbon nanotubes caused significant protein exudation and granulomas on the peritoneal side of the diaphragm [132].

2.30.4 Crystallinity The crystalline structure of nanoparticles may influence their toxicity [121]. Anderrson et al. showed that the titanium dioxide nanoparticle uptake and toxicity in lung epithelial cells were found to be polymorph-dependent. These findings highlight the need of ­precisely characterizing the nanoparticles polymorphic form for effective toxicity assessment [133].

2.30.5 Surface Coating Surface coatings of nanoparticles are used to change their characteristics. Due to bioavailability, the surface modification can cause toxic particles to become benign, while less dangerous particles can become more harmful [121]. Xu et al. coated iron oxide nanoparticles with silica and investigated their in vitro toxicity on HeLa and A549 cells. Surface immobilization of nanoparticles can make them benign and can limit their effects in biological processes such as on iron homeostasis and oxidative stress. So, when compared to nonpassivated nanoparticles, overall toxicity during cell internalization is reduced in coated nanoparticles [134].

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2.30.6 Dissolution The nanoparticles ability to dissolve is a crucial characteristic that determines their safety, absorption, and related cytotoxic or toxicity mechanisms. Depending on the surface modification, two identical nanoparticles having equivalent content and size may have completely different dissolving behavior [121, 135].

2.30.7 Agglomeration Because of their high-free surface energy, nanomaterials are prone to agglomeration in solution [136]. Nanomaterials are protected with protective agents so as to prevent agglomeration. Nanoparticle aggregation has the potential to induce inflammatory lung illnesses in humans [137]. For example, Zook et  al. found that large sized silver nanoparticle agglomerates were less toxic and showed lower hemolysis activity as compared to those with smaller size agglomerates [138].

2.30.8 Ethical Issues in Nanomedicine The clinical application or clinical translation of nanomedicine is quite limited compared to research carried out by different researchers on preclinical platforms. This may attribute to the risk assessment of nanomedicine surpassing the benefits. Therefore, a proactive approach is needed to investigate the potential risks of nanomedicine, which should not be played down just to favor the benefits. To evaluate the risks that can result from nanomedicine use, we first need to understand its interaction with cells or organisms. Some probable risks are already reported, such as people and activists have already questioned the use of nanoparticles and unwanted exposure to nanotechnology products including nanomedicines due to the uncertainty surrounding the properties of nanoparticles and the potential consequences of exposure [139]. Because nanomaterials are not a well-understood class of compounds, their safety must be assessed separately for each kind of material [123]. Particles lower than 200 nm can evade and bypass the natural defense systems in circulation and penetrate any human cell. It is worth emphasizing that particles that pass the blood–brain barrier can remain in the central nervous system, causing or initiating neurodegenerative illnesses [140]. Particles have the ability to cause damage to free radicals or to be teratogenic, harming future generations. Some coated particles cannot be removed from cells, while others may accumulate in the immune system [139]. As the concept of nanomedicine is comparatively new and is extremely diverse in terms of nature of applications, material used, and change in properties as compared to native materials, to configure one platform for the safety assessment of all types of nanomedicine is challenging. However, there is a possibility of framing rules and regulations keeping in mind certain types of risk and uncertainties. Generally, firm pieces of evidence are required

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to frame rules and regulations for manufacturing a material at industrial or pharmaceutical scale, which itself is a problematic area for nanomedicine as we lack these evidences. Although scientists have defined nanomedicine, still there is no definition for nanomedicine with consensus from all concerned quarters, there is a confusion about whether it should be classified under medicine or medical devices. Some of the products fall into both categories, so the primary goal, in this case, is to identify which regime or laws it falls under. The second problem is the challenges involved in manufacturing (such as purity limits, control over stability, and particle size distribution) of nanomedicine as procedures and equipment available are designed for conventional dosage forms. According to guidelines, medicine has to be characterized first; however, there is no gold standard for the characterization of nanomedicine. The third issue is the development procedure of nanomedicine, a one-size-fits-all approach is not applicable for nanomedicine. General safety criteria such as stability, physiochemical characteristic, cytotoxicity, and genotoxicity cannot be applied to risk assessment of all types of nanomedicine. To promote national and international justice in the availability of nanomedicine, countries must guarantee that intellectual property legislation and policies or regulations do not give manufacturers control of the market, develop a finance system for health care that assists poor people in receiving nanomedicine, participate in global efforts to assist various emerging nations in obtaining access to nanomedicine, and begin negotiating fair terms [141, 142]. On this avenue, organizations such the WHO should take the lead and formulate a plan to develop and implement such policies that are helpful in this regard. Another ethical question concerning for the social fairness is nanomedicine use for the purpose of enhancing the physical instead of diagnostic treatment. The challenge of medical enhancement is not limited to nanomedicine; practically every newer medical technology that may be used for diagnosis, preventing, or treating illnesses can also be utilized for improving the function or body or mind appearance [143]. There are compelling reasons for anticipation and adaptation of society for the use of nanomedicine for the purpose of improvement of a condition. First, the distinction between improvement and treatment is not clear, as both are based on the illusory truth effect idea. Improvements aim to make people “better than” normal, whereas therapeutic therapies aim to get people back to regular performance [144]. Second, any rules or laws controlling the nanomedicine use for improvement may be difficult to implement. A rule can only be successfully enforced if society has a method for reliably recognizing rule infractions [145].

2.30.9 Regulatory Issues in Nanomedicine Throughout the previous few decades, nanomedicines have been successfully introduced into clinical practice, and continued breakthroughs in pharmaceutical research are developing more complicated ones that are presently being examined in clinical trials. The

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European Union’s nanomedicine market includes nanoparticles and nanocomplexes [146, 147]. The primary purpose is to create a foundation for studying follow-on nanomedicines once the conventional medicine’s patent expires [148, 149]. Nanomedicine comprises both biological and nonbiological therapeutic devices. Nonbiological complex medications are obtained from nonbiological sources, with the active principle consisting of numerous synthetically created structures [149–151]. For both biological and nonbiological nanomedicines, a more complete examination that includes measurements of plasma concentration is necessary. A progressive investigation of bioequivalence, safety, quality, and efficacy in comparison to the reference medication is required, which adds to medical similarity [152]. In Europe, the European Medicines Agency (EMA) regulates biological nanomedicines. There is a need to formulate regulatory policies for future biological nanomedicines, which should contain recommendations for assessing quality and also regarding nonclinical and clinical research [153]. The EMA, for instance, is developing a regulatory system for the upcoming nonbiologic complex pharmaceuticals. The industry often asks scientific advice, which the EMA considers on a specific instance approach [154]. After a nanomedicine achieves marketing approval, there is still a long path ahead until it is utilized in clinical practice, especially in all EU countries. In order to provide patients with medicine access, the multidisciplinary method of Health Technology Assessment (HTA) is being developed. HTA collects data on pharmaceutical safety, efficacy, and cost-­ effectiveness to aid health and policymakers.

2.31 Future Prospects and Outlook Progression of nanomedicine is validated by many successful examples. However, there is still a way forward as health systems face a huge challenge of handling chronic diseases and cancers. As more materials are being investigated for nanomedicine development, there are some factors which need to be considered for future development. A major point is thriving on commercially acceptable regimen and then provide unearthing solutions combined with in-depth investigations of novel materials. Commercially relevant lipid nanocarriers have an added challenge of getting digested by enzymes and often temperature-­ sensitive. The two examples of the challenge demarcate the need as lately, safe-by-design concept has been introduced where safety is assessed during product development rather than evaluating safety after complete development. Quality-by-design is a similar approach taken into consideration for overall product development and is relevant for new product approvals. A recent study found that there is a threshold count of nanoparticles to achieve desired therapeutic effect [155]. So, such factors must be investigated by designing suitable physical characterization and in vivo studies during nanomedicine development. A closer look at approved nanoparticle therapeutics indicates, they are mostly lipid-­ based or albumin-based particles with some success shared by iron-based nanoparticles.

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Silica-based quantum dot (8 nm) is a diagnostic agent undergoing clinical trial. An interesting technology capable of scale-up has been built by Precision nanosystems. The technology Nanoassemblr® depending on the volume of scale-up is being used in laboratories across academia and industry. Availability of a robust scale-up technology has enabled decision-making faster and prioritizes research and development projects using lipid carriers to make commercially viable candidates. There is nonetheless a pressing need that the stakeholders are made aware on simplicity and scale-up possibilities of nanoparticles as pharmaceutical industry management are usually reluctant to take up complex lead for commercial scale preparation.

Take-Home Message

• • • •

Nanomedicine is superior to conventional medicine given their small size. Nanomedicine can deliver drugs directly at target sites to reduce adverse effects. Nanomedicine can improve the therapeutic effect of conventional drugs. Care must be taken to design the nanomedicine considering their potential of toxicity. • Special consideration must be given to design of nanomedicine to allow scale-up for commercial production of nanomedicine.

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129. Huang X, Li L, Liu T, Hao N, Liu H, Chen D, et  al. The shape effect of mesoporous silica nanoparticles on biodistribution, clearance, and biocompatibility in  vivo. ACS Nano. 2011;7:5390–9. 130. Li W, Zhang X, Hao X, Jie J, Tian B, Zhang X. Shape design of high drug payload nanoparticles for more effective cancer therapy. Chem Commun. 2013;49:10989–91. 131. Lippmann M. Effects of fiber characteristics on lung deposition, retention, and disease. Environ Health Perspect. 1990;88:311–7. 132. Muller J, Huaux F, Moreau N, Misson P, Heilier JF, Delos M, et al. Respiratory toxicity of multi-wall carbon nanotubes. Toxicol Appl Pharmacol. 2005;207:221–31. 133. Andersson PO, Lejon C, Ekstrand-Hammarström B, Akfur C, Ahlinder L, Bucht A, et  al. Polymorph- and size-dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells. Small. 2011;7:514–23. 134. Malvindi MA, De Matteis V, Galeone A, Brunetti V, Anyfantis GC, Athanassiou A, et  al. Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. PLoS One. 2014;9:e85835. 135. Misra SK, Dybowska A, Berhanu D, Luoma SN, Valsami-Jones E.  The complexity of nanoparticle dissolution and its importance in nanotoxicological studies. Sci Total Environ. 2012;438:225–32. 136. Kumar CSSR, Hormes J, Leuschner C. Nanofabrication towards biomedical applications: techniques, tools, applications, and impact. Hoboken, NJ: Wiley; 2005. 137. Bantz C, Koshkina O, Lang T, Galla HJ, Kirkpatrick CJ, Stauber RH, et al. The surface properties of nanoparticles determine the agglomeration state and the size of the particles under physiological conditions. Beilstein J Nanotechnol. 2014;5:1774–86. 138. Zook JM, MacCuspie RI, Locascio LE, Halter MD, Elliott JT.  Stable nanoparticle aggregates/agglomerates of different sizes and the effect of their size on hemolytic cytotoxicity. Nanotoxicology. 2011;5:517–30. 139. Allon I, Ben-Yehudah A, Dekel R, Solbakk JH, Weltring KM, Siegal G. Ethical issues in nanomedicine: tempest in a teapot? Med Health Care Philos. 2017;20:3–11. 140. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med. 2013;19(12):1584–96. 141. Resnik DB. Fair drug prices and the patent system. Health Care Anal. 2004;12(2):91–115. 142. Resnik DB, Tinkle SS. Ethics in nanomedicine. Nanomedicine. 2007;2:345–50. 143. Resnik DB. Developing drugs for the developing world: an economic, legal, moral, and political dilemma. Dev World Bioeth. 2001;1:11–32. 144. Stein E, Buchanan A, Brock DW, Daniels N, Wikler D. From chance to choice: genetics and justice. Philos Rev. 2002;111:130–132. 145. Allen DB, Fost N. hGH for short stature: Ethical issues raised by expanded access. J Pediatr. 2004;144(5):648–52. 146. Hafner A, Lovrić J, Lakǒ GP, Pepić I. Nanotherapeutics in the EU: an overview on current state and future directions. Int J Nanomed. 2014;9:1005–23. 147. Soares S, Sousa J, Pais A, Vitorino C.  Nanomedicine: principles, properties, and regulatory issues. Front Chem. 2018;6:360. 148. Ehmann F, Sakai-Kato K, Duncan R, Pérez De La Ossa DH, Pita R, Vidal JM, et  al. Next-­ generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines. Nanomedicine. 2013;8:849–56. 149. Tinkle S, McNeil SE, Mühlebach S, Bawa R, Borchard G, Barenholz YC, et al. Nanomedicines: addressing the scientific and regulatory gap. Ann N Y Acad Sci. 2014;1313:35–56.

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150. Hussaarts L, Mühlebach S, Shah VP, McNeil S, Borchard G, Flühmann B, et al. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks. Ann N Y Acad Sci. 2017;1407:39–49. 151. Mühlebach S. Regulatory challenges of nanomedicines and their follow-on versions: a generic or similar approach? Adv Drug Deliv Rev. 2018;131:122–31. 152. Astier A, Barton Pai A, Bissig M, Crommelin DJA, Flühmann B, Hecq JD, et al. How to select a nanosimilar. Ann N Y Acad Sci. 2017;1407:50–62. 153. Mühlebach S, Borchard G, Yildiz S.  Regulatory challenges and approaches to characterize nanomedicines and their follow-on similars. Nanomedicine. 2015;10(4):659–74. 154. Schellekens H, Stegemann S, Weinstein V, De Vlieger JSB, Flühmann B, Mühlebach S, et al. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider. AAPS J. 2014;16(1):15–21. 155. Ouyang B, Poon W, Zhang Y-N, Lin ZP, Kingston BR, Tavares AJ, et al. The dose threshold for nanoparticle tumour delivery. Nat Mater. 2020;19:1362–71.

Part II Nanomedicine in Treatment of Diseases

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Nanomedicines for the Treatment of Bacterial Diseases Rida Siddique, Ammara Saleem, Faqir Muhammad, Muhammad Furqan Akhtar, Bushra Akhtar, and Ali Sharif

Contents 3.1  Introduction  3.2  History of Antibiotics  3.3  Limitations of Antibiotics  3.4  Antibiotic Resistance Pattern in Bacteria  3.5  Therapeutic Efficacy of Nanoparticles  3.6  Nanoparticles as Drug Delivery System  3.7  Treatment of Targeted Bacterial Killings  3.8  Future Outcomes Regarding the Nanomedicine as Antibacterial  References 

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R. Siddique · A. Saleem (*) Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan e-mail: [email protected] F. Muhammad Department of Biosciences, Faculty of Veterinary Sciences, Bahauddin Zakariya University, Multan, Pakistan M. F. Akhtar (*) Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan B. Akhtar Department of Pharmacy, University of Agriculture Faisalabad, Faisalabad, Pakistan e-mail: [email protected] A. Sharif Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_3

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What You Will Learn from This Chapter

Bacterial infections pose serious threats to the lives of humans worldwide. Extensive applications of antibiotics have resulted in an increased resistance among various pathogenic bacteria against those antimicrobials. Development of such resistance has led to increment in the microbial virulence, increased hospitalization frequency, mortality and morbidity, and increased potential of the pathogens to evade the immune system by forming biofilms. The retention as well as efficacy of these drugs in the target tissues are affected by their bioavailability, pharmacodynamic, and pharmacokinetic parameters. All these hurdles result in the development of need for higher doses and frequent administrations for obtaining effective treatment doses and hence, induce undesirable outcomes. Treatment using nano-sized delivery methods is regarded as one of the major approaches, and thousands of researches and related articles have supported drug delivery system based on nanoparticles. Nanodrug delivery involves the mechanism by which the NPs are combined with one or more antimicrobial adjuncts, which can lead to increase or decrease in the bioavailability of the drug and related side effects. Administration of NPs as antibacterial material is an ingenious and cost-effective approach against a range of pathogenic bacteria. Hence, application of NPs as a cost-effective antimicrobial delivery method should be opted to increase the life and effectiveness of the drug. The dramatic increase in the bacterial resistance against a variety of antibiotics has emerged to pose a key threat to human health. The uncontrolled, frequent, and unprescribed usages of antibiotics have resulted in the induction of antibiotic resistance in numerous bacterial strains. The world is on the verge of entering into the postantibiotic era, where the more population will die because of bacterial infections than cancer. Therefore, the discovery of potent and novel bactericidal agents in current times, is inevitable and is of considerable clinical importance. In recent times, nanotechnology has developed as a new tool to tackle the deadly bacterial infections and is thought to have overcome the barriers experienced by conventional antimicrobials such as antibiotic resistance. The nanoparticles (NPs) have been increasingly reported to interact with major biomolecules such as ribosomes, enzymes, DNA that directly interfere with the gene expression, oxidative stress, and membrane permeability. As, the NPs target several biomolecules at the same time, it turns out to be very challenging for the bacteria to deal with them and develop resistance against them. In this chapter, we have highlighted the history of antibiotics and how different bacterial strains have developed antibiotic resistance to certain drugs. Moreover, the role of nanotechnology and efficacy of various nanomaterials in the fight against bacterial infections have been discussed along with pervious researches. In the end, future outcomes of using the nanomaterials in the field of medicine have been explored.

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3.1 Introduction Bacterial infections and ailments pose a significant threat to public health which are responsible for deaths of almost 14 million people annually [1, 2]. Naturally, bacteria exist in the form of biofilms, where they adhere themselves to the inert or biological surfaces and enfold within the self-produced extracellular polymeric substances (EPS) such as exopolysaccharides, extracellular DNA (eDNA), proteins, and so on [3]. The formation of biofilm not only imparts the bacteria with the ability to withstand the host innate immune system, but also, enhances their tolerance to antibiotics, in comparison with their planktonic form. Earlier researches have exhibited that nearly 60–70% of the bacterial-based infections are attributed to the biofilm formation, which generally cause recalcitrant chronic infections, dental caries, musculoskeletal infections, periodontitis, chronic wounds, and so on [4]. In 1891, William Coley observed that injection of Bacillus prodigiosus and Streptococcus pyogenes in the cancerous patients caused regression of tumor [5, 6]. Since that discovery, the medical researchers have developed an encouraging interest at implying bacteria and related traits for their advantages. With the advancement in the field of nanotechnology, the therapeutic efficacy of the bacteria has also been checked against several noncancerous diseases such as diabetes mellitus, infection as well as inflammatory bowel disease [7] as bacteria deal with an extensive array of processes. Biomimicry of different bacterial species with their taxis, motility, dynamic host interactions, and immunomodulation has provoked substantial interest and has discovered exhilarating avenues of research [8]. It is meaningful to judiciously consider both their supportive and destructive impacts and suggest that how these interactions could be exploited for therapeutically useful conclusions. Different nanoscale derivatives of bacteria, i.e., extracellular vesicles, membrane ghosts, spores as well as secreted proteins, often require little or no attenuation for innocuous application and hence, promise reliable and auspicious direction for further advancements [8, 9].

3.2 History of Antibiotics Antibiotics belong to an important class of pharmaceuticals, and are the most persuasive medical development of the twentieth century. These are the bioactive compounds having low-molecular weights and have been extensively employed against bacterial infections for more than 70 years as well as in several other medicinal applications [10]. They have proved to be a great blessing on the mankind in lieu of their battle against microbes, by protecting millions of lives [11]. Inadequate information regarding the microbially mediated contagious diseases prevailed during the preantibiotic period. Similarly, the prevention as well as treatment against these infectious diseases were not satisfactory and resultantly, they progressed as epidemics, causing deaths of people [12]. The Plague outbreak can effectively reflect the catastrophic conditions of the people at that time, caused

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by a bacterium “Yersinia pestis,” which was transmitted via infected animal flies, and caused numerous pandemics throughout the history [13] such as “Black Death” in fourteenth century, resulting in the deaths of over 50 million people in Europe and “Justinian Plague,” which resulted in the deaths of almost 100 million people. In 1676, Antonie van Leeuwenhoek discovered “animalcules” microscopically and rested the foundation for antibiotic development [14]. Joseph Lister in 1871, observed the inhibitory impacts caused by Penicillium glaucum on the bacterial growth, which enabled him to treat a nurse’s injury using the P. glaucum extract, and this finding sparkled the concept that bacteria cause infection [15]. Similarly, German physician “Robert Koch” and French bacteriologist “Louis Pasteur” performed independent studies on the bacteria in second half of the nineteenth century, and found out that individual bacterial species and associated disease share a corelationship. These outcomes pushed microbiology as well as antibiotic development toward modern era [16]. In 1893, Italian microbiologist “Bartolomeo Gosio” discovered the first antibiotic from P. glaucum, responsible for suppressing the growth of B. anthracis and named it “mycophenolic acid” [17]. Then, Paul Ehrlich and coworkers explored first ever As-based antibiotic “Salvarsan” (arsphenamine) in 1909, which was found to be effective against Treponema pallidum [18], responsible for Syphilis. Later, “Alexander Fleming” (a Scottish bacteriologist) in 1928, experienced that a fungus “Penicillium notatum” can suppress the growth of bacterium “Staphylococcus aureus” which was attributed to release of some compounds by the fungus, which could have inhibited bacterial growth and was later on, isolated by him in 1929 and named as “penicillin,” which was firstly discovered true antibiotic. The structure of penicillin G was elucidated in 1939 by Ernst Boris Chain and Howard Walter Florey, who purified the antibiotic and elevated its production [19]. The next breakthrough in the antibiotic discovery was the administration of penicillin for treatment purpose [20]. Later, French microbiologist “René Dubos” isolated “tyrothricin” (mixture of tyrocidine and gramicidin D) from soil bacteria “Bacillus brevis” in 1939, and unlocked a new section on the antibiotic discovery. The discovered bacterial species was found to be effective against Gram-positive bacteria. In 1940s, Selman Waksman studied the soil bacteria, particularly Streptomyces spp. And looked for its antimicrobial behavior. He discovered many antibiotics such as actinomycin, streptomycin, neomycin, fumigacin, and clavacin [11]. His initiatives started the overwhelmed era (between 1940s and 1970s) of antibiotic discovery [15] and many of them (neomycin, streptomycin, actinomycin, etc.) have been extensively used in clinical use until now [21]. Following the Waksman platform, various pharmaceutical agencies used rational screens for the development of new molecules by relying on the available knowledge of antibiotics-related mechanism of action [14]. Unfortunately, only a small number of antibiotics have been perceived such as macrolides, quniolones, nitrofuran, and tetracyclines, and no new group has been detected during the last 50 years [16]. Despite their tremendous efficacy, the number of multidrug-­ resistant bacterial-mediated infections have increased considerably on a global scale and the danger of untreatable infections has been imminent since the start of the twenty-first century [22].

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3.3 Limitations of Antibiotics Despite the extensive and common use of antibiotics as therapeutic and prophylactic agents, their widespread application to humans and animals creates a selective pressure, which contributes to the persistence, selection, and propagation of antibiotic-resistant bacteria [23, 24], which is by far, their greatest concern and limitation. Their considerable amounts are released into the environment owing to their indiscriminate application in medicine, veterinary, and as growth promoter in animal husbandry and fish farming [25]. According to the estimates of a recent UK report, nearly 700,000 people die every year owing to the infections caused by the antibiotic-resistant bacteria and the number has been expected to rise to ten million by the end of 2050 if immediate steps are not taken (http:// amr-­review.org). The global prevalence of antibiotic resistance has turned into a major threat to public health. A resultant increase in the antibiotic-resistant bacteria along with their antibiotic-resistant genes has been observed [26]. Of major concern are the abrupt global widespread of multidrug-resistant bacteria, which mediate infections that cannot be treated by using current antimicrobials [27] and the lack of these antimicrobials affects the global health system, which led to the development of antimicrobial resistance (AMR) [28]. Some antibiotics are easy to degrade such as penicillin whereas, others are considerably persistent in nature, i.e., tetracyclines and fluoroquinolones and this recalcitrance permits them to stay in the environment for a longer time period, and also leads to their further accumulation [25] (Fig. 3.1). Nguyet et al. [29] determined the antibiotic susceptibility as well as genotype profiling of E. coli causing diarrhea in piglets. The strains were isolated from the rectal swab of piglets suffering from diarrhea in Thailand during 2018–19. Their outcomes exhibited that out of 37 tested strains, 28 strains (75.7%) carried the colistin-resistant mcr genes. They ascribed this induced resistance in E. coli to the recurrent application of antibiotics in pig farms which resulted in genetic modification in E. coli.

Fig. 3.1  Adverse effects of antibacterial agents

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3.4 Antibiotic Resistance Pattern in Bacteria The antimicrobial resistance (AMR) prevalence has exponentially enhanced owing to the irrational prescription and nonjudicious application of antibiotics. In addition, lack of reliable laboratories, especially blood culture in areas very away from the hospitals also contributes to the problem. All these factors result in compromised care and resistance induction [30, 31]. The increased incidence of antibiotic resistance in human and animal pathogens has become one of the leading global concerns. Drug resistance pattern in gram-negative and gram-positive bacteria has resulted in the development of untreatable infections using the conventional antimicrobials. This is because, the early identification of causative microorganisms as well as their antimicrobial susceptibility patterns in different patients with serious infections is lacking in many healthcare units and broad-spectrum antibiotics are mostly unnecessarily used [32]. Current antimicrobial profile studies have shown that can lead to nosocomial as well as community levels infections, can become pan-resistant against different groups of antibiotics and hence, the situation has shifted toward a clinical threat [33]. Hence, investigation of resistance pattern in bacteria against various antibiotics may lead to suitable prescription of antibiotics and can also aid in halting some new resistance patterns by erasing the antibiotics having borderline sensitivity from therapeutic regimens in certain regions [34]. Reta et al. [35] provided an overview of the literature indicating the antibiotic resistance pattern of selective bacterial strains that can be obtained from various clinical samples in Ethiopia. Their database consisted of total 3459 studies and upon scrutiny on a different basis, 39 articles were shortlisted for the systemic review. The study encompassed 12 g positive and 15 g negative bacterial species along with their resistance patterns against twelve antibiotics. The resistance patterns of the isolates ranged from 0% to 100% and they concluded that total 28 bacterial samples were collected from samples obtained from different geographical areas including Mycobacterium tuberculosis. They observed that among the tested strains, most of the bacterial species were resistant against the commonly used antibiotics. Ali et al. [36] investigated the incidence rate of bacterial meningitis (BM)—an infectious disease and its resistance pattern among the population of bacteria in Quetta, Pakistan. They performed a cross-sectional study among patients suffering from BM and admitted in the government hospital in Quetta. They observed 35.9% confirmed BM cases among the population of Quetta and the identified isolates belonged to Treptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli, and Klebsiella pneumoniae. In their findings, they observed that the majority of the observed cases of BM patients belonged to rural areas having limited access to basic health facilities and paramedic staff. High-fatality rate (11%) among patients exhibited increased antibiotic resistance among the BM isolates. Similarly, Mihankhah et al. [37] investigated the bacteria related to urinary tract infection (UTI) and antibiotic resistance pattern in Northern Iran during 2013–2015. For the study, total 3798 patients were examined who were having clinical symptoms of UTI. Among individuals, almost 15% were found to be

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positive for a UTI and among them, 88% were observed to be resistant to at least one antibiotic. Furthermore, Pseudomonas and Staphylococcus spp. and E. coli were found to be predominant. These bacterial species were found to be resistant to ampicillin, methicillin, imipenem, and amikacin antibiotics. They illustrated a strong concern for emerging UTI-related multidrug-resistant bacterial strains. In gram-negative bacteria, antibiotic resistance develops owing to the enzymatic and nonenzymatic mechanisms [38, 39] and among them, enzymatic mechanisms occur by the expression of different enzymes responsible for the antibiotic inactivation whereas, nonenzymatic mechanisms are the result of gene mutations, which result in resistance development on account of alterations in the efflux pumps or membrane stability [40]. In a study, Ahmadi et al. [34] identified the Klebsiella pneumoniae and evaluated their phenotypic as well as molecular characterization responsible for resistance development against various antimicrobials. For this purpose, they collected specimens from various laboratories and hospitals in Tehran, Iran during 9-months period. Among the collected strains, 52% were found to be multidrug-resistant having the highest resistance to ceftriaxone (65%) as well as lowest was observed against colistin (23%). They concluded that increased prevalence of antibiotic resistance reflects the strong pathogenicity of the strains of K. pneumoniae. Kebede et al. [41] reviewed regarding the prevalence of gram-negative bacteria and their antibiotic resistance profile in Ethiopia by performing a web-based research using different search engines. Their collected database comprised of total 2684 studies and after careful screening, 19 articles were selected for review process. Among their selected database, Escherichia coli (10.13%) was proved to be the predominant and frequently isolated bacteria followed by Klebsiella species (9.11%). In their screened isolates, nearly 67% were found to be resistant to ampicillin. Similarly, among the isolated strains, Citrobacter, Klebsiella, and Pseudomonas aeruginosa were found to be 100% resistant for cefepime. Similarly, among other bacterial strains, Haemophilus influenzae was observed to be 100% resistant against meropenem and Salmonella species were found to be 63.64, 78.26, and 93.30% resistant to cotrimoxazole, chloramphenicol, and tetracycline respectively. They also regarded gram-negative bacteria as the most common pathogen causing infection in pediatrics, and level of resistance to commonly used antibiotics was considerably higher in Ethiopia. In another study, Ahmed et al. [42] conducted a cross-sectional examination to assess the prevalence of bacterially mediated infection in urinary tract infection patients, and to examine the resistance against antimicrobials in Lahore, Pakistan. Total 1899 clinical samples were collected, and evaluated for bacterial cultures by following the standard procedures. Identification of the isolates revealed that more than 58% strains belonged to Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and other isolates. Among them, nearly 16.93% of the S. aureus were found to be methicillin-resistant, and were highly resistant against gentamicin, fusidic acid, amikacin, tobramycin, and clindamycin. However, highest sensitivity of these methicillin-resistant bacterial strains was found against linezolid (100%) and vancomycin (100%). They reported that prevalence of this high antimicrobial resistance posed crucial therapeutic stress to the clinically

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ill persons. Silva et al. [43] studied the prevalence and pattern of AMR of the major bacterial strains involved in urinary tract infections in Portugal by collecting urine samples during a five-year period, and performing an antimicrobial susceptibility test. They observed that incidence of urinary infections predominantly occurred in females (79.6%) in comparison with males (20.4%), and among them, more saturation of elderly patients (56.9%) was observed. Among the isolated strains, Escherichia coli (70.1%) was found to be dominant followed by Klebsiella pneumoniae (8.9%). They also stated that the involvement of bacterial strain in the urinary tract infections was highly sex-dependent as Pseudomonas aeruginosa and Enterococcus faecalis were more frequent in males, and a positive correlation between the antimicrobial resistance and age of the patient was observed. In most cases, in male patients, the resistance of bacteria was statistically different from that of female patients, and in general, higher resistance was observed in males. They concluded that prevalence of resistant bacterial pathogens is the chief cause of urinary tract infections, and hence, the periodic assessment of the microbial resistance in each region is inevitable for selecting the most suited empirical antimicrobial therapy against the infections, and to avoid or decrease the resistance among urinary tract infections causing strains. Hashemzadeh et al. [44] identified the antimicrobial resistance patterns and bacteriological profiles of burn-related infections in southwest Iran by taking clinical samples from 325 burn patients and preparing their cultures. Total 287 isolates were extracted from those samples, were identified and evaluated for their antimicrobial susceptibility. Among gram-negative bacteria, Pseudomonas aeruginosa was observed to be the most frequent bacterial strain among the gram-negative bacteria having resistance against different antibiotics such as gentamicin, ceftazidime, imipenem, amikacin, and ciprofloxacin. While, Staphylococcus epidermidis was the predominant gram-positive strain and was observed to be resistant to ciprofloxacin, gentamicin, and ampicillin. They stated that due to diversified ranges of bacteria causing burn-related infections, investigation at regular intervals and diagnosis of resistance patterns in bacterial strains are needed to be ensured for determining the suitable antibiotic prognosis for proper therapy.

3.5 Therapeutic Efficacy of Nanoparticles Bacterial-based infections are a leading cause of global hospitalization where, nosocomial infections commonly trigger increase morbidity and mortality particularly, within health care facilities [45–47]. Such infections can be efficiently treated by using various antibiotic-­ based therapies as several antimicrobials have been developed with time; however, their overuse/misuse has resulted in emergence of resistance among the bacterial communities [48–51]. Development of such resistance has led to increment in the microbial virulence, increased hospitalization frequency, mortality and morbidity, and increased potential of the pathogens to evade the immune system by forming biofilms [52–54]. The natural physiological barriers of the human body hinder the conventional drug delivery and, thereby, limit the reachability of drugs to the desired tissues and organs.

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In addition, the retention as well as efficacy of these drugs in the target tissues are affected by their bioavailability, pharmacodynamic, and pharmacokinetic parameters. All these hurdles result in the development of need for higher doses and frequent administrations for obtaining effective treatment doses and hence, induce undesirable outcomes [55]. In modern-day medicine, nanotechnology has emerged as an indispensable tool for monitoring the disease and associated therapy. Nanotechnology comprises the conjugation of advanced manufacturing sciences, where any material is assembled at nanoscale meter (1–100 nm) having more surface to volume ratio [56]. Advancements in the nanotechnology have efficiently leveraged diverse areas of knowledge, i.e., tissue, chemical, and material engineering as well as nanomedicine [57]. These advancements are strictly correlated to nanometer scale of materials [58]. Nanotechnology applications for medical purposes have revolutionized the prevention, monitoring, diagnosis as well as treatment of several diseases [59–62]. Of typical interest is the development of various nano-vehicles aimed at to ensure the controlled drug delivery, which can uplift the therapeutic efficacy of these drugs with a concurrent diminution of the related toxic effects [63]. Such significant therapeutic outcomes originate only owing to the advantages associated with the use of nanoparticles, i.e., surface charge, increased specific surface area, solubility, small size, drug-loading potential, and inherent antimicrobial effects, which could exhibit synergistic effects with antibiotics [52, 59, 64]. Owing to the remarkable advancements in the nanotechnology, numerous nanomaterials have been synthesized and developed as a drug delivery system (DDS). The “Nanomaterials” have been defined as materials having dimensions ranging in nanoscale ( alumina > Fe). They also observed that the tested NPs were more efficient in suppressing the growth of gram-positive bacteria as compared with gram-negative bacteria. In addition, the NPs offer the chance to achieve stimuli-responsive delivery of antimicrobials which enhances the nanotherapeutics efficacy and decreases off-target noxiousness. The inorganic NPs demonstrate remarkable advantageous in comparison with their organic counterparts, i.e., increased mechanical strengths and excellent chemical firmness and in addition, they also exhibit tremendous biocompatibility concomitant with low-­ degradation rates [162]. The aim is to enhance the efficiency and selectivity of antimicrobials, reduce their dose as well as frequency, and avoid undesirable side effects related to unspecified drug delivery, which can be attained by active or passive targeting or both [163]. For example, gold nanoparticles (Au-NPs) have attained significant attention now a days owing to their moldable antimicrobial properties. Gold (Au) has been the point of interest in lieu of its unique antibacterial behavior against infections owing to its biocompatibility and ease in conjugation with drugs or related other biomolecules. Conjugation of Au with different drugs has promoted their antibacterial potential and at the same time, has decreased their required dose and diminished their side effects [164]. Many reported about the effect of surface modification of legends on the antimicrobial efficacy of Au-NPs [165–167]. Moreover, functionalized Au-NPs along with drug have been proved to increase the antimicrobial activity as compared to the antibiotic or drug alone [168]. Similarly, Teixeira et al. [169] used the gold (Au-NPs) and silver nanoparticles (Ag-NPs) as DDS with various antibiotics (Fig. 3.2). Administration of NPs as antibacterial material is an ingenious and cost-effective approach against a range of pathogenic bacteria [170–172]. Recently, titanium NPs have gained much importance as an environment friendly and photocatalyst owing to their diverse optical properties, low toxicity, and enhanced chemical stability [173–176].

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Fig. 3.2  Nanoparticles used in treatment of bacterial diseases

Hazardless and biocompatible behavior of TiO2-NPs increase their usefulness in biomedical applications such as in bone tissue engineering and various pharmaceutical industries [177–179]. In a study, Anbumani et al. [180] synthesized titanium dioxide nanoparticles (TiO2-NPs) by using leaf extracts of Luffa acutangula and discovered their antimicrobial properties against different bacterial strains. They observed that the prepared TiO2-NPs were significantly toxic against a range of bacterial species such as Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. They stated that TiO2-NPs possess a strong antimicrobial potential, and hence, can be used as novel antimicrobial material for curing the bacterial infections. Now a days, consideration has also been allotted to imply biological routes for synthesizing the nanoparticles [181–183]. Using the environment friendly plant materials, i.e., fruits, roots, and leaves for synthesizing the nanoparticles, delivers particular advantages on account of their harmful nature, safety as well as ecological attributes [184–187]. Biological approaches using different plant extracts have gained much popularity as compared to the physicochemical methods. Despite the fact that herbs and related medicines are of low potency than the synthetic drugs but still, they are considered to be having low side effects and less toxicity than the conventional synthetic drugs [188–191]. Using the plant extracts for synthesizing the various metal oxide nanoparticles [192, 193] owing to

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the presence of different types of beneficial phytochemicals such as flavonoids, proteins, tannins etc., which are the main factors regulating the shape and size of NPs [194]. Moreover, phytosynthesis of NPs has been enormously used owing to its biosafety and nontoxic nature [195, 196] having the ability to be efficiently used against different gram-­ positive and gram-negative bacterial pathogens [197]. Different plant species are being used for preparing the zinc oxide nanoparticles (ZnO-NPs), i.e., Aloe vera [198], Azadirachta indica [199], Pongamia pinnata [200], and Parthenium hysterophorus [201]. Phytosynthesis ensures multidimensional highly potentially active nanocrystals [202], which exhibit increased antimicrobial properties [197, 203]. In a study, Tiwari et al. [196] examined the effect of ZnO-NPs against human pathogens Staphylococcus aureus, Escherichia coli, and Salmonella typhimurium by preparing them using the leaf extract of Murraya paniculata. All the tested bacterial pathogens were found to be susceptible to the ZnO-NPs and were proved to be eminent antibacterial tools in therapeutic challenges. Due to their extensive applicability, the ZnO-NPs have been widely employed for different medicinal purposes [204] (Table 3.1). Table 3.1  Various researches about nanomedicine for antibacterial issues Type of NPs Chitosan

Drug Size (nm) Ciprofloxacin, chlortetracycline HCL

Chitosan-­coated Ciprofloxacin iron oxide NPs

30–80

Heparin NPs

250

Ciprofloxacin

Bacteria S. aureus and E. coli

Result Increased antibacterial activity of chitosan was observed and the tested NPs were found to be most affected by Gram-positive bacteria as compared to the Gram-negative bacteria Urinary tract High efficiency of and intestinal drug loading infections (99%) was observed for a sustained drug release of 5 days E. coli MTCC Enhanced 443 efficiency of drug load (35.5 ± 2.5 to 45.5 ± 3.0%) and improved antibacterial activity as compared to free drug

References [205]

[206]

[207]

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3  Nanomedicines for the Treatment of Bacterial Diseases Table 3.1 (continued) Type of NPs Chitosan/ fucoidan NPs

Drug Gentamicin

Size (nm) 270–300

pH-responsive chitosan NPs

Vancomycin

220.57

PLGA

Amikacin

447 ± 7

PLGA and PEG-PLGA di-block NPs

Tobramycin

225–231

Alginate-­ Amikacin and Alginate-­ modified PLGA moxifloxacin coated NPs PLGA NPs (640 ± 32)

Bacteria K. pneumonia

Result Increased drug encapsulation potential (91– 94%) and enhanced antibacterial activity was 1.95 μg/mL MRSA Augmented encapsulation efficiency (59.89 ± 2.33) as well as sustained drug release at normal as well as acidic physiological conditions P. aeruginosa High encapsulation efficiency (76 ± 3.8) percentage No toxicity against raw macrophages until 24 h of exposure P. aeruginosa Low encapsulation and B. cepacia efficiency (3%). Powerful bactericidal activity in comparison with the free drug and no cytotoxicity was observed in human lung epithelial cells M. Elevated tuberculosis antimycobacterial (H37Ra) activities of the dually entrapped drug-loaded NPs

References [208]

[209]

[210]

[211]

[212]

(continued)

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Table 3.1 (continued) Type of NPs Chitosan-­ dextran sulfate NPs

Drug Ciprofloxacin

Size (nm) 350

Solid lipid nanocarriers

Clarithromycin 307 ± 23

Ag-NPs

–

14.2–67.8

Bacteria Gram +ve and −ve ophthalmic microorganisms

Result Greater drug encapsulation efficiency (83%) as well as monotonous controlled release for 21 h and in addition, powerful antibacterial activity of cipro-NPs than the sole ciprofloxacin S. aureus Maximum entrapment efficiency of 84 ± 9 was observed. Moreover, cytotoxicity study confirmed their safety perspective and proved to be effective at improving the therapeutic potential of clarithromycin Inhibition zone of E. coli, P. aeruginosa, S. different bacterial aureus, and K. strains such as E. coli, P. aeruginosa, pneumoniae S. aureus, and K. pneumoniae was found to be ranging between 10,11, 10, and 13 mm. Despite, E. coli, biofilm-­ forming ability in all the other strains was lost

References [213]

[214]

[215]

107

3  Nanomedicines for the Treatment of Bacterial Diseases Table 3.1 (continued) Result Encapsulation efficiency was observed to be more than 90% and proved to be an efficient source of rifampicin delivery to the alveolar macrophages Solid lipid Furosemide-­ 129.8 ± 38.5 Pseudomonas High encapsulation nanoparticles silver aeruginosa and efficiency (~93%) Staphylococcus Drug loading (~9.3%) aureus Sustained release over 96 h Enhancement of antibacterial activity AMB-PNs Amphotericin 110 Candida The AMB B (AmB) albicans availability was tremendously improved by the applied NPs with a simultaneous decline in its toxicity and incline in the antifungal properties y3-PLGA/S + T Sparfloxacin 183.7 ± 9.4 Pseudomonas Excellent NPs and tacrolimus aeruginosa antibacterial activity against both gram +ve and −ve bacteria and efficient reduction in the inflammation and immune response in acute lung infection were observed Type of NPs Nanostructured lipid carriers

Drug Rifampicin

Size (nm) 160

Bacteria M. tuberculosis

References [216]

[217]

[218]

[219]

(continued)

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Table 3.1 (continued) Type of NPs Meropenem-­ loaded nanoparticles

Drug Meropenem

Size (nm) 243–445

Bacteria Klebsiella pneumonia

Alginate NPs

Rifampicin

–

M. tuberculosis

Result References [220] Super-high encapsulation efficiency (76.3%) of the NPs was observed while sustaining their physicochemical characteristics. Similarly, improved antibacterial potential against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae was observed Increased drug [220] payload, enhanced therapeutic efficiency, and increased PK profiles

3.8 Future Outcomes Regarding the Nanomedicine as Antibacterial There exists plethora of studies regarding the antibacterial potential of an extensive number of nanomedicine [221]. Despite the tempting advantages of NPs, the complete potentiality of nanotechnology against the bacterial-mediated infections is far from achieving administrative agencies approval and authentication. Until now, no nanomaterial has been approved by the Food and Drug administration against bacterial diseases in comparison with other diseases, i.e., cancer which is mainly ascribed to scarce knowledge regarding the mechanisms of action of nanomaterials particularly, in humans [222]. An important strategy for developing highly efficient antibacterial agent could be to conjugate various multiple antibiotics using numerous mechanistic methods to interfere with the microbial defense system and concomitant with the delivery of multiple drugs with the carrier against the same pathogen. For example, using more than one drug in a single combination for improving the efficiency of the mixture by synergizing the combined effect of drugs such as gentamicin and chloramphenicol loaded on the Ag-NPs exhibited significant antimicrobial potential in comparison with the Ag-NPs used alone when examined against

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Enterococcus faecalis related to hospital-acquired infections [223, 224]. Furthermore, improving the vascular permeability as well as retention at the infection site could play a keen role in the NPs drug delivery management [225]. In addition, biogenic NPs as well as nanomaterials coated with natural compounds belonging to animal or plant origin have demonstrated considerable antimicrobial effects that could be of remarkable future value. Moreover, new antibiotic classes, which have not been examined yet against bacteria in combination with the nanomaterials can also enhance the efficiency and can delay the process of resistance development [226].

Take-Home Message

During the long evolutionary process, bacteria have acquired various capabilities to adapt themselves against wide ranges of antibiotics, which have made it a real challenge to treat the bacterial infections within the human body. The problem is further worsened by the delay in the discovery of new novel antibiotics during the recent decades, whereas, the number of resistant bacteria continue to increase at exponential rates due to swift growth of nanomedicine in the past decade, i.e., drug delivery, PDT, PTT, catalytic therapy, etc. Nanotechnology has shown remarkable potential to be used against bacterial infections. Firstly, nanomaterials can encapsulate, deliver, and release the drugs to the microbial biofilm and lead to their accumulation in the biofilm, enhance their local concentrations, and reduce their systemic toxicity. Secondly, the rich physicochemical properties of nanomaterials have ensured tremendous opportunity for the development of novel therapeutic techniques with entirely different mechanisms for combating bacterial infections by using the antibiotics [227, 228]. Nanotechnology has supplied increased feasibility for developing therapeutic strategy with unique mechanisms, which renders high difficulty for the bacteria to evolve resistance. In addition, the versatility to manufacture nanomaterials with varying sizes, compositions, surface charges, and other properties also imparts great practical significance for developing multifunctional nanoagents with increased therapeutic efficacy.

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Further Reading Further related reading material can be found from the below mentioned sites. https://www.frontiersin.org/articles/10.3389/fchem.2020.00286/full https://www.hindawi.com/journals/jnm/2020/6905631/ https://link.springer.com/article/10.1007/s11274-­021-­03070-­x https://www.futuremedicine.com/doi/10.2217/nnm-­2019-­0371 https://www.mdpi.com/2079-­6382/10/11/1338/htm https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-­020-­00714-­2 https://www.scielo.br/j/babt/a/DdtNzrygN7WPR4CtNhKgSLc/?lang=en

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Nanomedicine in the Treatment of Viral Diseases Ammara Akhtar, Muhammad Ijaz, Fatima Batool, and Javeria Pervaiz

Contents 4.1  4.2  4.3  4.4  4.5  4.6  4.7  4.8 

Introduction  Virology  Structure of Viruses  Pathogenesis  Hinderances in Virus Entry  Prospects of Treatment of the Viral Infections  Challenges of Current Antiviral Therapy  Nanodelivery Systems  4.8.1  Lipid-Based Nano Drug Delivery system  4.8.2  Polymer-Based Systems  4.8.3  Dendrimers  4.8.4  Cyclodextrin Derivatives  4.8.5  Nanosuspensions  4.8.6  Stimuli-Responsive Nano Drug Delivery System  4.8.7  Carbon-Based Polymers  4.8.8  Gold Nanoparticles  4.8.9  Silver Nanoparticles  4.8.10  Nanocrystals  4.8.11  Nanovaccines 

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A. Akhtar · F. Batool Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan M. Ijaz (*) Department of Pharmacy, COMSATS University Islamabad, Lahore Campus, Lahore, Pakistan J. Pervaiz Institute of Molecular Biology, Medical University of Innsbruck, Innsbruck, Austria © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_4

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124 4.9  Toxic Effects of Nano Drug Delivery System  4.10  Obstacles and Challenges in the Practical Application of Nanomedicine  4.11  Nanotechnology-Based Approaches to Overcome COVID-19 Pandemic  References 

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What You Will Learn from This Chapter

In this chapter, you will learn about virus, its morphology, classification, structure, pathogenesis, and hurdles in viral invasion of host cells. The mechanisms of traditional antiviral therapies. The reasons of low efficacy of the conventional antivirals including low solubility, low permeability, adverse events, drug-drug interactions, multiple drug resistance, and incompetence to reach the target site. Different nanocarriers-­based approaches were also discussed to overcome the obstacles in conventional antiviral therapy. The lipids and polymer-based nanocarriers are discussed which have intrinsic antiviral abilities. Furthermore, nanoemulsion, nanosuspension, cyclodextrin derivative nanoparticles, dendrimers are discussed. Nanovaccines and smart nanoparticles, i.e., stimuli-responsive nanoparticles are discussed. All the nanocarriers discussed have some disadvantages as well which can be overcome with continuous research. You will learn how nanotechnology-­ based drug delivery system and diagnosis will revolutionize the traditional therapeutics and diagnostics of not only antivirals but other treatments as well. Likewise, the use of nanocarriers in eradication of SARS-CoV-2 pandemic.

4.1 Introduction Throughout recorded history, disease epidemics have plagued human civilization, including the Spanish flu of 1920 and the horrific Antonine Plague in 250, as well as the Bubonic Plague in the 1720s and the Bubonic Plague of the 1720s [1]. Although many aspects of the world have advanced, viral infections still exist and contribute to human mortality along with its numerous social expressions. Infections caused by the corona virus, nipah virus, Ebola virus, zika virus, dengue virus, chikungunya virus, and several influenzas viruses strains, including H5N1 (avian flu), H1N1, and H3N2 have all been on the rise recently (swine flu). The novel coronavirus (nCoV) has recently sparked a serious pandemic that has claimed the lives of over 210 thousand individuals to date and had significant socioeconomic effects all over the world. Nineteen Nipah virus cases—including 17 fatal ones—were reported in India in 2018 alone. Since 2001, between 68 and 100% of deaths in India have been attributed to Nipah virus infection [2]. Out of the 28,616 cases that were documented, the major Ebola virus outbreak in West Africa between 2014 and 2016 resulted in 11,315 fatalities. About 27,540 cases  of influenza were recorded in Australia in the first quarter of 2019. Even though global influenza activity has declined, different influenza virus strains have been identified in different regions of the world, with

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the seasonal influenza A virus predominating [3]. In several regions of the world over the past few years, zika virus transmission has reached epidemic proportions. The current prevalence of dengue in Southeast Asia is 17 times higher than that of other viral illnesses, driving up the cost of dengue treatment to over $950 million. Additionally, in May 2018, there were around 164,000 dengue incidents worldwide [4]. Because of this, viral illnesses have had significant economic consequences. Various environmental risks, such as water supply, sanitation infrastructure, and climate, lifestyle risks, such as smoking and alcoholism, specific geographic areas, and various medical procedures, such as blood transfusions, surgery, and transmission from vectors, among others, have all been identified as risk factors for viral infections. Aims can be made to influence the other aspects to elicit a good response, even though some of these are inescapable and steps must be taken to avoid them [3].

4.2 Virology Viruses are submicron-sized acellular infectious agents. Their genetic material is encapsulated by protein layer called capsid. The single virus can proliferate immensely, and this process always begins after infiltration of the host cell as the viruses lack the genetic code required for macromolecules synthesis and require biosynthetic machinery of host cells. Viruses are not viable outside the host and some virus can exist as, e.g., tobacco mosaic virus [5]. Viruses are classified based on the type of genetic materials and various mechanisms by which viruses interact with host cell are shown in Fig. 4.1 [6].

Fig. 4.1  Classification of viruses and mechanism of interaction of viruses with host cells

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4.3 Structure of Viruses Virus consists of two units, outer layer made up of protein which is called capsid and it protects the core, i.e., genome of virus from nucleases. The outer protein shell could be single layered or double layered and the core nucleic can either be single-stranded or double-stranded DNA or RNA. Some viruses have another layer outside the capsid called envelope which is made up of lipid bilayer and have glycoprotein spikes known as peplomers. These peplomers exhibit the antigenic function. The genome and capsid arrangement decide the symmetry of the virus. Viruses have two types of symmetry: helical and icosahedral symmetry. In helical symmetry, capsid is arranged in helical fashion around the nucleic acid and in icosahedral symmetry, the capsid protein is arranged in geometric shape having 20 side and each side consists of equilateral triangle which envelopes the nucleic acid [5].

4.4 Pathogenesis The pathogenesis began with the entry of the virus in the host cell by adsorbing at the host cell surface. The virus can enter the host cell through disrupting the cell membrane or by endocytosis, called penetration. This invasion of the virus in the host cell is mediated through different receptors. The next step is taking over the biosynthetic machinery of the host cell and DNA virus owing to structural similarity to the host genetic material incorporate into the host DNA and use the host cell biosynthetic machinery for replication. After that translation of different viral protein starts and after replication, the viral components are packaged together and new virus is released by induction of cell lysis or apoptosis, this is termed as lytic pathway. The viral envelope is made of host cell as the virus bud out of the cell. This cycle is repeated and thus the proliferation of virus happens. Some viruses remain in latent stage in the cases of long-term infection. The virus remains dormant by using episomes or incorporation into host genome. In this state, the viral material remains in the cytoplasm and large reservoir of viral genome is developed, the activation takes place by the mixture of external and internal stimuli, this process is termed as lysogenic pathway [7].

4.5 Hinderances in Virus Entry The viral invasion in host cell is receptor mediated and different viruses have affinity for specific host cells owing to presence of glycoprotein on the outer shell of the virus. Thus, the specific virus infects the specific host cell and tissue. Many natural mechanisms exist in human physiology that block the viral invasion such as respiratory track blocks the entry of foreign particles with the help of the thick mucus layer present in lumen, the trapped viruses get either engulfed or coughed out. Another mechanism by which respira-

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tory track is secured is the presence of Nasal-associated lymphoid tissue and Bronchi-­ associated lymphoid tissue. Nevertheless, the respiratory track most commonly acts as the passageway of viral entry. The gut is protected by acidic pH of stomach, digestive enzymes, thick mucus layer, pancreatic juice, and bile. Additionally, B lymphocyte secrete Immunoglobins A in gastrointestinal track and Mucosa-associated lymphoid tissues also provide further security. The viral entry still occurs via oral route. Another site of viral entry is skin, it acts as a physical barrier owing to presence of thick stratum composed of keratin, furthermore lymphatic system provides extra resistance in viral entry. Eye specifically conjunctiva is another source of viral entry which is not that well protected, but it is frequently cleaned from lacrimal secretions and blinking of eyelids. Genitalia is also a route of viral entry and transmission and causes various sexually transmitted viral diseases. Entry of virus in brain is hindered by blood–brain barrier (BBB) by closely knitted endothelial cells, pericytes and astrocytes projection, and microglial cells. Virus crosses the BBB dissemination of endothelial cells due to inflammation or transfer across the cribriform plate to brain by entry into olfactory endothelium [8].

4.6 Prospects of Treatment of the Viral Infections The life cycle of the virus gave clues to develop various antiviral therapies. The antivirals developed either disrupt different steps of pathogenesis or target different viral components. The approved antivirals halt the viral replication by inhibiting the viral DNA polymerase, reverse transcriptase, or proteases. Many drugs used against HIV such as lopinavir inhibit reverse transcriptase of the virus. Some antivirals impart their action by disrupting the structure, i.e., some drugs rupture the envelope of the virus halting the adsorption of virus to the host cells, C5A peptide known to disrupt the envelope of hepatitis C virus by converting the envelope to planer bilayer. Blocking the entry of virus into host cell can also be achieved by passive immunization by identifying the antigenic surface of enveloped virus or the virus fused to the host cell. This is accomplished by the development of monoclonal antibodies against different virus such as Ebola virus, zika virus, HIV, etc. Preventing the spread and stopping the propagation can be very effective in eradicating the infection which is done by stopping the assembly and cleavage of new virions through inhibition of the protease enzyme. Many drugs against HIV prevent spread of the virus by inhibiting the protease enzyme such as indinavir. Viruses tend to become latent by developing the reservoirs in the host tissues. Moreover, host remains asymptomatic as the virus in latent stage. So, the approach is used for eliminating the reservoir by reactivating the virus, e.g., HIV reservoirs are reactivated by interleukin-­15 super agonist. Viruses are known to induce inflammatory reaction which may result in cytokine storm and this process can be life-threatening. This cytokine storm is life-threatening and can be seen beforehand in the infection caused by influenza virus and nowadays in COVID-19. These inflammatory reactions can be reduced by immunomodulators such as thiazoli-

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dines. The other mechanism to lower the inflammation is through antioxidants by reducing reactive oxygen species but antioxidant alone is not effective against cytokine storm, so antivirals are coadministered. Other therapeutic approach is using tumor necrosis factor which captures the cytokine and reduces the inflammatory reactions [9].

4.7 Challenges of Current Antiviral Therapy Despite the continuous efforts of researchers, there are certain challenges associated with antiviral therapies. Foremost, drug resistance is the major challenge. The monotherapy against the virus will surely result in drug resistance to overcome this combination of drug is employed but still if the all the drugs in multidrug therapy belong to same class resistance could develop as the virus continues to evolve through mutation in target proteins, efflux of drugs, enzymatic degradation, under expression of target proteins, and prodrug not being converted into active drug [3]. Additionally, limited drugs are available for pediatric use. The lamivudine, a resistance observed against Hepatitis B virus only after 6-month exposure [10]. Broad-spectrum drugs are not much effective as the steps in viral pathogenesis are limited. The new drug discovery and development for the specified targets are expensive and time-taking alternative; therefore, modifying the current therapies seems more advantageous [8]. The other hindrance is low permeability and solubility of many antiviral drugs such as Acyclovir and ganciclovir. This results in lower efficacy and less concentration available at site of action. Increasing dose and frequency of dosing may result in increased risk of adverse events [11]. Another disadvantage is short half-life and extensive metabolism in which also low efficacy of the drug and the oral route of administration are not feasible to deliver drug to distant sites as by this route, the drug further undergoes first-pass effect and metabolism in the gastrointestinal tract. Due to shorter half-life, it is difficult to manage the missed doses. The severe drug-drug interaction and organ toxicity are also associated with antiviral therapies [8]. The problems like site specification, viral mutation, targeting the latent viral reservoir are not addressed by current antiviral therapies and nanoparticles can be helpful to overcome these challenges effectively [8].

4.8 Nanodelivery Systems Nanodelivery system is very promising in overcoming the difficulties being faced while treating the viral infections including the crossing the blood–brain barrier (BBB), targeting the specific site such as lymph nodes, lymphoid tissues, macrophages, liver, vagina, etc. Furthermore, many antiviral treatments are in oral dosage form and have various disadvantages like gastric degradation, inadequate solubility, inadequate permeability, and

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short gastric residence time. Moreover, the conventional antiviral treatments are inadequate as they lack targeted drug delivery, face fast viral resistances, have high elimination rate, and produce high toxicity. Besides, the development of new and innovative antiviral are very time-consuming and very perilous. The research on nanomedicines may help to overcome these problems and can combat the virus infection in efficient manner [12, 13]. Nanodelivery system not only heightens the bioavailability and solubility but also they can act as an antiviral agent through different mechanisms [3, 12]. The definitive advantage of nanotechnology is improvement of pharmacokinetic profile and bioavailability of drugs along with prolonged therapeutic action. Nanotechnological approaches improve the half-life of hydrophobic drugs and made the administration of hydrophobic drugs easier. Other advantage is decreasing the systemic exposure of locally administered drugs. The stimuli-responsive delivery system, targeted delivery system increasing the concentration of drug at the target site. Nanoparticle size ranges are also favorable for interacting various biological substrates. Other than that, nanoparticles’ decoys interact with virus directly and halt mobility and fusion of the virus. These decoys have size more than 10 μm and can move freely in the body [9].

4.8.1 Lipid-Based Nano Drug Delivery system The majority of antiviral delivery systems currently available on the market use polymers, but due to their inertness, biodegradability, absence of immunological side effects, nontoxicity, and affordability, lipid-based methods have some benefits over those [14]. Moreover, value of lipid-based nanomedicines is further enhanced owing to the distinctive properties of lipids such as high capacity of drug of loading, smaller size, improved interface interactions, larger surface area, and controlled release [15]. Furthermore, lipids proved to have enhanced pharmacokinetic profile, improved efficacy owing to its accessibility to previously inaccessible sites and lower incidence of adverse effects [16]. Most used lipids comprised of triglycerides, lecithin, fatty acids, and glycerol palmitostearate. The lipid-based Nano Drug Delivery system consists of liposomes, solid lipid nanoparticles (SLN), nanostructure liquid carriers (NLCs) nanoemulsions, self-nanoemulsifying drug delivery systems (SEDDS) [17].

4.8.1.1 Liposomes Liposomes are vesicular system that have the capacity to incorporate both hydrophilic and lipophilic drugs, this unique property is due to its structure as it is composed of bilayer phospholipid encapsulating the aqueous core. The size of the liposomes ranges from 15 to 1000 nm [18]. There is extensive research available on liposomes and doxorubicin-loaded PEGylated liposomes have been approved for cancer treatment by FDA in 1995. Also, due to high accumulation of liposomes in liver, makes it an exceptional drug delivery system for the treatment of liver-related diseases such as Hepatitis C [19]. When the liposomes enter bloodstream, the plasma opsonin attaches to liposomes which make them susceptible

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for macrophage uptake, this mechanism is helpful to deliver the drugs against HIV virus which infiltrate macrophage. Besides, macrophages travel to infectious sites and assist the delivery of drug from the entrapped liposome, this type of drug delivery system is known as Trojan Horse [20]. The macrophage uptake of liposome is key mechanism to reach the target site which is dependent on shape, surface charge, and size of liposome [21]. Ligands like mannose, galactose are both cationic and anionic, when attached to liposomal surface, target lecithin receptors of macrophages and the infiltration of lymph nodes and spleen is enhanced [22]. Cationic ligands include chitosan and stearyl amine. The charged liposomal have increased efficacy as compared to conventional liposomes [23]. Crossing blood– brain barrier is another challenge, magentoliposomes have been developed using 3′-azido-3′-deoxythymidine-5′-triphosphate which indicated threefold increase in penetration of blood–brain barrier in  vitro without affecting the integrity of BBB [24]. The methodology used for preparing liposomes includes solvent dispersion method, active and passive loading, detergent removal method, mechanical dispersion method, freeze-drying method, membrane contactor technology, cross flow filtration, and dual asymmetric centrifugation [25] . Liposomes might be a very good candidate to deliver antiviral but it has certain limitations including physicochemical instability, low efficiency of encapsulation, very expensive production, and quick elimination [26].

4.8.1.2 Niosomes Niosomes are another vesicular system with same advantages as biodegradability, better bioavailability, targeted delivery, and low toxicity but no such limitation as liposomes. The phospholipids’ bilayer is replaced with nonionic [27] surfactant and niosomes also have ability to encapsulate both hydrophobic and hydrophilic drugs. There is no research done to incorporate antiviral drugs into niosomes. Moreover, segregation of niosomes is toxic [28]. Table 4.1 shows the incorporation of antiviral drugs in liposomes to achieve better outcome of the therapy. 4.8.1.3 Solid Lipid Nanoparticles Solid lipid nanoparticles (SLNs) are made up of lipids which are solid at body temperature such as triglycerides, fatty acids, waxes, and steroids. SNLs are colloidal disperse system with size range of 10–1000 nm [34]. SLNs can successfully overcome the physiological barrier such as gastrointestinal degradation, and other presystemic and enzymatic degradation. SLNs provide sustain release of the drug with fast onset of action. Along with that, SLNs provide targeted delivery, enhanced tissue distribution, increased stability, low toxicity, and improved loading capacity [35, 36]. SLNs have properties of liposomes and fatty emulsion and an excellent vehicle for delivery of lipophilic drugs [37]. The mechanisms by which SLNs deliver drug are passive targeting and receptor-mediated endocytosis [38]. The preparation of SLNs can be achieved by solvent emulsification, ultrasonification, high-pressure homogenization, fluid extraction of emulsion, supercritical-assisted injection in liquid antisolvent, and spray-drying. SLNs are stabilized with emulsifiers or surfac-

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Table 4.1  Liposome-based antiviral treatment Virus/viral disease Retrovirus/ murine-­acquired immuno-­deficiency syndrome CMV retinitis and acute retinal necrosis (ARN)

Nanocarrier type Liposomal encapsulation

Incorporated drugs

Liposome

Ganciclovir

HIV

Anti-HLA-DR Indinavir immunoliposomes

HIV

Stealth anti-CD4+ Nevirapine and conjugated saquinavir immunoliposomes Gelatin liposomes Stavudine

HIV

3′-azido-3′deoxythymidine/ zidovudine (AZT)

Outcome Better in reducing plasma reverse transcriptase activity than free AZT Achieve therapeutic level in rabbit after 28 days and no repeated intravitreal injection is required along with no observed toxicity 126-fold increase in accumulation and penetration into lymph nodes which are the primary HIV reservoir without affecting the efficacy of the drug Fourfold reduction in p24

References [29]

[30]

[31]

[32]

Enhanced targeting of [33] reservoir sites and limits residual viremia

tants such as fatty acid coester, lecithins, polysorbates, bile salts, and poloxamers, and the drug loading, drug release, and size and stability of SLNs depend on these emulsifier and surfactants Also, SLNs can be scale up on industrial level. The intrinsic low loading of SLNs caused by the crystalline lipid structure and unpredictably high-gelatin propensity are the main drawbacks [39]. These drawbacks are overcome by nanostructure liquid carriers (NLCs) which are considered second-generation SLNs. They have improved capacity of drug loading with enhanced controlled release and have ability to attain targeted drug delivery by surface modification [40]. Table 4.2 shows the incorporation of antiviral drugs and solid lipid nanoparticles to achieve better outcome of the therapy.

4.8.1.4 Nanoemulsions Nanoemulsions may appear as a single-phase system, but it is biphasic system and is thermodynamically unstable consisting on water oil, surfactants, and cosurfactants. The size of disperse globules ranges from 50 to 500 nm [45]. The oil phase contains lipids like triglycerides, edible oils such as soybean oil, castor oil, peanut oil, etc. [46]. Nanoemulsions can increase the solubility, absorption, and bioavailability of lipophilic drugs to many

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132 Table 4.2  Solid lipid nanoparticles-based antiviral treatment Virus/viral disease Chronic hepatitis B, chronic hepatitis C, condylomata acuminata Hepatitis B

HIV

HIV

Nanocarrier type SLNs

Incorporated drugs Yak alpha interferon

SLNs

Adefovir & dipivoxil

CD4-targeted PEGylated SLNs NLCs

Indinavir

Saquinavir

Outcome Controlled release for 16 days with same efficacy and minimum toxicity

References [41]

Improved antiviral efficacy and showed time- and dose-dependent reduction of DNA and antigen level hepatitis B virus Efficient targeting CD4+ and improved drug delivery

[42]

Improved transport of drug across Caco-2 cell monolayers. Improved oral delivery system

[44]

[43]

folds. Additionally, oral nanoemulsions provide prolong GIT retention time. Nanoemulsions also have high loading and like other nano drug delivery system provide targeted delivery via reticuloendothelial uptake (macrophage depot) [47]. This attribute can be enhanced by using cationic lipids such as chitosan, stearyl amine, etc. PEGylating the nanoemulsions lowers the reticuloendothelial uptake from the blood stream and increases the half-life of nanoemulsions [48, 49]. The nanoemulsions can be useful in decreasing the drug efflux, improving the drug release profile, and for better brain penetration [50]. Another advantage of nanoemulsions is lack of sedimentation owing to small globule size and increased surface energy and Brownian motion [51]. Table 4.3 shows the incorporation of antiviral drugs and nanoemulsions to achieve better outcome of the therapy.

4.8.1.5 Self-Nanoemulsifying Drug Delivery Systems Self-nanoemulsifying drug delivery systems (SNEDDS) are more stable than nanoemulsion as the emulsification process occurs in situ [56]. SNEDDS can be also helpful in solving the solubility and permeability limitation of BCS class IV drugs without affecting efficacy [57]. SNEDDS are monophasic, thermostable, and contain oil, water surfactants, and emulsification occurs spontaneously with gentle stirring [56]. The importance of this delivery system increased with the successful clinical trials of two anti-HIV drugs Saquinavir and Ritonavir available as ortovase® by Roche Pharmaceuticals and Norvir® by Abbott Laboratories, respectively.

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Table 4.3  Nanoemulsions-based antiviral treatment Virus/viral disease HIV

Dengue virus (DENV)

Herpes simplex virus HSV-1 (strain 29R) HIV

Nanocarrier type Lipid nanoemulsion

Incorporated drugs Outcome Darunavir Improved BBB crossing and higher bioavailability in brain which is one of the main HIV reservoirs with oral administration Nanoemulsion Curcumin Improved physiochemical properties of curcumin. Furthermore, enhanced cellular uptake and effectively reduced growth of both DENV-1 and DENV-2 Cationic Genistein Increased retention of drug in nanoemulsions mucosa with no effect in the efficacy of genistein Nanoemulsion

Saquinavir

Higher brain penetration with intranasal nanoemulsion in comparison to intravenous saquinavir

References [52]

[53]

[54]

[55]

4.8.2 Polymer-Based Systems Polymeric-based nanodelivery system used polymer of natural, semi-synthetic, and synthetic origin to develop nanocarriers. They can be modified in such a way that drug can be released in response to pH, rapidly oscillating magnetic field, any heat source, and chemical stimuli [58]. The advantages include targeted drug delivery, improved efficacy, and decreased drug efflux. Whereas the limitations include high-production cost and low biocompatibility [17].

4.8.2.1 Polymeric Nanoparticles Polymeric nanoparticles have better drug loading and stability than liposomes. These are the colloidal in nature and size is below 500 nm and comprise of biocompatible matrix made up of either natural or synthetic polymer [59]. Polymeric nanoparticles are made by solvent evaporation, salting out, dialysis, emulsion-diffusion evaporation, coacervation, phase inversion method, ionic gelation, and interfacial polymerization [60]. Polymeric nanoparticles can be nanocapsules or nanosphere depending on the entrapment of drug. Nanocapsules have size less than 300 nm and entrap drug in the aqueous core [61]. While, nanosphere size ranges from 10 nm to 200 nm and have drug adsorbed on the surface or entrapped in the matrix [62]. The natural polymer being used in the manufacturing includes, chitosan, gelatin, dextran, alginate, etc. The synthetic polymers being used are polylactide–polyglycolide copolymers, poly(lactic-co-glycolic acid) (PLGAs), polylac-

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134 Table 4.4  Polymeric nanoparticles-based antiviral treatment Virus/ viral disease HIV

VZV, HZV, HSV HIV

HIV

Nanocarrier type Incorporated drugs Conjugated anti-CD4 Saquinavir antibody to the surface of polymeric nanoparticle (PLGA) Polymeric nanoparticles Acyclovir

Polymeric nanoparticle Efavirenz (poly(epsilon-­ caprolactone) (PCL)) Polymeric nanoparticles Combination of (PLGA) ART drugs (lopinavir, efavirenz, and ritonavir)

Outcome Twofold-enhanced CD4+ targeted drug delivery hindering the HIV infection of vaginal tract Intracellular drug delivery, sustained drug release, and higher efficacy Controlled drug release, increased oral bioavailability Controlled release for 28 days, enhanced bioavailability, and no sign of toxicity

References [66]

[67]

[68]

[69]

tides (PLAs), polycaprolactones (PCLs), and polyacrylates (PCAs), where most used polymer is PLGAs [63]. The benefits of polymeric nanoparticles are site targeting, controlled release, low toxicity, protection of drug molecule from degradation, and their capability to be theranostic [64]. They are an excellent option to deliver antiviral drug to HIV reservoir sites like brain and lymphatic nodes owing to its ability to target monocytes and macrophages [65]. Table  4.4 shows the incorporation of antiviral drugs and polymeric nanoparticles to achieve better outcome of the therapy.

4.8.2.2 Polymeric Micelles Polymeric micelles are colloidal nanostructures having size usually between 10 and 100 nm. They contain block copolymer which is amphiphilic, where each monomer has lipophilic and hydrophilic part and these monomers assembled through chemical conjugation into micelles when critical micelle concentration is reached [70, 71]. The core incorporates lipophilic drugs and the outer hydrophilic shell makes the system stable by reducing surface free energy and keeps the drug protected from degradation and plasma protein and reticuloendothelial interactions [72]. The system provides high drug loading with minimal early drug release. The micelles can be functionalized by attaching ligands to the surface to achieve targeted drug delivery [70, 73]. They also support stimuli-based drug release, micellar antiviral drug responding to pH is 24 fold more effective in reducing the cytotoxicity, DNA replication, and viral antigen expression. Poly-(N-­ isopropylacrylamide) and poly(methacrylic acid) are the polymers used to make pH- and temperature-sensitive micelles [74]. The preparation methods include solution casting method, solvent extraction method, and dialysis [75].

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Table 4.5  Polymeric micelles-based antiviral treatment Virus/viral disease HIV

HIV

HBV

Nanocarrier type Polymeric micelles of different poly(ethylene oxide)-poly(propylene oxide) (PEO-PPOs) block copolymer Chitosan-g-poly(N-­ isopropylacrylamide) polymeric micelles with thermo-responsive and mucoadhesive properties Stearic acid-g-chitosan oligosaccharide polymeric micelles

Incorporated drugs Outcome Efavirenz Oral bioavailability improved by threefold

References [76]

Indinavir

Improved aqueous [74] solubility by 24 fold and enhanced drug residence time

Lamivudine

pH-responsive drug release, reduce HBV DNA replication, and antigen expression with minimal toxic effects Sustain release of drug, targeted drug delivery

Influenza A Polymeric micelles prepared Amantadine from poly (l-lactic acid)-b-­ poly(ethylene b-PEG)-mRNA diblock copolymer

[77]

[78]

Table 4.5 shows the incorporation of antiviral drugs and polymeric micelles to achieve better outcome of the therapy.

4.8.2.3 Polymer-Drug Conjugates Polymer-based drug conjugates consist of covalently bonded drug and a polymer. This help to improve the efficacy and plasma stability of drug, also provide safe targeted drug release. Polymer conjugates with antiviral, themselves have antiviral tendency, thus act synergistically with the drug. Interferon α2A is conjugated with polyethylene glycol to have better efficacy against HCV. Polymer-containing salic acid imparts their antiviral effect by inhibiting the viral entry. Negatively charged polymers have tendency to block HIV entry in the cells, the polymers include dextran sulfate, keratin sulfate, heparin sulfate, glycosaminoglycans, etc. [3]. Albumin was conjugated with N-(2-hydroxypropyl) methacrylamide (PHPMA) polymer and ART drugs to achieve residence time and lymphatic accumulation, thus delivering right proportion of drug and providing better protection from HIV than the individual ART drugs [79]. 4.8.2.4 Hydrogel-Based Nanocarriers Hydrogel consists of network of cross-linked polymers which can swell. The linking is topological, and they have tendency to absorb the fluid and swell up. The polymers used are biocompatible, have high drug-loading capacity, and provide controlled drug release. The nanogels have larger surface area and surface modification with various ligands and provide targeted drug delivery. Hydrogels are being under research to develop the formu-

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Table 4.6  Hydrogel-based nanocarriers’ polymeric nanoparticles-based antiviral treatment Virus/viral disease Herpes simplex viruses (HSV) HSV-2

HSV

HSV

Nanocarrier type Chitosan/xanthan gum-based hydrogels AgNPs-based mucoadhesive hydrogel PLGA NPs fused in carbomer hydrogels Vesicle-integrated hydrogel

Incorporated drugs Acyclovir

Outcome References pH-responsive controlled [80] drug delivery, enhanced apsorption, and bioavailablity

Tannic acid

Efficiently treat HSV-2 genital infection

[81]

Cymbopogon citratus volatile oil Acyclovir

42 fold in inhibition of virus

[82]

Topical HSV infection treatment, less frequent application, and minimal adverse effects

[83]

lation to deliver the antivirals to treat neuro-AIDS and transvaginal antiviral nanogels are being explored to decrease the STDs transmission with prolong efficacy [13]. Nanolipogels are the hydrogels combined with liposomes through UV-induced gelation. It has excellent drug entrapment and provides control release of drug and topical nanolipogel under research for HIV infection prophylaxis [13]. Table 4.6 shows the incorporation of antiviral drugs and hydrogel-based nanocarriers to achieve better outcome of the therapy.

4.8.3 Dendrimers The word Dendrimers derived from a Greek word meaning “tree-like.” Dendrimers have unique, well-defined, 3D architecture and are called novel polymers. They have tendency of being microbicide and owing to its low polydispersity and high molecular uniformity, a good candidate to develop Nano Drug delivery system. The size is between 2 and 10 nm and has core and outer shell having multiple functionalities. The shape or 3D configuration, solubility, and reactivity of dendrimer depend upon subunits in the core, while increasing functions at surface make dendrimer bulkier and even globule like. The core has voids that can entrap guest molecule. They have similarities with vesicular system like liposomes as they can entrap molecules in its core and also have similarities with micelles and globular proteins (having inner recognition groups “endoreceptors” and outer groups known as “exoreceptors”). They are synthesized with divergent or convergent approach, through click or lego chemistry. Hydrophobic drug is entrapped inside, and the hydrophilic drug attaches covalently to surface ends. Poly amido amine is the first family of dendrimers, while other widely used dendrimer includes poly-propylene imine (PPI), and Poly-l-lysine dendrimers (PLL) [84]. The dendrimer that has anionic groups on surface

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halts viral replication [85]. The FDA-approved PLL dendrimer which is functionalized with naphthalene disulfonate is invention of star pharmaceuticals and named VivaGel that have microbicide effects along with that it prevents transmission of STDs including HIV.

4.8.4 Cyclodextrin Derivatives Cyclodextrin (CDs) is cyclic oligosaccride, they are synthesized from hydrolyzed starch by enzymatic reaction. CDs contain 6–12 α-1,4-linked cyclic α-d-glycopyranose monomers. They have unique toroidol shape, where inner surface is hydrophobic while the outer surface is hydrophilic owing to presence of –OH groups. Commonly used cyclodextrins are alpha, beta, and gamma cyclodextrin containing varying number of glycopyranose units. They have hydrophobic cavity that can entrap the molecules based on geometry and polarity of the molecule. CDs make inclusion complexes with wide range of lipophilic organic and inorganic drugs and β-cyclodextrin owing to its easier manufacturing and safety. CDs improve the stability, bioavailability, and solubility. Additionally, it is good antiviral as it destroys protein or lipid outer shell of virus. It can stabilize the vaccines and act as a polyvalent antigen vector and antibody stabilizer [86, 87]. Table 4.7 shows the incorporation of antiviral drugs and cyclodextrin derivatives to achieve better outcome of the therapy.

4.8.5 Nanosuspensions Nanosuspension is biphasic disperse system with size range between 10 and 100 nm, the two phases could be solid in liquid or solid in semi-solid. The disperse phase is nano-sized drug or mixture of drugs. The nanoparticles of nanosuspensions can be integrated to solid matrix by spray-drying of lyophilization [91, 92]. Nonsuspension can carry hydrophilic drugs and overcome the cellular barriers easily and have time-dependent drug release [92]. Table 4.7  Cyclodextrin derivatives-based antiviral treatment Virus/ viral disease HSV-1

RSV

HIV

Nanocarrier type β-cyclodextrin-poly(4-­ acryloylmorpholine) conjugate nanoparticles β-cyclodextrin-­ functionalized with graphene oxide β-cyclodextrin complexes

Incorporated drugs Acyclovir

Curcumin

Efavirenz, saquinavir

Outcome Enhanced efficacy, minimal toxicity, and sustained drug release High efficacy, inactivation of virus, preventing viral attachment. Can be used therapeutically and prophylactically Improved solubility and physiochemical properties

References [88]

[89]

[90]

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138 Table 4.8  Nanosuspensions-based antiviral treatment Virus/viral disease Retrovirus

Nanocarrier Incorporated type drugs Nanosuspension Nevirapine

HIV

Nanosuspension Rilpivirine and cabotegravir

HIV

Nanosuspension Ritonavir, lopinavir

HBsAg, HBeAg, and HBV-DNA

Herpetrione

Outcome Improved cellular uptake, targeted drug delivery to main virus reservoir like lung, spleen, thymus Phase II trials for long-acting injectable formulation for prevention and treatment of HIV infection Intranasal route of administration and low-particle size provides enhanced brain bioavailability Enhanced oral bioavailability, dissolution, and absorption in GIT

References [95]

[96]

[97]

[98]

The targeting of the specific site can be achieved by surface modification and is good candidate to carry antiviral drugs. Nanosupension can be formulated into oral, ­intramuscular, intravenous or pulmonary delivery system [93]. Oral nanosupension can protect the gastric destruction and first-pass effect and also due to the submicron size targeting the colon mucosa [94]. Nanosuspension is prepared by various processes including high-­pressure homogenization, super-critical fluid method, using emulsion or microemulsion as a template and precipitation. Table 4.8 shows the incorporation of antiviral drugs and nanosuspension to achieve better outcome of the therapy.

4.8.6 Stimuli-Responsive Nano Drug Delivery System Stimuli-based nanocarriers can release drug on the stimulus that can be change in pH, electric pulse, temperature, magnetic field, enzyme concertation, etc. [99]. The nanoparticles are being developed to respond to the stimuli of semen, enzymes, temperature, and magnetic, the purpose of this delivery system is to prevent HIV infection. Eudragit® S100 is tenofovir containing stimuli based  vaginal formulation, drug release is  linked  to the changes in vaginal pH during transvaginal ejaculation [100].

4.8.7 Carbon-Based Polymers Carbon-based polymers are effective way to improve the antiviral therapy as the cytotoxicity is lower and alteration of the properties for specific functions is easier using this approach. This includes grapheme, fullerenes, and carbon dots (C-dots) [101].

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4.8.7.1 Grapheme Oxide Grapheme oxide is derived from graphene and is nanosized having high surface area and electrical charge. It is being explored for cancer therapy, cellular imaging, and drug delivery. The antiviral effects are due to its sharp edges as it destroys the virus before invading the host cells. It also interacts electrostatically with the viruses. Moreover, it also causes photodegradation of viruses and mimics the cell surface and when the viruses attached to these false surfaces, the magnetic nanoparticles released inactivating the virus through infrared radiation. Hypercin loaded onto grapheme oxide proved to be more advantageous and produces less cytotoxicity [101]. 4.8.7.2 Carbon Dots Carbon dots (C-dots) is newly discovered approach, and it consists of amorphous carbon nanoparticles, amorphous fluorescent polymeric nanoparticles, graphitized core carbon nanoparticles, and grapheme quantum dots (GQDs). Owing to the functional groups attached to the surface of each C-dot can be used as an antiviral. Bromic acid C-dots observed to be effective against herpes simplex virus type 1. It prevents virus and host cell interactions and cytotoxicity is minimal. Similarly, anhydrous citric acid enhances C-dots effective against HIV-1 through inhibition of hydrogen bonding which subsequently causes inhibition of host cell and viruses’ interactions [101]. 4.8.7.3 Fullerenes Fullerenes are discovered in mid of 1980s. Fullerenes specifically block the HIV protease proteins and diamido diacid diphenyl fulleroid is developed for the same purpose. The cytotoxicity of fullerenes is low, but the disadvantage includes low solubility which can be overcome by surface modification by attaching alkali metal salts. The synthesis of fullerenes become more complex by metal salt attachment. Fullerenes have photosensitive properties and inactivate the virus by photodynamic process. This increases the toxicity of fullerenes and the low solubility becomes an advantage now as the removal from the body becomes easier. The fullerenes are being explored against different viruses including Herpes Simplex Virus, human cytomegalovirus, H1N1, Zika virus, hepatitis C virus, and dengue virus [101].

4.8.8 Gold Nanoparticles Gold nanoparticles are nontoxic and colloidal nanocarriers for drug delivery. Their surface to volume ratio is huge and their characteristics can be tailored. Owing to the free electrons, it possesses optical properties. Gold nanoparticles have capabilities to reach the HIV reservoirs such as endothelial cells of brain, lymphocytes, and macrophages. Raltegravier linked with gold nanoparticles showed inhibition of HIV replication. Another advantage of gold nanoparticles was explored which had shown virus was being deformed due to

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attachment of gold nanoparticles to the viral ligands and deforming the virus with generation of strong force. This antiviral mechanism is effective against number of viruses including RSV, HPV, RSV, and dengue virus. Gold nanoparticles have very minimal toxicity and can be effective to reduce the toxicity of certain drugs such as acyclovir. The gold particles essentially inhibit the viral attachment and subsequently viral penetration [102].

4.8.9 Silver Nanoparticles Silver nanocrystals possesses intrinsic antiviral activity due to its certain properties that consist of high chemical stability, localized plasma resonance, and high conductivity. They undergo rapid dissolution owing to their enormous surface area [103]. The size range of silver nanoparticles is between 1 and 10 nm and due to their small size, they effectively inhibit the viral pathogenesis by incorporating in place of sulfur and oxygen in thiol and phosphate groups of proteins or nucleic acid and amino acids. This process is effective against HIV-1 as the reverse transcriptase reduced which results in a smaller number of viral copies being produced [104]. Silver nanoparticles are also used as surface decoration, e.g., silver nanoparticle-coated oseltamivir inhibited the surface adsorption of H1N1 virus on the host cells [105].

4.8.10 Nanocrystals Nanocrystals size ranges from 100 to 1000 nm and are not true nanocarriers. The pure drug is converted into nanocrystals by precipitation or pearl milling technique, these nanocrystals are stabilized with surface active agents and then converted into suitable drug delivery systems such as tablets [106]. The nanocrystals based on Carbon-60 along with H5 protein and its derivatives including H5N, H5V, and H5Y were developed, and the initial antiviral activity was not impressive but after enhancement with nitric acid and trimaseic acid, the number of carboxylic group and antiviral activity increased substantially [107].

4.8.11 Nanovaccines In last few years, nanocarriers are being integrated into the vaccine development. The conventional vaccines have disadvantages mainly activation pathogenic of virulence in live attenuated vaccine and inadequate immune response and fractional immunization with inactivated and subunit vaccines, respectively. The nanovaccines not only address these obstacles but also provide better immunization by protecting the basic structure of antigen and increasing immune cells and antigen exposure duration. The antigens can be integrated into nanocarriers via conjugation and encapsulation [108]. Nanocarriers themselves stimulate immune response by acting as an adjuvant against the antigen [109]. The nanocarriers integrated with particular viral antigen have specific size, shape, and surface

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charge which can be recognized by specific antigen presenting immune cell for producing targeted and strong immune response [108, 110]. Nanovaccines are used in prophylaxis of infectious diseases, and in therapeutics for the treatment of cancer and many other diseases like Alzheimer’s and hypertension [109]. Many nanovaccines are FDA-approved and are being marketed. Vaxfectin® is liposomal-­based anti-influenza nanovaccine. Inflexal® is another anti-influenza vaccine prepared from virosome-based trivalent subunit. Cervarix® is prepared from virus like particles and protects from cancer-causing strains of HPV. Epaxal® is virisome-based vaccine containing inactivated Hepatitis A and used for prophylaxis and provides long duration of protection [3]. Various nanocarrier-based vaccines are in clinical trials including HIV IM nanovaccine which is in phase 1 trial under clinical trial code NCT03408262 and NCT03934541. Vaxisome is another cholesterol-based liposomal nanovaccine under phase 2 of clinical trials and is effective against influenza. There are multiple vaccines including Fluzone® vaccine, Ebola Virus Glycoprotein (GP)-Matrix M1™ adjuvant, RSV-F protein, RABV-G Protein, SARS-CoV-2 rS vaccine, SARS-CoV-2 rS/Matrix-M Adjuvant, SARS-CoV-2 Recombinant Spike Protein (SARS-CoV-2 rS) With Matrix-M1™ Adjuvant effective against influenza, Ebola, Respiratory syncytial virus, rabies and COVID-19, respectively. These vaccines either contain liposome or nanoparticles as nanocarriers and currently in phase 1 or phase 2 of clinical trials [8].

4.9 Toxic Effects of Nano Drug Delivery System To integrate the nano drug delivery systems, it is important to evaluate their toxic effects as well. The advantageous properties such as submicron size, larger surface area, accessibility to nonspecific target sites, surface polarity that led to increased efficacy may also be the reason to cause toxic effects. The major toxic effect is high amount of inflammatory mediator and oxidative stress which may cause damage to the healthy protein, lipids, or DNA. The accumulation of nanocarriers is maximum in highly perfused organs and thus the free radicals cause damage to these organs. Hence the nanocarriers cause nephrotoxicity, cardiotoxicity, immunotoxicity, hepatotoxicity, and genotoxicity [111]. Other than that synthetic polymer used in the nanomedicine may cause toxicities, e.g., cationic polymer and lipids which are considered ideal for gene delivery cause cytotoxicity and hemolysis of the healthy cells [112].

4.10 Obstacles and Challenges in the Practical Application of Nanomedicine There is extensive research done on nanomedicine and nanomedicine is successful in overcoming the limitation of conventional medicine but still there is lack in clinical translation owing to substandard experimenting protocol and inadequate characterization. FDA also

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published guidelines for better clinical translation of nanomedicines, besides all the clinically available nanomedicines are anticancer and for neurological disorders and widely used Nanodelivery system is liposome and polymer-based nanocarriers. Now the trends are hanging, and more research is being done on antimicrobial and nanocarriers being employed are micellar systems, nanocrystals, dendrimers. Other big hurdle is stability on storage which is being investigated and liquid formulation is converted into solid formulation by the process of freeze-drying and spray-drying. Another hurdle is scale-up to industrial level. The functionalization of the surface for targeted binding to the virus and receptor is major hurdle in scalability. Cost of the therapy could be hurdle in underdeveloped and developing countries. The efficacy must be proved both in vitro and in vivo for clinical translation. The final hurdle is compliance with the regulatory authorities [8]. If all the challenges are handled well, next era will see rise in nanodelivery system for treating microbial and viral infection [113].

4.11 Nanotechnology-Based Approaches to Overcome COVID-19 Pandemic COVID-19 became a pandemic and caused huge loss of lives. Under such circumstances, it was necessary to make effective treatments to save lives and eliminate the virus. Various nanotechnology-based approaches were employed to develop vaccines, medicines, and diagnosis holding potential to overcome COVID-19 pandemic. Nanoparticles-based diagnostic methods are developed for efficient and accurate diagnosis. Graphene was coated on the sensor of field transistor containing specific SARS-­ CoV-­2 antibodies. The device was highly specific and can distinguish SARS-CoV-2 and MERS-CoV.  Another device was developed using gold nanoparticles which contain SARS-CoV-2-specific thiol-modified antisense oligonucleotide capped with gold nanoparticles and the device can produce a diagnosis within few minutes. RT-PCR is being used for SARS-CoV-2 detection and the results are never precise as the incidence of false positive and false negative is common. The precise results of the test can be obtained by conjugating the probe of the viral RNA with fluorescent nanoparticles. The device having magnetic nanoparticles and fluorescent zirconium quantum dots conjugated with corona virus antibodies was developed and thus the virus antibody-complex can be isolated magnetically and fluorescence can be measured at 412 nm [102]. Various Emergency authorized vaccines were sanctioned by FDA to combat the COVID-19 and some of these vaccines used nanoparticles as a carrier. As the scale of viruses and nanoparticles are same and developing the nanoparticles-based vaccine can prove to be very efficient. Pfizer-BioNTech vaccines use lipid particles that deliver mRNA into the host cell that encodes the spike protein and provokes immune response. Self-­ emulsifying RNA vaccine is developed by Acuitas Therapeutics in alliance with Imperial College London. This vaccine was incorporated into the lipophilic nanoparticles and has condensed prefusion alleviated Spike protein. In animal trials, it was observed that there is

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greater titer of antibodies, thus these results encouraged to use lipid nanoparticles for delivery of vaccine as it provides better neutralization capacity, antibodies titer, and cellular reactions. Other vaccine including Moderna vaccine is developed using mRNA Technology, AstraZenca and COVISHEILD are developed from recombinant chimpanzee adenoviral which encodes for spike protein and COVAXIN is developed by using whole inactivated virion derived from Vero cell platform technology [8]. Take-Home Message

• • • •

How the nanotechnology can be incorporated into therapeutics and diagnostics Revolution in the conventional therapy How to overcome hurdles of conventional antiviral therapy What are the impediments in conversion of the traditional therapy into nanomedicines? • Role of nanoparticles in combating global pandemic of COVID-19

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Further Reading Baron S, editor. Medical microbiology, 4th ed. Galveston, TX: University of Texas Medical Branch at Galveston; 1996. Encyclopedia of Virology 2nd Edition - July 27, 1999-Editors: Allan Granoff, Robert Webster. Viral and Antiviral Nanomaterials by Kavita Pal, Mayuri Iyer 1st Edition; 2022. Viral and Antiviral Nanomaterials Synthesis, Properties, Characterization, and Application-Edited by Devarajan Thangadurai, Saher Islam, Charles Oluwaseun Adetunji; 2022.

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Nanomedicines in the Treatment of Nervous System Disorders Zakiah Zeb, Ali Sharif, Mohamed M. Abdel-Daim, Syed Muhammad Muneeb Anjum, Atif Ali Khan Khalil, Muhammad Furqan Akhtar, Ammara Saleem, and Muhammad Imran Khan

Z. Zeb · A. Sharif (*) Department of Pharmacology, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan M. M. Abdel-Daim Department of Pharmaceutical sciences, Pharmacy Program Batterjee Medical College, Jeddah, Saudi Arabia Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt e-mail: [email protected] S. M. M. Anjum Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan A. A. K. Khalil Colleg of Pharmacy and Research, Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, Republic of Korea Department of Pharmacognosy, Faculty of Pharmaceutical and Allied health Sciences, Lahore College for Women University, Lahore, Pakistan M. F. Akhtar · M. I. Khan Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan e-mail: [email protected] A. Saleem Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_5

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Contents 5.1  5.2  5.3  5.4  5.5 

5.6 

5.7  5.8 

5.9  5.10 

5.11 

5.12  5.13 

5.14 

Introduction  Neurodegenerative Disease  Neuropsychiatric Disorders  Challenges for the Treatment of Brain Disorders  Problems to Conventional CNS Therapies  5.5.1  Brain Tumors  5.5.2  Alzheimer Disease (AD)  5.5.3  Parkinson’s Disease (PD)  5.5.4  Epilepsy  5.5.5  Mood Disorders and Schizophrenia  Transport Mechanisms for Drug Delivery to the CNS  5.6.1  Paracellular Transport  5.6.2  The Transcellular Pathway for BBB/BBTB Crossover  5.6.3  Factors to Consider for the Transcellular Route  Nanomedicine in Brain Cancer/Brain Tumors  Core Signaling Pathways  5.8.1  Mitogen-Activated Protein Kinase (MAPK) Signaling  5.8.2  Phosphoinositide 3-Kinases (PI3K) Signaling  5.8.3  Cyclic Adenosine 3′, 5′-Monophosphate (cAMP) Signaling  5.8.4  PI3K and MAPK Pathway Targeting  5.8.5  Targeting the cAMP Pathway  Functionalization of Nanocarriers for Active Brain Targeting  Alzheimer’s Disease  5.10.1  Nanotechnological Strategies for Alzheimer’s Disease  5.10.2  Superparamagnetic Iron Oxide Nanoparticles (SPIONs)  5.10.3  Lipid-Based Nanoparticles for Alzheimer’s Disease  5.10.4  Polymeric-Based Nanoparticles for Alzheimer’s Disease  5.10.5  Metal-Based Nanoparticles for Alzheimer’s Disease  5.10.6  Targeting Amyloid Beta Aggregates  5.10.7  Nanomedicine for Clearance of Tau Aggregates  5.10.8  Modulation of Cholinergic System  Parkinson’s Disease  5.11.1  Inorganic Nanomaterials  5.11.2  Organic Nanoparticles  Nanomaterials for Parkinson Disease Diagnosis  Epilepsy  5.13.1  Intranasal Delivery of Antiepileptic Drug (AED)-Loaded Polymeric Nanoparticles  5.13.2  Potential Nanotherapies for Epilepsy  Schizophrenia  5.14.1  Polymeric Nanoparticles  5.14.2  Solid Lipid Nanocarriers  5.14.3  Lithium Nanoparticles  5.14.4  Nanostructured Lipid Carriers 

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5  Nanomedicines in the Treatment of Nervous System Disorders 5.14.5  Liposomes  5.14.6  Polymeric Micelles  5.15  Challenges and Perspectives  5.16  Conclusion  References 

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What You Will Learn from This Chapter

The chapter overviews different diseases of central nervous system (CNS), the problems associated with conventional therapies to CNS and transport mechanisms associated with the delivery of drugs into the CNS. Different signaling pathways are also discussed. CNS disorders like Alzheimer Disease, Parkinson’s disease, Epilepsy, and Schizophrenia are discussed with reference to available nanocarrier-based therapeutic options.

5.1 Introduction The science of health has typically contended with effective drug distribution. There are still many diseases that can be healed given current medical and technological advancements; Targeted drug delivery is a challenge in many locations. One of these locations is the CNS, where effective medication delivery is essential to all interventions. It is estimated that 1.5 million population of the world is affected by CNS disorders and accounts for 1% death rate [1]. The reported burden for brain disorders was predicted to raise up to 14.7% by the year 2020 [2]. These disabilities can be linked with intrinsic dysfunction of the brain along with interaction of brain with environmental factors [3]. Brian is responsible for CNS malignancies. The malignant cancer of the brain is classified under the primary brain tumors. About 2% of cancers are produced from glial cells and are named as gliomas [4]. Metastasis of brain affects nearly 10–30% of all cancer patients with almost 70–80% develops several injuries. Although newer chemotherapeutic medicines have been able to transform prognosis for a number of cancers but at the same time, these medicines are failed to prevent the spread of neoplasms into the brain, which is associated with poor penetration into the brain owing to the presence of blood–brain barrier (BBB). To address the mentioned issue, new therapeutic approaches that can help in preventing the hindrance associated with BBB, are required which also enhances the efficacy of the treatment modalities. Researchers around the world are looking for development of therapeutic delivery methods to address this issue [5]. Different techniques for solving of abovementioned issue are under consideration. Nanomedicine-based approaches are the most important advancements in the delivery of therapeutic agents to CNS [6]. Several kinds of

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nanomaterials are used to prepare nanoparticles in the size range of 1–100  nm [7]. Nanotechnology has opened new horizons in the field of biomedical science. Several types of nanoparticles prepared from different methodologies are used in brain-related research studies. These include quantum dots (QDs), polymeric nanoparticles, micelles, and metallic nanoparticles [8]. Nanoparticles are smaller in size so they interact with biological systems in a better way [9], thus incapacitating a substantial obstacle related to delivery into the brain [10]. The first line of action in treating malignancies associated with brain is the surgical removal of tumor. It is usually followed up by radiations, administering chemotherapy and lastly symptomatic approaches [11]. The reappearance is usually common when we talk about the brain cancers because they are prone to relapse. Median time of survival for brain metastasis is 8 months [12]. At the same time, malignant brain tumors vary a lot in characteristics making it impossible for a sole therapy to provide response in all patients. It means that each medicine would be beneficial for a certain target population or a particular stage of disease. The issue can be addressed by concurrent administration of imaging and therapeutic substances [13]. This technique has a good potential in the treatment of different stages of malignant brain tumors. Promising therapeutic drugs have been identified in the treatment of CNS disorders [14]. These drugs have shown better efficacy but effectiveness is restricted due to the presence of BBB and blood cerebrospinal fluid (BCSF) [15–17]. Presently the research is focused on the development of strategies using nanotechnology in order to address the challenges associated with CNS therapy. Nanoparticle synthesis and loading of drugs in these carriers may be considered an effective approach in CNS drug delivery by enhancing the efficacy and safety in the patients [18–21]. Nanoengineered medicines are helpful in the treatment of the diseases. They have the ability to penetrate the BBB, overcoming the major hindrance in the targeting of medicines to CNS. Nanoscaffolds, nanofibers provide trophic and structural support for endogenous and transplanted cells. The significance of nanoengineered product depends upon the existence of different properties into the assemblies which provides bioactivity, targeting, and imaging capabilities in a single product [22, 23]. Nanoparticles also interact with specific cellular substances allowing for better targeting in CNS. Along with this, incorporating enzyme cleavage substances in nanomaterials helps in modulating the activity like pH-responsive modification or cation-mediated self-assembly [24]. Nanomaterials are natural, accidental, or manufactured particles that are either unbound or aggregate and contain particles with one or more outer dimensions of 50% or more of the particles in the size range of 1–100 nm [25]. Effective drug delivery is hampered by a number of factors including renal, hepatic, and immunological clearance. These natural obstacles can be surmounted by drug-loaded nanoparticles, boosting efficacy while decreasing morbidity. By expanding the therapeutic indices of the active pharmaceutical substances incorporated within nanoparticles, nanomedicine has introduced a new era for medication delivery. Over 1.5 billion individuals are currently affected by central nervous system disorders, which make up nearly one-third of all diseases in the world. As CNS problems are predicted to become the primary focus of the twenty-first century, this healthcare challenge is expected to grow in the decades to come. The frequency of many CNS disorders has increased exponentially beyond age 65, combined with the inescapable rise in the number of overweight people, especially the obese, and is mostly due to a tre-

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Fig. 5.1  Nanomedicines in the treatment of CNS disorders

mendous increase in people over 65 starting in 2010 [26]. Figure 5.1 demonstrates different aspects of nanomedicines which can be used for the treatment of CNS disorders.

5.2 Neurodegenerative Disease Degenerative illnesses of the CNS are major causes of death among the elderly in developed nations. While the causes of neuronal degeneration are still unknown, the incidence of neurodegeneration increases with age, peaking in mid-to-late adulthood. This syndrome, which primarily affects the elderly, arises after viral infections in neurodegenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Viruses directly harm neurons by killing them or inducing apoptosis, resulting in neurodegeneration. The pathological hallmarks of MS include BBB permeability, myelin sheath degradation, axon injury, glial scar development, and the presence of inflammatory cells, mostly lymphocytes infiltrating into the CNS. Clinical signs of myelin degeneration include neuropathic pain, paralysis, muscular spasms, and optic neuritis [27].

5.3 Neuropsychiatric Disorders Neuropsychiatric illnesses are increasingly recognized as brain and neural network disorders caused by injury, psychological trauma, persistent hardship or hereditary susceptibility. Several mental disorders, including schizophrenia, are now known to have a strong

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biological component and debilitating psychiatric symptoms are known to occur from neurological conditions, such as depression after a stroke. Indeed, integrated understanding of psychiatry and neurology today holds considerable potential for vastly enhancing medical therapy for brain diseases. Major depressive disorder (MDD) was placed fifth among the top ten causes of disability in industrialized nations globally. Second, the worldwide burden of mental disorders has been progressively increasing in recent years. The prevalence of neuropsychiatric and drug use disorders increased by about 22% between 1990 and 2010 [28].

5.4 Challenges for the Treatment of Brain Disorders Brain disorders present different challenges in the developing countries as compared to well developed countries. Medications and other treatments are often unavailable. In addition, adherence to available treatment is poor. Research on effective treatments and methods of delivery are lacking. Many of mentally ill in developing countries have been homeless or housed in asylums. Currently, the available treatments for mental disorders have severe side effects and may not provide effective payload. Hence there is still a major deficit in efficient therapy for CNS disorders. Novel therapeutic approaches may bridge this gap in the near future.

5.5 Problems to Conventional CNS Therapies 5.5.1 Brain Tumors BBB, is composed of a cellular structure that is very much unique and present between blood and brain interstitium. It possesses intracellular tight junctions and efflux pumps. Brain tumors not only invade a major organ in the body but at the same time, it is present usually at a place where effective surgical removal is difficult. BBB is responsible not only for the nutrients exchange among blood stream and brain but also poses a limitation for the systemic chemotherapeutic agents to reach the location site inside brain [29]. To combat these catastrophic CNS malignancies, aggressive therapeutic regimens like radiations in higher doses or combination chemotherapy are frequently undertaken, resulting in dreadful adverse events leading to poor quality of life.

5.5.2 Alzheimer Disease (AD) Many of the adverse effects of acetylcholinesterase (AChE) inhibitors are due to peripheral cholinergic actions. The most common symptoms are nausea, vomiting, and diarrhea. AD is a prominent cause of death worldwide and various medications targeting the development, aggregation, and clearance of amyloid plaques are being studied, but have yet to

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yield a conclusive therapeutic outcome. In the absence of effective and documented treatments for AD, despite the minor clinical effects produced by AChE inhibitors and while waiting for better therapy techniques, these medications should remain in the therapeutic armamentarium of AD [28].

5.5.3 Parkinson’s Disease (PD) Motor and nonmotor features are resistant to currently available treatments. Several treatments cause disabling adverse reactions, and quality of life and life expectancy remain abnormal. Furthermore, the most current therapy advancements are either too expensive or overly difficult for many patients. To address these unmet medical requirements in the management of PD, there is still a need for effective, safe, and inexpensive symptomatic, neuroprotective or restorative antiparkinsonian medication [30].

5.5.4 Epilepsy Carbamazepine, phenytoin, and valproic acid are anticonvulsants with limited therapeutic index (TI). The gap between the hazardous and therapeutic dose ranges in all of these medications is minimal, which frequently causes issues when dosages are modified significantly or in combinations with other drugs. Drug-related issues include ineffective treatments, adverse effects, and exorbitant treatment expenses. Gender and age may impact side effects in people using anticonvulsants for narrow TI. Furthermore, according to a prior study, 25–30% of pregnant women suffered higher seizure frequency. Catamenial epilepsy affects women as well, increasing the incidence of seizures during menstruation or ovulation. These two situations need greater dosages, which result in higher serum anticonvulsant concentrations and an increased risk of adverse effects. Finally, the effects of age on medication adverse effect rates in senior people have been linked to changes in pharmacokinetics [12, 31].

5.5.5 Mood Disorders and Schizophrenia All serotonin reuptake medications venlafaxine and duloxetine have a side effect of sexual dysfunction. Bupropion and nefazodone are the least likely to cause sexual adverse effects. During the first month or two of antidepressant medication, the risk of suicide may increase; physicians, patients, and family members should be on the lookout for symptoms of suicidal thoughts and behavior. Serotonin reuptake inhibitors appear to be safer and more tolerated in elderly people than tricyclic antidepressants. The selection should be based on the side effect profile and medication interactions. Weight gain, like sexual problems was noted infrequently during premarketing clinical studies of SSRIs. Because of the weight loss shown in the early, short-term clinical studies with fluoxetine, it was looked at

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as a potential weight loss drug. Weight gain, on the other hand, has since emerged as a typical adverse effect of long-term SSRI medication. Although several SSRIs are associated with weight reduction during initial therapy, weight is frequently recovered after 6 months, and long-term usage can result in significant weight gain [32].

5.6 Transport Mechanisms for Drug Delivery to the CNS 5.6.1 Paracellular Transport It involves endothelial cell transfer through the intercellular space that is entirely dependent on the breakdown of blood–brain barrier/blood–brain tumor barrier (BBB/BBTB) integrity leading to increase the permeability and residence (EPR) time. As a result, size and blood retention profile are critical in this procedure. For successful transvascular transport, nanomaterials (NM) should be lesser than the upper threshold limit of the pore size. However, the size variation in BBTB was 12–140 nm. Even at the tumor core, pore size of BBTB has been found to be as large as 500 nm. If the size is greater than threshold of renal clearance, it promotes retention of blood, enhances the formation of tumor via EPR effect. Effect of poly(amidoamine) (PAMAM) dendrimers size on the accumulation in orthotopic 9L rat glioblastoma (GBM) model and murine glioma cells (GL261) mouse GBM model after systemic treatment was determined. Fast renal clearance compensated for increased tumor accumulation in this example, as did uniform distribution due to the small size. Given the extremely low-paracellular permeability in the healthy brain region, this method can give the anticipated selectivity between tumor and healthy brain region [29].

5.6.2 The Transcellular Pathway for BBB/BBTB Crossover Three kinds of transcytosis mechanisms are involved in transcellular pathway: adsorptive-­ mediated transcytosis (AMT), receptor-mediated transcytosis (RMT), and carrier-­mediated transcytosis (CMT) with RMT offering as the basic pathway for transporting essential macromolecules such as transferrin, lipoproteins, and insulin across the BBB. RMT starts with conventional ligand receptor binding at the apical side of Bronchial epithelial cells (BECs), that will lead to enhanced endocytosis. It is channeled via different endosome vesicles to the basolateral side. The receptor recycling continues to carry on the transcytosis process. Nanocarriers are often coated with peptides in this procedure which are specific ligands to BEC receptors and do play their part in receptor recycling. Transferrin receptor (TfR), is a common target for the delivery of medication to brain during malignancies. It is responsible for the transfer of iron and also undergoes constitutive recycling. The expressions of TfR are overexpressed in BBTB and cancerous brain cells as compared to healthy brain cells. This overexpression makes it an ideal candidate target in GBM.  Poly (L-malic acid), a natural biopolymer scaffold, was used to develop a

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nanoscale immunoconjugate. The polymer was linked to immune checkpoint inhibitor monoclonal antibodies through a covalent binding. This resulted in activation of local brain antitumor immune response in the mice bearing intracranial GL261 GBM [33–35].

5.6.3 Factors to Consider for the Transcellular Route Some special issues like the shuttling of BBB to NMs to be effective against aggressive brain tumors need to be addressed. One of these concerns is the diversity in the expressions of receptors in the tumors and its subtypes. The major concern is to ensure that animals/humans undergoing testing show similar or at least comparable expressions of BEC and related peripheral organs. It is necessary so that experimental results can be transferred into clinical practice. Several receptor types like insulin-like growth factor-1 receptor (IGF-1R), solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1/ GLUT1), TfR, low-density lipoprotein receptor-related protein (LRP) 1, and LRP8 are overexpressed in microvessels of mice brain as compared to microvessels of human brain [36, 37].

5.7 Nanomedicine in Brain Cancer/Brain Tumors Brain tumors share certain characteristics and obstacles for diagnosis and treatment with tumors elsewhere in the body, but they also offer distinct concerns due to the particular attributes of the organ in which they reside. The BBB separates the majority of the brain from the blood and imposes considerably more stringent control over chemicals that are

Fig. 5.2  Nanotherapeutic approaches for brain cancer. Adapted & reproduced with permission from [38]

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permitted to pass (or may even be subject to promote transit) than most other organs. Figure 5.2 represents nanotherapeutic approaches for brain cancer.

5.8 Core Signaling Pathways 5.8.1 Mitogen-Activated Protein Kinase (MAPK) Signaling This route plays critical functions in cell proliferation, survival, and metastasis. Phosphorylation of proteins leading to enhanced MAPK levels are linked to poor survival rate especially in GBM. MAPK is activated followed by binding of growth ligands with the receptors in receptor tyrosine kinase (RTK) family. The receptor gets dimerized, leading to autophosphorylation and starting a series of phosphorylation with multiple protein substrates. The autophosphorylation leads to recruitment of proteins. These proteins may include growth factor proteins (GRB2) and seven less homologs (SOS). SOS is responsible for the recruitment of guanosine triphosphate (GTP) and stimulation of receptor-linked tyrosine kinases (Ras); it activates rapidly accelerated fibrosarcoma (RAF) which is membrane-­bound kinase. It triggers Mesenchymal to Epithelial Transition (MEK) also known as MAPK kinase leading to activation of MAPK. Tumor suppressor NF1 possesses the ability to inhibit this pathway by hydrolysis of Guanosine triphosphate (GTP), which converts it into Guanosine diphosphate (GDP) leading to inactivation of Ras [39].

5.8.2 Phosphoinositide 3-Kinases (PI3K) Signaling One of the major disrupted pathways in cancer is Phosphoinositide 3-kinases (PI3K) signaling. Different physiological activities of cell like differentiation, proliferation, adhesion, motility, invasion, and survival of cell are dependent on this pathway. It is a very closed controlled process and consists of different stages. Receptor tyrosine kinases (RTKs) are stimulated by growth factors leading to PI3K activation. It occurs so by catalytic interaction of p110 and p85 regulatory subunits. This interaction converts phosphatidylinositol (4,5)-bisphosphate (PIP2) lipids to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) lipids. Phosphoinositide-dependent kinase-1 (PDK1) gets phosphorylated and activated through binding of Protein kinase B (PKB/Akt) and binds to PIP3 in plasma membranes. Members of the Ras family can also activate PI3K. Akt has multiple downstream targets, including mechanistic target of rapamycin (mTOR). The cell growth and proliferation in homeostatic conditions are regulated by the monitoring of mTOR. Hyperactivation of PI3K pathway leads to hyperactivated mTOR. It acts on multiple targets that can promote synthesis of proteins. The phosphatase and tensin homolog (PTEN) protein activation is responsible for the dephosphorylation of PIP3. It leads to inhibit the signaling mechanism and is a negative regulator of PI3K pathway. Different components of PI3K system are amplified in glioblastoma. These include mutation of epidermal growth factor receptor (EGFR), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) amplification or removal of tumor-suppressing PTEN [39].

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5.8.3 Cyclic Adenosine 3′, 5′-Monophosphate (cAMP) Signaling Multiple biological activities are regulated by the cyclic adenosine 3′, 5′-monophosphate (cAMP) pathway. The binding of a ligand to a G-protein-coupled receptor (GPCR) often initiates signaling. G-proteins are activated, causing the enzyme adenylyl cyclase (AC) to convert adenosine triphosphate (ATP) to the second messenger cAMP. As a result, cAMP can activate a number of effectors, including the cAMP-dependent protein kinase A (PKA). This pathway’s negative control by phosphodiesterases (PDEs), which breakdown cAMP, is a key regulatory mechanism. Other pathways, such as MAPK and PI3K, interact with the cAMP pathway. PKA triggered by cAMP, for example, can inhibit the MAPK, Raf. PKA, on the other hand, has been demonstrated to inhibit the extracellular signal-­ regulated kinase (ERK) tyrosine phosphatase, protein tyrosine phosphatases (PTPs), boosting ERK signaling [39].

5.8.4 PI3K and MAPK Pathway Targeting GBM progress and growth of tumor are regulated by both PI3K and MAPK pathways. The progress in developing the drugs that can target these pathways can greatly impact the survival rate of patients and quality of life. A new and important drug pan-PI3K inhibitor, BKM120 (Buparlisib) is currently under multiple phase I/II/III clinical trials for the treatment of different cancers including GBMs and breast cancer. Another potent drug Vemurafenib which targets MAPK pathway, inhibits v-raf murine sarcoma viral oncogene homolog B1 (BRAF) protein and downstream Ras is approved by FDA for the treatment of melanoma at late stage [39].

5.8.5 Targeting the cAMP Pathway cAMP pathway has a close association with other signaling pathways of cancer. It makes this pathway a good therapeutic target. A complex interaction exists between cAMP and MAPK pathways, that controls cAMP-induced BCL-2–interacting mediator of cell death (Bim) expression and apoptosis. cAMP activation will lead to PKA inhibition of cRAF that leads to inhibit MAPK pathway [39].

5.9 Functionalization of Nanocarriers for Active Brain Targeting The quest for novel moieties that can be doped to the surface of nanocarriers has been the primary focus of nanotechnology in recently. This method aims to build the amount of single-dose chemotherapy that passes across the BBB and eventually reaches the tumor. For instance, doxorubicin-loaded polymeric micelles have been explored for improving

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therapeutic efficacy with ectodomain (EGa1) nanobody-modified nanocarriers. To treat tumors that upregulate the epidermal growth factor receptor (EGFR), this key target ligand is currently under clinical investigation. The use of artificial peptides or natural epidermal growth factor (EGF) to target glioma cells that express the EGFR can be employed. In reality, when connected to its receptor at the cell surface, EGF is able to start and speed up the endocytosis of nanoparticles. The various particle endocytosis mechanisms that these two peptides induce in the cell may be highly relevant for the treatment of tumors. Ironically similar to this, connexin 43-directed monoclonal antibodies and those that recognize glial fibrillar acidic protein (GFAP) have been used to target liposomes to an experimental intracranial glioma model, demonstrating their ability to deliver therapeutic or diagnostic agents into the peritumoral zone in the brain., whereas EGF causes a decrease in EGFR levels, synthetic peptide-targeted nanoparticles do not. As a result, in the first scenario, cells will maintain their receptivity for circulating polyplexes for a longer period of time, and a stronger response to cancer therapy is anticipated. Dual (vasculature and tumor)-targeting strategies are being explored to enhance the efficacy of nanocarrier systems. In addition to these approaches, integrin receptors and glioma cells make these receptors favorable for nanoparticle active targeting what is known as dual (BBB and tumor)-targeted strategy or cascade delivery is an advancement in the field of active targeting. For instance, both tumor cells and the BBB have high levels of the transferrin receptor (TfR). Transferrin (Tf), its ligand, has been employed as a dual-targeting ligand for inducing receptor-mediated transcytosis in order to treat brain tumors. Micelles made of Tf-modified poly (ethyl ethylene phosphate) (PEEP) and polycaprolactone (PCL), loaded with the anticancer drug paclitaxel have demonstrated strong antiglioma action as well as an extension of the survival time of tumor-bearing animals [39].

5.10 Alzheimer’s Disease Dementia, which is characterized by a decline in thinking and independence in daily tasks, is mostly brought on by AD, a sickness that results in the degradation of brain cells. The cholinergic and amyloid hypotheses were put up as two key causes of AD and AD is thought to be a complex illness. The condition is also influenced by a number of risk factors including as advancing age, hereditary factors, head injuries, vascular diseases, infections, and environmental variables. In AD, amyloid-β deposits (senile plaques) are often seen in the neocortex, while tau inclusions such as a neurofibrillary tangle manifest in a neocortical neuron [40]. AD is categorized based on when the first symptoms appear. Early-onset Alzheimer’s disease (EOAD), which develops before the age of 65, accounts for around 1–6% of all cases. Late-onset AD (LOAD), on the other hand, is defined by the development of symptoms beyond the age of 65 and accounts for approximately 90% of cases. Alzheimer’s disease (AD) is the most prevalent kind of dementia globally, accounting for up to 50–80% of cases. Alzheimer’s disease will undoubtedly place a significant strain on economies and health-care systems, with instances predicted to reach 131 million by 2050. The incidence of severe memory loss, global cognitive decline, and impairment

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of daily living activities is usually used to diagnose AD symptomatically Although it is estimated that more than 50 million individuals worldwide are affected by AD, the number of cases are steadily rising because of the longer average lifespan as well as hereditary and environmental factors. Inflammation in CNS is associated with microglia and astrocytes. Microglia are 10% of total CNS cells. They serve as a primary defense against any type of brain damage. Two major cytokines that are found in the brain of an AD patient are Tumor necrosis factor (TNF) and Interleukin-6 (IL-6). These cytokines are involved in increased Amyloid beta production. Aging has a significant impact on the etiology of Alzheimer’s disease, as well as the body’s innate immunity. Inflammasomes become the components essential for the release of interleukins, however as people age, their numbers decrease, resulting in a decrease in cytokines. An imbalance in the control of proinflammatory and anti-­ inflammatory activity can result in brain damage [41]. Figure 5.3 depicts hyperactive glial cells, including astrocytes and microglia, in response to A and tau interaction Toll-like receptors are in charge of activating NF-B pathways. It is a transcription factor that is only found in B-lymphocytes. NFB activation induces phagocytosis mediated by microglia, releases cytokines, and activates molecules essential for adaptive immune response function [42]. Microglia activation also causes the stimulation of other signaling pathways, such as the PI3K/Akt signaling mechanism, which is involved in programmed cell death and the control of inflammatory outcomes. PI3K activation also promotes NF-B translocation [42]. The generation of Aβ peptides increases throughout AD pathogenesis, but their clearance decreases. A1-40 and A1-42 fragments predominate, increasing peptide

Fig. 5.3  Hyperactive glial cells, including astrocytes and microglia, in response to A and tau interaction. Adapted & reproduced with permission from [41]

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aggregation and, as a result, the development of senile plaques. BACE1, the primary enzyme that triggers the production of A peptide, is being investigated as a possible Alzheimer’s disease biomarker. Although BACE1 can be tested in CSF, its prognostic utility is debatable. Some studies have found that BACE1 levels and protein activity are higher in AD patients, and that this is a strong predictor of MCI development [43]. The first pathological event in AD is glucose. This event is associated with dysfunction of cognition leading to impaired functionality. Intervention at an early stage has become a standardized approach before occurrence of irreversible deterioration. These techniques majorly target mitochondria that have shown good results in preclinical testing but no success was obtained in clinical trials [44].

5.10.1 Nanotechnological Strategies for Alzheimer’s Disease The neuronal damage is already set and permanent when the first symptoms arise. As a result, gadgets that can detect Alzheimer’s disease biomarkers in the early stages of memory loss and cognitive decline have piqued the interest of clinical researchers [45].

5.10.2 Superparamagnetic Iron Oxide Nanoparticles (SPIONs) Diagnosis of AD initially was made with the help of superparamagnetic iron oxide nanoparticles (SPIONs) and magnetic resonance imaging (MRI). The surface of the nanocarrier was modified with the help of antibodies that can be used to identify biomarkers of AD. This type of modification has exhibited good targeting in different in vitro, in vivo, and ex vivo AD models. The Amyloid plaques were detected with MRI agents consisted of iron oxide nanoparticles which were coated with sialic acid, A1-42 antibody, and curcumin. Similarly, liposomes were modified using an amyloid target ligand (gadolinium and ET6-21). The performance in standard MRI was remarkable when used in AD in vivo model. These diagnostic tests were performed using intranasal route of administration. Intranasal injection is a noninvasive method that facilitates the transportation across BBB and also reduces the side effects. Tau and A antibodies were used to modify graphene oxide surface when connected with magnetic core-plasmonic coat nanomaterials easily identified the respective proteins in an in vitro model of AD [46]. The precise binding of disease-specific proteins is another diagnostic use of nanocarriers. Nanocarriers can be helpful in monitoring of these indicators and provide a precise diagnosis and staging of AD [46].

5.10.3 Lipid-Based Nanoparticles for Alzheimer’s Disease One of the most frequently used delivery technologies for targeting in brain is Lipid-based nanoparticles (LNPs). These lipid nanocarriers are safer, biocompatible, and most importantly have biodegradative nature. Owing to its lipidic nature, they can easily pass-through

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BBB via transcellular pathway [45]. Lipo-nanocarriers are mostly comprised of fatty acids, waxes, mono- and triglycerides [47]. Lipo-nanocarriers are devised in form of liposomes, solid lipid nanoparticles (SLN), and nanostructured lipid carriers (NLC). The variation among these carriers exists like loading capacities, mean particle size, electrokinetic properties, lipid layers, and shape [48]. These carriers possess the ability to entrap lipophilic and lipophobic drugs [49]. The limitation for these nanocarriers includes lesser stability, complex manufacturing process, polymorphic transitions, and release of drugs during storage. These limitation poses hindrance in their synthesis on massive scale. Recent preclinical research combining cutting-edge LNPs with AD animal models has yielded intriguing outcomes [50].

5.10.4 Polymeric-Based Nanoparticles for Alzheimer’s Disease One of the most commonly employed carriers used in nano drug delivery is Polymeric NP (PNP). It is attributed to simple production using different processes [51]. The size range varies from 10 to 1000 nm and they have the ability to entrap higher concentrations of both hydrophilic and hydrophobic drugs [52]. Different polymers both natural and synthetic can be employed to prepare PNPs with either of the surface charge. Existence of both positive and negative charge provides significant effect on different properties like biological behavior, adhesiveness to the mucous membrane, and penetrability. Nanocapsules consists of a vesicular polymeric capsule entrapping the drug in a liquid core whereas nanosphere is a matrix of polymers and drug is either distributed or adsorbed on the sphere surface [53]. Polylactide (PLA), poly(lactide-­ co-­glycolide) (PLGA), chitosan, polyethyleneimine (PEI), and polycaprolactone (PCL) are the most often utilized polymers in the production of PNPs. These polymers are approved by FDA for biomedical use [54]. The limitation for these carrier systems includes requirement of organic solvents during preparation processes.

5.10.5 Metal-Based Nanoparticles for Alzheimer’s Disease The most important inorganic nanocarriers are metal-based NPs (MNPs) [55]. The size range of particles varies from 10 to 100 nm. They possess larger surface area and provide with the advantage of coating different compounds which include antibodies, peptides, and genes. These coating enable them to work as biosensors and targeting devices. Different metals like gold, silver, iron, zinc, and copper are used to prepare MNPs and each one of them provides unique characteristics to the nanocarriers [56]. Oxidative stress induction is critical in the development of AD. It promotes the H2O2 production. The toxic effects of reactive oxygen species can be minimized by use of metal chelators. These metal chelators pose nonspecific interaction with metal ions which are involved in normal functioning of cellular events and also exhibit a low penetration through BBB. These events restrict the therapeutic potential [57]. The neurotoxic and theragnostic potential of metal-

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lic nanoparticles are studied. There are certain concerns that must be addressed regarding neurotoxicity of nanocarrier devices specially about MNPs. Irrespective of the potential toxic effects, certain metallic nanoparticles like cerium dioxide nanoparticles (NPs) have received a lot of attention in recent years due to their radical scavenging abilities [58].

5.10.6 Targeting Amyloid Beta Aggregates Reversing AD pathogenesis can be accomplished by targeting cellular components involved in A production or by decreasing the development of neurofibrillary tangles. Recently discovered A-binding drugs have been coupled to NPs for AD medicinal objectives. Now a days, PEG-PLA NPs and liposomes are commonly used nanocarriers. These carriers exhibit no toxicity, little immunogenic potential, and absolute biodegradation. Curcumin derivatives incorporated in liposomes exhibited strong binding (1–5 nM) with amyloid fibers [59].

5.10.7 Nanomedicine for Clearance of Tau Aggregates Recent research suggests that methylene blue can be used to prevent or reduce tau aggregation in tauopathies. Curcumin has been proposed to have possibly neuroprotective characteristics [59]. Curcumin compounds were discovered by Okuda et al. as dual inhibitors of A and tau aggregation [60]. Gao et al. conducted a study on curcumin NPs and exhibited that tau targeting resulted in slowing AD by inhibiting the aggregation of tau [61].

5.10.8 Modulation of Cholinergic System Acetylcholinesterase (AChE) is a potential therapeutic target that can improve cognitive impairment in AD patients. Rivastigmine was incorporated in liposomes and administered via oral and intraperitoneal route in mice. It exhibited a higher AChE inhibitory potential as compared to drug solution alone [62]. Similarly, donepezil was used to prepare a nanoformulation in combination with apolipoprotein A-I. It produces dual therapeutic effect against Aβ-targeting and AChE. Like wise, epigallocatechin-3-gallate and ascorbic acid were incorporated in poly ethylene glycol NPs to improve the therapeutic effectiveness against AD [63].

5.11 Parkinson’s Disease Parkinson’s disease is a progressive disorder of CNS that largely effects elderly population. About 1–3% of the population above 65 years of age mainly got effected from PD. The number may raise from 8.7 to 9.3 million by the year 2030. The major effects manifested in PD are due to dysfunction in somatic motor system like rigidity, bradykinesia, postural

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instability, gait dysfunction, and tremors). The underlying pathological mechanism involves degradation of nigrostriatal pathways. It leads to depletion of dopamine levels. Nonmotor functions are also impaired [29]. The pathological basis of the PD includes the formation of cytoplasmic inclusions mostly synuclein aggregations in form of Lewy bodies (LB). Phosphorylation of synuclein results in Lewy bodies development leading to neuronal death [64]. Dysfunction of mitochondria is associated with pathological alterations both in idiopathic and familial PD [65].

5.11.1 Inorganic Nanomaterials 5.11.1.1 Metal Nanoparticles The most commonly used nanoparticles for the treatment of PD are gold and magnetic iron oxide nanoparticles (IO single bond NPs). Iron oxide nanoparticles were used to evaluate the neuroprotection in 6-hydroxydopamine (6-OHDA) model of PD. The results exhibited an improvement in the function of mitochondria and volume of lesions in the intervention groups [66]. 5.11.1.2 Quantum Dots Quantum dots (QDs) exhibited extraordinary electrical and optical properties. Basically, they are zero-dimensional nanostructures. They nanostructures have opened new horizons in drug delivery. The accumulation of synuclein (syn) in the midbrain is associated with the PD pathology. No therapeutic agent is available for the inhibition of this aggregation. Recently, quantum dots of graphene have shown response in blocking syn fertilization. These graphene quantum dots can also disaggregate the mature fibrils. The studies were supported by in vivo studies where they exhibited good penetration to BBB and also provide protection against the dopamine neuron loss [67]. 5.11.1.3 Cerium Oxide Because of the unusual properties of cerium oxide NPS (CeO2), they have garnered a lot of attention in recent years. CeO2 NPs have lately been found to have unique effects in various neurodegenerative diseases. The harmful effects of syn were reduced with the use of CeO2 NPs. They hindered the production of reactive species and improved mitochondrial dysfunction in yeast cells. These NPs possess the potential to adsorb syn making them a potent syn toxicity inhibitor [67].

5.11.2 Organic Nanoparticles 5.11.2.1 Polymeric Nanoparticles Different topologies used for the management of PD include the use of Poly (lactic-co-­ glycolic acid) (PLGA), chitosan, poly (ethylene glycol) (PEG) [67]. Selegiline-loaded chitosan NPs can be used for the nasal targeting of brain [68]. Rotigotine can be delivered

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intranasally for the treatment of PD. Researchers constructed lactoferrin surface modified with poly (lactic-co-glycolic acid)-poly (ethylene glycol) (PLGA-PEG) nanoparticles (NPs) [69]. Amphiphilic block copolymers which contain poly (L-dopa (OAc)2) were devised for treating PD in a mouse model. It was named as nano-DOPA. The pharmacokinetic properties were enhanced by solubilizing the nano-DOPA in physiological conditions and later on activated slowly. Nano-DOPA exhibited remarkable efficiency in improving PD symptoms when evaluated in neurotoxin-induced PD model as compared to L-dopa [67].

5.11.2.2 Solid Nanoparticles Solid lipid nanoparticles (SLNs) exhibit the property of protection from enzymes and chemical degradation, carry the drug to the required site posing a little effect on the surrounding tissues, and also show good penetrability, thus enhancing bioavailability [70]. Conjugation of apolipoprotein E with SLNs of resveratrol can be easily identified by LDL receptors f BBB. Similarly, curcumin and piperine were coloaded in glyceryl monooleate NPs and later on covered with different surfactants. It improved the bioavailability of curcumin and enhanced the penetrability of both drugs in CNS to maximize the antiparkinsonism effect of drugs. The results in the mice model exhibited improved motor coordination and dysfunction of dopaminergic neurons [71]. 5.11.2.3 Gene Therapy in PD Gene therapy use different vectors for the carrying of genetic material into the neurons. These are responsible for the inhibition of transcription of one or the other particular gene [72]. Gene therapy has been employed for the management of PD in a number of ways. The goals for the gene therapy in PD were to improve the production of dopamine, enhancing trophic factors creation, improvement in lysosomal functioning or alteration in the connection of responsive nodes in basal ganglia [73]. Brain-penetrating nanoparticles (BPNs) produced continuous expressions of GDNF in nerve cells. Gene delivery experimentation in PD rat models has expressed optimal levels of GDNF proteins after single treatment that lasted for 10  days. Gene therapy improved the density of dopaminergic neurons and dopamine levels. It also helped in curing the motor and behavioral symptoms. Gene therapy did not pose any toxicity [74]. 5.11.2.4 Dopamine Modulation Carboxylate carbon nanotube (c-CNT) was devised that helped in improving the dopamine levels in the brain. This biocompatible device increases the permeability of brain and decreases adverse effects [75]. Improvement in water solubility of monoamine oxidase B inhibitor (MAO-B) was produced by using PEGylated PLGA nanoparticles (NPs) [76].

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5.12 Nanomaterials for Parkinson Disease Diagnosis Breakthroughs in nanotechnology have permitted the development of biosensing devices capable of tracking various biomarkers in clinical samples in real time. Dopamine measurement was already popular and was generally done using spectrophotometry and chromatography. Other approaches for detecting Parkinson’s disease have also been used (mitochondrial dysfunction, synuclein detection, and breath testing) [67].

5.13 Epilepsy According to the World Health Organization’s (WHO) April 2018 study “Epilepsy,” epilepsy is the fourth most frequent global neurological issue after migraine, stroke, and AD. When two or more unprovoked seizures occur, a person is considered epileptic [77]. Seizures are caused by an abnormally synchronized and prolonged firing of a group of neurons. The massive entrance of Ca2+ into neurons is the main neurotoxic process that led to cell death and finally to neurodegeneration. Seizures can be caused by anything that disrupts the regular pattern of neuronal activity, from disease to brain injury to atypical brain development. Indeed, epilepsy can be caused by a variety of factors, including genetic factors, abnormalities in brain wiring, an imbalance of nerve signaling in the brain, infection, traumatic brain injury, oxygen deprivation, stroke, brain tumors, and metabolic derangements, but for approximately half of those suffering from this condition, no specific causative factors have been identified [78].

5.13.1 Intranasal Delivery of Antiepileptic Drug (AED)-Loaded Polymeric Nanoparticles Several properties of NPs might provide a good platform for direct drug delivery to the brain. Several authors have shown that the physicochemical features of NPs determine their destiny in the brain following intranasal (IN) injection. The transport of NPs is known to be affected by size, shape, surface, and stability qualities (the 4S laws) [72]. NPs with particle sizes less than 300 nm are used in various formulations to load and transport medications to the brain via the olfactory pathway. Several animal studies have demonstrated that NPs administered intravenously may improve pharmacological activity or therapeutic efficacy, as well as lessen medication adverse effects when compared to traditional drug delivery systems (DDSs). According to the literature, there is considerable difficulty understanding the exact mechanism of direct transport of NPs from the nose to the brain. Another significant issue to consider is the drug’s strength; in fact, it is conceivable to speculate on the usage of only highly concentrated molecules (20 mg per dosage), as the dose must be supplied in a 100–200 L spray or solution. This emphasizes the significance of high-water solubility; if this is not the case, the formulation must include solubilizing

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agents. In the case of AEDs, we know that benzodiazepines have poor water solubility at pH 5–7. The drug’s water solubility can be improved by encapsulating it in a nanomedicine product. In this situation, the complete mass of product (nanoparticle plus medicine) should be supplied in the same volume, and the drug should be powerful enough to reach the brain at a therapeutic concentration (1–2 mg per dosage) [77].

5.13.2 Potential Nanotherapies for Epilepsy Relevant preclinical research utilizing biodegradable nanoparticles for epilepsy diseases has been shown in the following Table 5.1. Table 5.1  Preclinical research utilizing biodegradable nanoparticles for epilepsy diseases. Adapted & reproduced with permission from [79] Nanoparticle Lipid nanoparticle (SLN)

Matrix Glyceryl monostearate

Carbamazepine Lipid nanoparticle (SLN)

Phospholipon R80 H

Drug Alprazolam

Lipid nanoparticle (NLC and SLN)

Polymeric nanoparticle

Lipid myristyl myristate Cetyl esters wax NF Crodamol® GTCC-LQ PLGA

Route Results IV, Increased concentration IN to brain followed by in intranasal intervention Increase in bioavailability at lower dose PO Better results with solid lipid nanoparticles with chitosan in maximal electroshock method Better results were obtained in isoniazid-­ induced convulsions followed by solid lipid nanoparticles administration without chitosan IN Incorporation of formulation in mucoadhesive gel Protection against chemical convulsions by NLC IV Efficacy was 30 times greater than when compared to free drug No effect was seen on encapsulated carbamazepine by PgP porter

References [80]

[79]

[81]

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Table 5.1 (continued) Drug Catechin hydrate

Nanoparticle Polymeric nanoparticle

Matrix PLGA-chitosan

Clonazepam

Lipid nanoparticle (SLN and NLC)

Glycerol monostearate

Curcumin

Lipid nanoparticle (SLN)

Diazepam

Polymeric nanoparticle Polymeric nanoparticle

EGCG

Glyceryl monooleate Glyceryl behenate Oleic acid Stearic acid Lecithin

Route Results References i.n. Decrease of catechin [82] hydrate was decreased Biodistribution improved in brain First-pass metabolism was avoided followed by administration of IN route [83] – Thermosensitive mucoadhesive gel was used to incorporate the formulation Protection against chemical-induced convulsions –

PLGA

–

PLGA-PEG

IN

Lamotrigine

Lipid Glyceryl nanoparticles monostearate (NLC) Oleic acid

IN

Oxcarbazepine

Polymeric PLGA nanoparticles

IN

Protection against oxidative stress in brain Proteins for p-P38 MAPK and apoptosis were downregulated Diazepam encapsulated in NPs Neuroprotection Neuroinflammation decreased owe to anticonvulsant effect Intranasal administration resulted in higher brain concentrations Reduced dosage resulted in anticonvulsant effect Enhanced accumulation in cerebral tissues Better compatibility with neuronal cells

[84]

[85] [86]

[87]

[88]

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Table 5.1 (continued) Nanoparticle Matrix Route Results IN Better anticonvulsant PLGA-­ Polymeric activity nanoparticles functionalized with copper oxide quantum dots-coated hyaluronic acid Polymeric Chitosan-STTP IP Improved protection to nanoparticles neurons Improved anticonvulsant effect Improvement in activation of astrocytes when compared with free piperine in epilepsy models TRH analogues Polymeric PLGA-chitosan IN Limited damage to (NP-355 and nanoparticles neurons owe to better NP-647) anticonvulsant effect Improved biodistribution of NP loaded with analogues of TRH Lipid Valproic acid Cetyl palmitate IN Increased concentration nanoparticle in brain followed by IN (NLC) administration IP Lower dose produced Soy lecithin same effect Octyldodecanol Drug Piperine

References [89]

[90]

[91]

5.14 Schizophrenia Schizophrenia is a cognitive disorder which is characterized by emotional disturbances that affect the quality of life [92]. It is estimated that 1% of the world population is affected by schizophrenia accompanying delusions, loss of initiation, cognitive dysfunction, and hallucinations [93]. Schizophrenia produces a variety of symptoms. They are classified as positive symptoms also called psychotic symptoms and negative symptoms known as deficit-like symptoms. Positive symptoms comprise of cognitive (perceptive) distortions and delusional approach. Deficit-like symptoms include social deficit and interpersonal symptoms [94]. There are multiple factors involved in the pathogenesis of the schizophrenia ranging from metabolic, auto-immunological, genetic, environmental factors along with neurotransmission abnormalities in the brain structures [95]. The mainstay therapy for treating schizophrenia includes drugs that try to cater the increased dopamine transmission in patient’s brain. Some atypical agents are characterized by lesser adverse effect.

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They can also be used to treat bipolar disorders in combination with lithium and antiepileptic drugs. The pharmaceutical issues of antipsychotic therapy which include lesser bioavailability, therapeutic inefficacy, drug toxicity in peripheries, and poor patient compliance were tried to address using nanotechnology. Different researchers have conducted studies and reported the effects of nanocarriers as drug delivery vehicles. The studies reported improvement in pharmacokinetic and pharmacodynamics profiles of drug molecules when delivered via nanocarriers. Antipsychotic drugs for the treatment of schizophrenia and similar disorders were delivered using nanocarrier systems like liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipid carriers, and solid lipid nanoparticles [96].

5.14.1 Polymeric Nanoparticles One approach to treat schizophrenia is to deliver therapeutic drugs incorporated in the small size (10–100 nm) polymeric nanoparticles. Clozapine (CLZ) and risperidone (RIS) were coencapsulated in polylactide-co-glycolide (PLGA) nanoparticles with the help of spray-drying technique. The nanoparticles exhibited an entrapment efficiency of 126.3 mg/ mg of CLZ and 58.2 mg/mg of RIS. The nanoformulation exhibited a release of 80% of both drugs over a period of 10 days. Both drugs did not exhibit chemical interaction with the polymer. The neuronal cell lines PC12 were used to access in vitro cytotoxicity and no cytotoxicity was observed indicating biocompatible nature of nanoformulation. Low-­ molecular weight PLGA used in the prepared formulation exhibited not only extended but also a faster release. This concludes that CLZ-RIS-PLGA-NPs are a beneficial approach for CNS delivery to coup up refractory schizophrenia. Another approach for the treatment of schizophrenia can be used of solid lipid nanoparticles. These solid lipid nanocarriers are very efficient in the delivery of antipsychotics in combination with other drugs [97]. Paliperidone nanoparticles were prepared with stearic acid to enhance the oral bioavailability. These solid lipid nanoparticles were prepared using stearic acid by Kumar and Randhawa. No chemical interaction was observed between the components used for nanoparticles, stearic acid, and paliperidone as was evident from differential scanning calorimetry, Fourier infrared spectroscopy, and X-RD analysis. They identified the size range of these solid lipid nanoparticles from 230 ± 30 nm. They explored reduction of the molecular dispersion in matrix of stearic acid. They found an entrapment efficiency of 42.4 (% w/w) and 4.1 (% w/w) drug loading in the lipid matrix. The therapeutic ability of these solid lipid nanoparticles revealed cytotoxicity in cell lines against murine macrophages (RAW 264.7). The investigators revealed that handsome amount of solid lipid nanoparticles can be delivered because stearic acid provides neuroprotective effect with lesser toxicity and a controlled release of paliperidone [98].

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5.14.2 Solid Lipid Nanocarriers Solid lipid nanocarriers can be used as a promising tool or the delivery of drugs but at the same time, they also express some disadvantages. These include their lesser drug loading and expulsion of drug after reaching a polymorphic form. To overcome this disadvantage, nanostructured lipid carriers are modified from solid lipid nanoparticles. These nanostructured lipids consist of mixture of solid and liquid lipids which are stabilized in solution of aqueous surfactant [99].

5.14.3 Lithium Nanoparticles The reduction in the renal toxicity of the lithium salts used to treat schizophrenia was attained by preparing the nanostructured lipid carriers lithium carbonate (LiCO3) with thioctic acid (THA an antioxidant). These nano lipid structures exhibited a drug release of 12 h in a time-dependent fashion as compared to pure drug. Therapeutically, these lithium-­ thioctic acid revealed lesser nephrotoxicity when compared to control group [100].

5.14.4 Nanostructured Lipid Carriers The neuroprotective effect of idebenone was enhanced by fabrication of the iloperidone (ILO) and idebenone (IDB) in nanostructured lipid carriers. At the same time, the carrier was prepared to reduce the catalepsy induced by iloperidone. The carrier mediated an increase in the transportation of drugs to the brain by 2.12- and 2.53-fold from co-nano lipid-structured carriers as compared to individual drug entrapped in nano lipid structure. Similarly, 3.15- and 3.09-fold increase of drug transport was observed to the brain from ILO+ IDB nano lipid structures than alone ILO and IDB nano lipid structures. Catalepsy score was attenuated by the use of ILO + IDB nano lipid structures for 28 days in wistar rats as compared to ILO nano lipid carriers. The fabricated formulation exhibited better concentrations in the brain followed by intranasal route of administration and enhanced the neuroprotective effect by compensating the oxidative stress generated due to IDB [101]. Vitorino prepared the nano lipid carrier structures of the antipsychotic drug olanzapine. They prepared the combination of simvastatin and olanzapine to coup up the dyslipidemia and cardiovascular risk associated with olanzapine. The nano lipid structures were treated with a permeability enhancers, ethanol (Eth) and limonene (L), and a gel was formed. A steady state level was achieved in 10 h and retained it up to 48 h after transdermal application in rats. Whereas the studies conducted on newborn pig skin also revealed a controlled release of 48 h after transdermal application. The new strategy opened new horizons for the development of gels to use clinically for treating schizophrenia and schizoaffective disorders [102]. Nanostructured lipid carriers can be used as a preferable carrier for the combination of antipsychotic therapy owing to better stability and longer

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durability. They possess the potential to minimize toxicity of peripheries by targeting antipsychotics directly to the brain directly.

5.14.5 Liposomes Liposomal drug delivery is another carrier with unique properties like biodegradability biocompatibility, better safety, and good absorption capabilities of poorly soluble drugs. They can encapsulate both lipophilic and hydrophilic drugs [103]. Liposomes have been proved efficient tool in the provision of efficacious delivery of combinational antipsychotics. Amisulpride is used for the treatment of schizophrenia. Shukr and Ahmed prepared two types, single- and double-loaded liposomes. They prepared single-loaded liposomes using hydroxyl propyl–β–cyclodextrin (HP–β–CD) in aqueous phase and double-loaded liposomes consisted of HP–β–CD in the aqueous phase and free amisulpride in the lipidic bilayer. They found that maximum plasma concentration was achieved by double-loaded liposomes exhibiting 1.55- and 1.29- fold higher concentration than the available market drug (Solian) and conventional liposomes [104].

5.14.6 Polymeric Micelles Polymeric micelles are amphiphilic nanosystems for the delivery of drugs. It is constituted by a water-loving shell in which micelles are stabilized in an aqueous solution and core is made up of hydrophobic part. Micelles were developed using paliperidone palmitate and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) for the management of psychiatric disorders. The investigators prepared micelles of PP with Vitamin E by solvent casting technique followed by sonication for the fabrication of PP-TPGS formulations. Therapeutically, these micelles attenuate apomorphine-induced sniffing and climbing in Swiss albino mice after 24 h. The results were better than control PP formulation. The cataleptic score was also improved during 24 h. Polymeric nanomicelles provided beneficial approach as a prolonged therapy for psychosis. They also exhibited better bioavailability and permeability in the brain [105].

5.15 Challenges and Perspectives It is believed that the aging of society is now at the door step. This process is leading to emergence of the CNS disorders at a pace greater than ever. CNS diseases not only effect the individuals themselves but also debilitates the people associated with the patients adding to the social burden. CNS diseases are listed second amongst the cause of death globally. It is highly desirable to synthesize novel moieties for the management of CNS disorders but delivery of these moieties to the brain poses even a greater challenge.

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Understanding of BBB structure and functions between physiological and pathological condition is of utmost importance. The focus of research should be on the discovery of specified targets leading to the development of selective carriers in brain. Another aspect that must be considered is the understanding of carrier characteristics and their interaction with the living system. The development of targeted therapeutic delivery to the brain is in early phase but recent new interventions and continuous investigation may pave a path for effective therapeutics for CNS disorders.

5.16 Conclusion Several breakthroughs to enhance CNS medication delivery have emerged from tremendous efforts over the last several decades. Many of the systems have great therapeutic application potential. Indeed, the successful combination of many techniques, such as drug encapsulation in nanoparticles coupled with vectors may offer encouraging results. The capacity to pack medicines in cells leading to alteration of neuronal regeneration and posing anti-inflammatory effect within the CNS has gained a lot of interest. These findings, taken collectively, provide a crucial basis for further investigations for improvement in pharmacokinetics, improving the toxicity and allowing for an early detection of human illness. These advancements cannot come fast enough, given the prospect of considerable increases in the prevalence and incidence of human neurodegenerative illnesses.

Take-Home Message

• Nanotechnology is leading to formulation development which can not only improve the therapeutic efficacy of drugs in CNS disorders, but also minimize the adverse effects. • Several breakthroughs to enhance CNS medication delivery have emerged from tremendous efforts over the last several decades. • Indeed, the successful combination of many techniques, such as drug encapsulation in nanoparticles coupled with vectors may offer encouraging therapeutic results in neurodegenerative diseases as well as different brain cancers.

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Further Reading Bonilla L, Esteruelas G, Ettcheto M, Espina M, García ML, Camins A. Biodegradable nanoparticles for the treatment of epilepsy: From current advances to future challenges. 2022;7:121–32 Mittal KR, Pharasi N, Sarna B, Singh M, Rachana HS, Singh SK, Dua K, Jha SK, Dey A, Ojha S, Mani S, Jha NJ. Nanotechnology-based drug delivery for the treatment of CNS disorders. Transl Neurosci. 2022;13(1):527–46. Quader S, Kataoka K, Cabral H.  Nanomedicine for brain cancer. Adv Drug Deliv Rev. 2022;182(114115)

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Nanomedicines in Treatment of Cancer Bushra Akhtar, Ayesha Tanveer, Ali Sharif, Fozia Anjum, Muhammad Shahid, and Saadiya Zia

Contents 6.1  I ntroduction  6.2  P  harmacology Aspects of Nanomedicines in Cancer  6.2.1  Pharmacokinetics of Nanomedicine  6.2.2  Mechanism of Action of Nanomedicines for Treating Cancer  6.3  Brief Overview of Cancer Pathophysiology & Role of Nanomedicines in Their Treatment  6.3.1  Cancer Types  6.3.2  Pathophysiology of Cancer  6.4  Role of Nanomedicines in Treatment of Different Cancers  6.4.1  Nanomedicines in Treatment of Breast Cancer  6.4.2  Nanomedicines in Treatment of HIV-Related Kaposi Sarcoma  6.4.3  Nanomedicines in Treatment of Lung Cancer 

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B. Akhtar (*) Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan e-mail: [email protected] A. Tanveer Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan A. Sharif Department of Pharmacology, Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Pakistan F. Anjum Department of Chemistry, Government College University, Faisalabad, Pakistan e-mail: [email protected] M. Shahid · S. Zia Department of Biochemistry, University of Agriculture, Faisalabad, Pakistan © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_6

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184 6.4.4  Nanomedicines in Treatment of Lymphomatous Meningitis  6.4.5  Nanomedicines in Hepatocellular Carcinoma  6.4.6  Nanomedicines in Treatment of Bladder Cancer  6.4.7  Nanomedicines in Treatment of Ovarian Cancer  6.4.8  Nanomedicines in Treatment of Prostate Cancer  6.5  Drug Resistance in Cancer and Nanomedicines  6.5.1  Multidrug Resistance  6.5.2  Intrinsic and Acquired Mutation  6.5.3  The Contribution of Microenvironment in Multidrug Resistance  6.6  Theranostic Nanomedicines Used in Cancer  6.7  Conclusion  References 

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What You Will Learn from This Chapter

One of the biggest risks to human health is cancer; it has complex cellular modifications that set it apart from healthy organs and tissues. It is generally known that the distinct tumor microenvironment (TME) would encourage tumor progression and metastasis while also causing cancers to become resistant to various types of therapy, so modulating TME can be beneficial. Nanomedicines have demonstrated tremendous potential in this direction that is discussed in this chapter. Cancer types and pathogenesis have also discussed in this chapter. In many clinical situations, cancer is still an incurable disease despite the availability of treatment drugs. In this regard, attention has been drawn to the use of nanomedicine, in particular, as a means of enhancing drug delivery. Polymeric nanoparticles can be utilized to improve the formulation of new therapies or to optimize already-existing drugs. Several diagnostic and therapeutic drugs that are developed by nanotechnology are currently undergoing clinical trials, and few have already received FDA approval. In this chapter, it is discussed how cancer cell invasion can be monitored and treated using the science of theranostic nanomedicines.

6.1 Introduction Cell invasion, which is defined as the movement of cells within a tissue, is a crucial mechanism for tissue growth, repair, and immune surveillance. However, this pathway can be aberrantly regulated in cancer cells, which can result in malignant invasion of nearby tissue and the formation of lymphatic vessels [1] These occurrences cause cancer to spread from its original tissue and then grow in other organs, a process known as cancer metastasis, the most dangerous cancer stage when it has spread to other body parts [2]. Many targeting therapeutic agents are being developed but insufficient delivery of therapies and the resistance of the tumor cells are still the hurdles toward treatment of invasion and metastasis [3]. The resistance can be natural or acquired; in natural resistance, the cancer cells are unresponsive to the initial drug while in acquired resistance, the cells did not

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respond after initial successful treatment [4]. To circumvent these limitations, the researches turned toward the application of nanotechnology in developing the nanomedicine. Nanomedicine is the application of the nanotechnology to achieve improvement in healthcare [5]. The European Science Foundation’s definition of nanomedicine is as follows: “Nanomedicine uses nanosized tools for the diagnosis, prevention, and treatment of disease as well as to gain understanding of the complex underlying pathophysiology of disease.” [6]. Additionally, nanomedicine may be able to penetrate natural barriers to reach new sites of delivery and interact with DNA or small proteins at various levels in blood or within organs, tissues, or cells [7]. Surface properties are becoming an intrinsic parameter of a particle’s or material’s potential actions at the nanoscale due to the surface to volume ratio [8]. The particles’ biocompatibility and blood circulation time are increased by coating them and functionalizing their surfaces. This also makes the particles more likely to bind to the desired target very specifically. Early detection, prevention, and treatment of many diseases, including cancer, may be made possible by nanomedicine [9]. There are currently numerous products in clinical trials for nanomedicine that address all major diseases, including cancer. By delivering therapeutic agents to the targeted site or cancer cells, nanomedicine has great potential to treat cancer at the molecular level and reduce toxicities [10]. The main advantage of nanoparticles use includes improving pharmacological aspects of existing anticancer compounds, providing more sensitive cancer detection, enhancing the drug efficacy, providing cost-effectiveness with an improved quality of life and most importantly treating the cancer with minimum toxicity [11].

6.2 Pharmacology Aspects of Nanomedicines in Cancer 6.2.1 Pharmacokinetics of Nanomedicine A nanomedicine is administered parentally, orally or transdermally after which it circulates into the blood. The circulation time in blood is comparatively more than other medicines. The nanoparticles are also administered by pulmonary route and like other medicines the therapeutic agent is not mucociliary cleared resulting in long residence time with greater concentration at the site [12]. The reticuloendothelial system’s macrophages then partially engulf it and extravasate to the tumor site. Nanomedicine enters cells through endocytosis, including patocytosis, potocytosis, and caveolar- and clarthrin-mediated endocytosis. In contrast, the macrophages of the reticuloendothelial system (RES) remove the large particles from the bloodstream [13]. This extravagance facilitates its interactions with the tumor tissue for improved target cell recognition and uptake. The tight and continuous vasculature causes nanomedicines to have poor extravasation at the normal tissue region and poor distribution there. Three levels of disposition to tumor cells are followed by the systemic circulation of nanomedicine in the blood for it to manifest its pharmacological effect [14]. Although many biological factors and the tumor microenvironment work against it, the nanomedicines at the tumor site eventually reach the tumor cells. The

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drug eventually reaches the subcellular organelle where it can start working, thus the use of nanomedicines aids in increasing drug dose response, targeting effect, and bioavailability [15]. The kidneys are typically responsible for the clearance of nanomedicine, which is crucial in preventing potential health risks from nonspecific and long-term accumulation. The renal clearance is a complicated process that involves the elimination of waste products through glomerular filtration, tubular secretion, and urinary excretion [16]. The size and size distribution, surface charge, and shape of nanomedicine are the factors that can alter the renal clearance. The cationic nanoparticles with diameter of 6–8 nm as compared to neutral or negatively charged, showed an enhanced renal clearance through the negatively charged glomerular basement membrane [17]. As single-wall carbon nanotubes with a length of 100–500 nm are cleared similarly to small molecules and have a half-life of about 6 min, shape is yet another crucial factor in renal clearance. The development of cancer treatment and diagnosis uses the ultra-small, 10 nm-sized nanomedicines with high-blood half-lives [18]. To avoid toxic effects, the injected agents should be eliminated in a reasonable amount of time. However, they should not be eliminated so quickly that their efficacy is compromised [13]. Because it theoretically enables the targeting of the particles to increase the concentration of the drug at the site of interest and reduce the systematic side effects, the nanodrug system is practicable and effective in the treatment of cancer. However, nanotechnology is now being used to treat a number of other serious diseases such as COPD, diabetes, dementia, and others, in addition to cancer [19].

6.2.2 Mechanism of Action of Nanomedicines for Treating Cancer The signaling of proteins of cancer cells are interacted with during targeted therapy [20]. Drug inhibits the transmission of a signal that activates cancer cells to proliferate, causing them to undergo apoptosis [21]. Nowadays, monoclonal antibodies are used to target a particular antigen on the surface of cancer cells and produce a specific effect. The risk to nearby normal cells is decreased by the selective drug delivery only to the tumor cells [22]. The monoclonal antibodies against EGFR in the conjugates of nanoparticles with therapeutic agents, such as ND-Cisplastin and ND-Cetuximab, have specific binding to the cancer cells [23]. Since different chemotherapeutic agents are transported by nanotubes, their precise and prolonged action on cancer tissues is made possible. The use of fluorescent nanotube markers helps identify cancer cells. Single-wall carbon nanotubes (SWCNTs) are primarily employed [4, 24]. Rituxan and Herceptin is a couple of examples of monoclonal antibodies that are used with SWCNTs. These antibodies identify the HER2 neu receptor and CD20 cell surface receptors on breast cancer cells [24, 25]. The carbon nanotubes emit radiation at 785 nm, which causes photoluminescence in the infrared spectrum. This separates normal cells from cancer cells, and the specific binding of antibodies to the antigens of cancer cells kills the cancer cells [26]. Most anticancer medications, like Paclitaxel, which is used to treat breast cancer, have poor water solubility,

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which limits their effectiveness. This solubility issue is formulated using nanotechnology in order to be resolved. It also forms a SWCNT-HAS complex with human serum albumin in order to carry the drug Paclitaxel, which is effectively delivered to the site of action [27]. When compared to when nanoparticle conjugate was not present, this more effectively slows the growth of MCF-7 tumor cells. By using this complex, the survival rate of tumor cells is reduced from 70% to 63%, having a potent antitumor effect [28]. The nanoparticles target the tumor cells by two pathways either by passive targeting or active targeting. The passive targeting is based on retention effect of particle of certain hydrodynamic size in cancerous tissues. The cancerous tissues have leaky blood vessels and also have enhanced permeability and retention EPR effect; so due to this, the nanoparticle will reach and act at the cancerous site [29]. The blood vessels surrounding tumorous tissues are defective and porous, whereas the nanoparticles injected into the blood stream do not penetrate through healthy tissues. When nanoparticles are injected into the blood, they pass through blood vessels and accumulate in tumorous tissues. The nanoparticles used here range in size from 70 nm to 200 nm [30]. In active targeting, specific nanoparticles that can bind to cancer cells are coupled with specific antibodies. Many cancers have overexpressed transferrin and folic receptors, which are primarily targeted in this pathway. This also targets specific cancer-related biomarkers, such as CA-125, which is overexpressed in more than 85% of ovarian cancer cases [31]. Anticancer medications can be delivered into cells using nanoparticles without activating the p-glycoprotein pump [32].

6.3 Brief Overview of Cancer Pathophysiology & Role of Nanomedicines in Their Treatment 6.3.1 Cancer Types The uncontrolled, uncoordinated growth that is not under physiologic control is the new growth. It is a condition wherein abnormal cells divide uncontrollably and can enter other tissues [33]. These cells with every cell division lose more of their chromosome tips called telomeres. The cancer cells turn on a gene for the enzyme telomerase that replaces the most lost telomere [34]. Before cancer develops, it requires multiple mutations. Mutation results in either increased growth rate of cell known as clonal proliferation or decreased apoptosis. The cancer is of two types, benign or malignant [34]. The benign neoplasm has controlled cell proliferation but is well differentiated and resembles a normal cell [35]. These cells are also surrounded by a fibrous capsule, grow slowly, and typically do not infiltrate, invade, or metastasize [36]. The ability of the malignant tumor to regulate differentiation and proliferation has been lost [37]. Malignant tumor cells lack the appearance of healthy adult cells and do not carry out the tissue’s normal functions [38]. They could release toxins, enzymes, signals, etc. They have the capacity to mutate and rapidly multiply on their own. The normal cells’ cell density-dependent or contact inhibition is absent in this tumor [39]. Cancer cells are not limited. In this type of tumor, the cells infiltrate, metastasize, invade to distant

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sizes [40]. These can also destroy the nearby cells by compression. There are two categories of tumors called solid tumors and hematological cancers. The solid tumors are initially restricted to a particular tissue or organ, but eventually they invade, penetrate, and may spread by invading the blood and lymphatic systems [22]. Hematological cancers spread quickly because they affect blood or lymphatic system cells. Leukemia, a type of cancer that affects white blood cells, and lymphatic leukemia, a subtype of leukemia that primarily affects B-cells but can also affect T-cells, are two examples [41]. The malignant neoplasm cells have genetic instability that they are unable to correct the errors in cell division. They have multiple copies of chromosomes and as they are more prone to gene mutation so they can affect the growth regulation and cell cycle arrest [42].

6.3.2 Pathophysiology of Cancer Different types of carcinogens that cause the initiation of cancer pathophysiology are shown in Fig. 6.1. When a normal cell sustains DNA damage from a carcinogenic agent, such as the chemical carcinogen benzene, physical carcinogens like ultraviolet radiation, or infectious pathogens like the Epstein-Barr virus, and growth-promoting oncogenes that control apoptosis are activated or altered [43]. Basically in all types of the cancer, there are three basic steps that involves the initial mutation or damage to the DNA [44]. The mutation can be a pointed mutation in a single nucleotide, in a gene code, chromosomal rearrangement or epigenic modification in which particular methane group or other group attaches also latterly identified as antigens [45]. When these mutated cells enter into the cell cycle, they pass the check points by the CDK and cyclines. In second step, called

Fig. 6.1  Pathophysiology of cancer

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promotion, the mutated cells are stimulated to divide through unregulated accelerated growth rate and this is also known as proliferation and the cell cycle ends up in an uncontrolled number of cells [46]. The last progression steps involve more mutations resulting more aggressive cancer to invade into the surroundings or become adenoma according to the different types of cancers [47]. Angiogenesis is essential for cancer to survive, to meet the elevated demand for nutrients and oxygen due to the high cell count [48]. These all cause abnormal cell count or unregulated cell differentiation and growth leading to neoplasm [49]. The uncontrolled cell growth is basically due to the alteration in growth factors initiating the growth or by the suppression of tumor genes [50, 51]. These changes produce more copies of the growth factor receptor [50]. The tumor suppressor genes are also intricate in the suppression of the division of the cells and without these genes, the genetically damaged cells also continue to divide. In cancer, the cells increase proliferation frequency and decrease apoptosis so fewer enter into the G-zero phase of the cell cycle [52, 53]. The cancer cells produce the fetal antigen to avoid detection from the immune cells. Initially as the cell growth increases, the tumor then moves into the process known as metastasis in which the cells in the primary tumor lose adhesion and develop the ability to escape, travel, and survive to develop a secondary tumor [54]. Although the tumor cells continue to mutate but they still maintain some of the characteristics of the primary tumor from which they were derived. Metastasis takes place via blood or lymph, e.g., sarcoma metastasizes more frequently via blood that often involves liver and lungs [55]. On the other hand, carcinoma metastasizes more frequently via lymph. The basic pathophysiology of each cancer is almost the same, the differences that occur are related to the origin of cancer, type of sarcoma or the stage at which it is diagnosed. Treatment is dependent on the stage of the diagnosis and is prescribed accordingly [56].

6.4 Role of Nanomedicines in Treatment of Different Cancers As the nanomedicine is the emerging technique for the delivery of the drug, multiple nanomedicines are at different clinical trials such as enlisted in the Table 6.1.

6.4.1 Nanomedicines in Treatment of Breast Cancer Breast cancer is the most common nonskin malignancy in women and can occur in males very rarely. Breast contains the mammary glands that are the modified sweat glands containing lobules and ducts. All the breast cancers are adenocarcinomas means are glandular cancer [57]. If carcinoma is in the basement membrane, then it is called ductal carcinoma in situ. This is asymptomatic and its clinical presentation is the microcalcification seen in the screening test [58]. This is asymptomatic and is malignant cancer. The biological classification of cancer is based on HER2 and ER. In HER2 type, there is overproduction of this gene and carcinoma will be called HER2-positive cancer, ER is the estrogen receptors

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190 Table 6.1  Nanomedicines for treating cancer Cancer type Breast cancer Breast cancers Metastatic pancreatic cancer HIV-related Kaposi sarcoma Lung cancer Breast cancer Pancreatic cancer HIV-related Kaposi sarcoma Lung cancer Lymphomatous meningitis Ovarian cancer Breast cancer Breast cancer Lung cancer Acute lymphocytic leukemia Pancreatic cancer Hepatocellular cancer Bladder cancer Ovarian cancer Prostate cancer

Active ingredient Liposome-encapsulated doxorubicin Albumin-bound paclitaxel nanospheres Nab-paclitaxel with gemcitabine Liposome-encapsulated daunorubicin Paclitaxel Paclitaxel

Drug product Myocet Paclitaxel

FDA approved date\ clinical trial status 2000 approved in Europe and Canada January 2005 September, 2013

References [65, 66] [71, 72]

DaunoXome April, 1996

[88, 90]

Polyglumex Clinical phase II EndoTAG-1 Clinical phase II

[35, 95] [76, 80]

Liposomal cisplastin analogue Liposomal vincristine Liposomal cytarabine

Lipoplatin

Clinical phase II

[91, 93]

OncoTCS DepoCyt

Clinical Phase II April, 1999

[100, 102] [105, 108]

Pegylated doxorubicin

Annamycin

November 1995

[78, 82]

Liposomal Vinorelbine PEG-asparaginase

Vinorelbine

December 1994

[80, 81]

Oncaspar

February 1994

[151, 152]

Paclitaxel Doxorubicin

Genexol-PM Clinical phase II Livatag November 1995

[153, 154] [114, 155]

Docetaxel Pegylated doxorubicin Docetaxel

BIND-014 Doxil BIND-014

[122, 123] [78, 82] [150, 156]

May 2004 November 1995 May 2004

present on the mutated breast cells, then it is called ER-positive cancer. Most of the 50–60% of breast cancers are ER-positive. The HER2-positive cancer can either be ER-positive or -negative and 10–20% of the breast cancer is of this type. The third category of breast cancer is triple-negative breast cancer in which ER, progesterone receptors, HER2 all these three are negative [59]. In the pathogenesis of the breast cancer, the three factors that interplay their role are hormonal effects, environment, and genetic effect as shown in Fig. 6.2. There are different susceptible genes causing cancer, the most common gene is breast receptor-1 (BRCA-1) and breast receptor-2 (BRCA-2), the mutation in both the alleles of this gene not only causes breast cancer but also ovarian, prostate, and pancreatic cancer. BRCA-1 is associated with triple-negative cancer and BRCA-2 is associated with ER-positive cancer. Another gene is the tumor suppressor gene Tp 53, and mutation in it is associated with triple-negative and HER2-positive cancer [60]. Few of the drugs being used for treating the breast cancer are, e.g., Myocet (liposomal drug). It serves as the first line of defense against meta-

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Fig. 6.2  Risk factors of breast cancer

static cancer. In case of breast cancer, it is presently being researched in combination with trastuzumab and paclitaxel [61, 62]. Due to a better pharmacokinetic profile, Myocet has an improved therapeutic index and comparable anticancer activity to Doxurubicin [63, 64]. The drug is encapsulated using the pH gradient method, with the inner compartment having a pH of 4 and the outer a pH of 7 [65]. The initial recommended dose of Myocet is 60–75 mg\ m2 and cyclophosphamide (600 mg\m2) every 3 week [66]. The clearance of doxorubicin in breast cancer patients receiving Myocet is 5–9 times lower and also the volume of distribution is lower 10–25 times than the conventional doxorubicin. The half-life is nearly 16–50 h, which is a significant increase over the half-­life of doxorubicin [64]. Despite having the same API, myocet and doxil are not bioequivalent due to differences in the lipid composition, loading method, size, and tissue distribution profile [65]. The second-most frequently prescribed medication is paclitaxel, which contains the hydrophobic active pharmaceutical ingredient. To combat this, a polyethoxylated castor oil derivative (cremophore EL) is combined with ethanol in a 50:50 ratio. This formulation has toxicities that are dose-limited [67]. Cremophore can cause hypersensitivity reactions, so as a preventative measure, oral dexamethasone or diphenhydramine should be given. There is no need for premedication with paclitaxel and Abraxane because they do not contain cremophore. Paclitaxel and human albumin are combined using nanotechnology and delivered to the tumor’s target area [68]. Albumin transports to the desired site without having any toxic or immunogenic effects, albumin is the perfect carrier [69, 70]. The SPARC (Secreted Protein, Acidic and Rich in Cysteine) is overexpressed in tumor tissues like the breast, prostate, gastric, lung, and kidney, which facilitates the accumulation of the albumin-bound drugs. The drug’s response is improved. Paclitaxel is given intravenously as a suspension

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(260 mg/m2) as an infusion for 30 min [71]. In contrast to the concentration of 0.3–1.2 mg/ ml for conventional drugs, the nanoparticle albumin-bound paclitaxel is reconstituted using normal saline at a concentration of 2–10 mg/ml. Large extravascular distribution was indicated by the volume of distribution [72]. Within the dose range of 80–375 mg/m2, the drug exposure (AUC) is proportional to the dose. Paclitaxel Poliglumex (PPX), another paclitaxel carrier created by cell therapeutics, is a drug delivery system. In this, the Paclitaxel is conjugated to a sizable macromolecule known as poly-L glutamic acid [73]. The paclitaxel concentration is 37%. This functions through passive targeting that utilizes drainage vasculature and builds up at the tumor site [74]. The macromolecule is large enough to persist at the site. The preclinical studies show that PPX is more effective than standard paclitaxel [75]. This has more convenient dose schedule increasing the patient compliance and also has less toxic effects as reduced chances of neutropenia and alopecia [69]. A cationic liposome, Endotag-1, that contains paclitaxel, is the third nanomedicine that is employed. In a ratio of 50:45:5, paclitaxel, 1,2-dioleoyl-3-­ trimethylammonium-propane (DOTAP), and 1,2-dioleoyl-snglycero-3-phosphocholine (DOPC) make up the liposome. The size is approximately 220 nm [76]. In phase II trials, it has also demonstrated efficacy in treating triple-negative breast cancer. HER2 receptors and estrogen and progesterone hormone receptors are absent in triple-negative breast cancers. Due to the ineffectiveness of conventional antihormonal therapy, there are few treatments available for this type of cancer [77]. Breast cancer is also treated with the nanoparticle conjugated Annamycin which is semisynthetic doxorubicin analogue. This was first looked into as an anticancer medication without the multidrug resistance brought on by p-glycoprotein. The anthracycline family of medications’ insufficient efficacy is largely due to the -glycoprotein. The Annamycin differs from doxorubicin in that it lacks an amino group in the sugar moiety [78]. Without affecting the antitumor effect, the amino group removal decreased the cardiac toxicity. Annamycin intercalated into DNA and stopped topoisomerase II from working. As well as RNA and protein synthesis, this prevents DNA replication and repair. Compared to the standard Annamycin, this is indicated for breast tumors and is less toxic [79]. Another nanomedicine used to treat breast cancer is called vinorelbine. This semisynthetic vinca alkaloid and microtubule inhibitor is helpful in the treatment of different diseases including cancers of neck, lung, breast, head, and ovary. Vinorelbine tartrate is encapsulated in the aqueous core of the liposome in a new formulation of Allocrest [80]. This formulation uses targeted delivery and sustained release. It is anticipated that Vinorelbine’s high intratumoral concentration will increase its ability to kill cancer. Without increasing toxicity, the anticancer activity is enhanced. Nano Vinorelbine is effective in treating lung and breast cancer [81].

6.4.2 Nanomedicines in Treatment of HIV-Related Kaposi Sarcoma Kaposi sarcoma means vascular neoplasm is malignancy of proliferative vascular endothelial cells. These lesions can also be on gut or other organs. This sarcoma is also described as idiopathic multiple pigmented sarcoma of the skin [82]. This is usually developed in the immunocompromised, HIV patients because of human herpes virus 8 (HHV-8) or may be

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due to Kaposi’s sarcoma-associated herpes virus (KSHV). This interaction between the HIV-1 and HHV-8 activates the immune system resulting in the secretion of the cytokines, e.g., IL-6, TNF-a, basic fibroblast factor, and oncostain M causing defective immunoregulation resulting in the sarcoma. Initially, this sarcoma involves lymph nodes and disseminated to viscera. There are lesions made on the skin that are prominent, irregular, purple dome-shaped plaques or nodules on the leg, chest, and neck mostly [83, 84]. The nanomedicines being used for treating are Doxil (Liposomal Doxorubicin), Pegylated liposomal Doxorubicin, and is the first FDA-approved nanodrug in 1995 for various types of cancer including metastatic ovarian cancer and AIDS-related Kaposi’s sarcoma [85]. This was developed to make the conventional Doxorubicin less toxic and more effective. Doxorubicin combats cancer through two distinct mechanisms. The topoisomerase II-mediated DNA repair is disrupted by the first mechanism, which involves intercalation into the DNA.  The second mechanism involves the production of free radicals, which cause damage to DNA, cellular membranes, and proteins [86]. Doxorubicin also causes some severe type of toxicity like heart failure, few of such toxicities some times are irreversible and can be fatal. The toxicity is reduced by using nanotechnology and the efficacy is improved as due efficient transportation of the drug. The use of liposome has increased the circulation time after intravenous administration as compared to uncoated Doxorubicin [63, 87]. Liposomal Daunorubicin, an anthracycline antibiotic with antineoplastic activity, is the second nanomedicine used to treat this cancer. Through a glycosidic linkage, the API anthracycline is connected to the amino sugar known as Daunosamine [88]. This contains an aqueous solution consisting of Daunorubicin citrate encapsulated with liposome. The size of the nanoparticle is 45 nm and the injection has the pH between 4.9 and 6. This is approved by FDA for treatment of HIV-associated Kaposi sarcoma in 1996. The liposome is not quickly cleared by the phagocytes, therefore it released the drug in sustained manner [89]. According to preclinical studies, daunorubicin is more concentrated in the brain, liver, spleen, and intestine than it is in the cardiac tissues and less concentrated in the liver, spleen, and intestine [90]. The third nanomedicine used is Lipoplatin, which is a liposomal-loaded drug product of the FDA-approved Cisplastin. The main adverse effect of cisplastin and platinum is nephrotoxicity [91]. Patients on these medications are required to be hydrated to reduce the risk of renal damage. Cisplastin is contained in the Lipoplatin product, whose liposomal shell is made up of cholesterol, methoxy polyethylene glycol distearoyl phosphatidyl ethanolamine lipid conjugate, dipalmitoyl phosphatidyl glycerol, and soy phosphatidyl choline [92]. It is a first-line treatment for pancreatic cancer when combined with ­gemcitabine. In comparison to paclitaxel or Cisplastin, it has demonstrated greater efficacy in the treatment of nonsmall cell lung cancer. Through the drained vasculature, Lipoplatin reaches the tumor site and accumulates there [93]. Despite of its effectiveness, it still has few limitations as it can cause hematological or gastrointestinal toxicity so are to be used with precaution. Lipoplatin is the efficacious drug in adenocarcinomas with least toxicity. In 2009, the European Medicines Agency approved the lipoplatin known as “Nanoplatin” as the first-line therapy for nonsquamous adenocarcinomas [75].

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6.4.3 Nanomedicines in Treatment of Lung Cancer Lung cancer is the leading cause of the cancer-related deaths and has become common in past few years. There are two types of lung carcinoma named nonsmall cell carcinoma and small cell carcinoma. The small cell carcinoma has poor prognosis [94]. They endure mutations that let them to harvest hormones that are normally not produced. These hormones will trigger the paraneoplastic syndrome. The nonsmall cell carcinoma is mostly developed. This type is further divided into three subtypes; one of them is adenocarcinoma which makes 40% nonsmall cell carcinoma [95]. This type of cancer tends to occur in peripheral lung tissues away from hilum and involves glands within the lungs. Squamous carcinoma is the second subtype and makes 20% of it. This type of cancer occurs close to main bronchus and can also cause obstruction of the airways. The squamous epithelial cells of the airways mutate and change from columnar cuboidal to squamous cells and essentially dysplasia cancer. The third subtype is the large cell lung cancer and this makes up 5% of the lung carcinoma and is the least common [96]. The nanomedicine used for lung cancer is Polyglumex. The basic need for the effective antitumor drug is to have prolonged time at the tumor site with decreased systematic exposure so the efficacy of paclitaxel drug conjugated with Poliglumex polymer is considered and currently is in phase III trials [97]. Genexol-PM, a different drug under consideration, is currently undergoing phase IV trials. While the core of the liposome contains paclitaxel, Genexol-PM is conjugated with two polymers called polyethylene glycol and polylactide [98]. These copolymers improve the bioavailability and solubility. The Genexol is thought to be effective in treating breast and lung cancer cells [99]. OncoTCS (Vincristine) is the second nanodrug that is primarily used to treat cancer. Both vincristine and vinblastine are alkaloids that are derived from plants, primarily Catharanthus Roseus flowering plants. Both of these alkaloids have potent anticancer properties [100]. The FDA has given the vincristine approval for its parenterally administered liposomal formulation. Comparing the liposomal formulation to the regular Vincristine, the former has a lower clearance and a higher AUC [101]. Other cancers, including non-Hodgkin lymphoma, are also being treated with it. For the treatment of triple-negative and nonsmall cell lung cancer, it is also coloaded with liposomal doxorubicin. Vincristine’s bioavailability is improved by this formulation as there was increase in vincristine circulation time. Additionally, the drug is gradually released, making it easy for patients to adhere dosing schedule [102].

6.4.4 Nanomedicines in Treatment of Lymphomatous Meningitis In lymphoma, when the cancer cells spread from the original site to the meninges, then it is known as lymphomatous leptomeningitis. This is morbid and often fatal CNS metastasis that develops in at least 4–8% of patients with non-Hodgkin lymphoma [103]. The malignant cells invade the leptomeningis via the cerebrospinal fluid and are transported through the central nervous system [104]. The nanomedicine for it is in the clinical trials and

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named DepoCyt, a sustained release cytarabine formulation. This is not a uni or multilamellar liposome but is a multivesicular system [105]. Large amounts of drugs can be encapsulated using this structure, which also ensures a slow release. Since this is the only liposomal medication approved for intrathecal use, it must be administered under medical supervision [106]. This is a cell cycle-specific anticancer substance that affects cells during a certain stage of cell division. The half-life of this sustained-release medication is 82.4 h in comparison to 3.4 h for uncapsulated medication. DepoCyt is evenly distributed throughout the cerebrospinal fluid, ensuring that tumor cells are continuously exposed to cytarabine [107]. Each particle is made up of a collection of compact, nonconcentric vesicles. The particles have a large volume of distribution and are 10 μm in size. Triolein, cholesterol, and dipalmitoyl phosphatidyl glycerol are all components of the liposome. This long-acting formulation is free of preservatives. This formulation’s half-life is 40 times longer than that of cytarabine in its conventional form [108].

6.4.5 Nanomedicines in Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the third-most common cancer-related cause of death globally [109]. This is the malignant tumor derived from hepatocytes or their precursors. This is usually developed in the cirrhotic liver where chronic injury leads to repeated inflammation, fibrinogenesis, and disordered liver architecture [110]. Hepatocellular carcinomas are phenotypically, genetically heterogeneous tumors driven by diverse molecular mechanisms. The identification of common genomic alterations has led to the development of targeted therapies that suppress carcinogenesis through multiple pathways [111]. Multikinase inhibitors have been developed that simultaneously target angiogenesis. Due to the mutation of particular genes that causes the release of growth factors, angiogenesis, or the formation of new blood vessels from existing blood vessels, facilitates the oxygen and blood supply to the developing tumor cells. The activation, proliferation, and migration of the tumor cells are started when the VEGF binds to its tyrosine-type receptor on endothelial cells. Few medications work to block hepatocyte vascularization and proliferation by binding to the FGF and VEGF receptors [112]. Another angiogenic factor such as platelet-derived growth factor is required for the recruitment of smooth muscle cells that surround and support new blood vessels. Several multikinase inhibitors including Sorafenin, Regorafenin are used to block platelet-derived growth factor receptor. These multikinase also inhibit tumor growth by blocking several other kinase r­ eceptors such as KIT and RET, e.g., Sorafenib, Regorafenib, and Lenvatinib [113]. Many drugs are used for the treatment of the hepatocellular carcinoma and the nanomedicines are also developed to overcome multidrug-resistant tumor environment and targeted drug delivery for improved treatment such as Livatag nanomedicine containing Doxorubicin drug and Genexol-PM containing Paclitaxel [114].

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6.4.6 Nanomedicines in Treatment of Bladder Cancer The second-most prevalent urological cancer is bladder cancer. Compared to women, men are four times more likely to get the illness, and the prevalence is two times higher in white men than it is in black men [115]. Hematuria, frequent urination, discomfort, and pain while urination are the early indicators of bladder cancer. There are numerous complex mechanisms that lead to urothelial carcinoma, many of which are currently poorly understood [116]. The invasive pathway and the noninvasive papillary pathway are the two pathways that are utilized to characterize the development of bladder cancer. It has been proposed that the papillary route develops from the bladder’s slow-cycling urothelium. The basal cells, intermediate cells, and umbrella cells that make up the urothelium line the bladder tissue, which is typically replaced every 6–12 months [117]. Genetic changes in various proto-oncogenes, such as the Harvey rat sarcoma viral oncogene and fibroblast growth factor receptor-3 (FGFR3), frequently cause this HRAS [118]. Invasive urothelial malignancies arise from either severe dysplasia or carcinoma in situ [119]. They frequently result from the inhibition of the antitumor TP53, RB1, or PTEN pathways. The genes PI3K, TSC1, PTCH, CDKN2A, and DBC1 are frequently mutated in both invasive and aggressive cancer types [120]. By attracting and activating stromal cells, adipocytes, fibroblasts, inflammatory cells, as well as mesenchymal and endothelial progenitors, cancers modify their microenvironment. They change the environment to mirror times when wounds heal as a result of releasing VEGF, EGF, CSF, and TGF-factors. Due to their function in tissue repair, mesenchymal stem cells in the bladder have been linked to tumor growth and metastasis [121]. By transforming into endothelial cells, they encourage angiogenesis into and around malignant tissues, which aids in tumor development. Many of the medications are being created for its treatment, for instance drug docetaxel in nanomedicine BIND-014 [122, 123].

6.4.7 Nanomedicines in Treatment of Ovarian Cancer The term “ovarian cancer” refers to a group of illnesses that start in the ovaries or in nearby organs such the peritoneum and fallopian tubes. In the pelvis, one ovary is situated on either side of the uterus in women [124]. The ovaries resemble a giant olive in both size and form. The malignancies are thought to be originated from the anatomical regions [125]. Numerous subtypes are included in each category. Ovarian cancer is a very ­aggressive and challenging to treat tumor that is typically discovered in advanced stages, where the majority of patients experience recurrence [126]. Numerous treatment techniques have been the subject of in-depth research, although targeted therapy and other such treatments have shown to be ineffective for this tumor. Low-grade ovarian neoplasms are genomically stable, whereas high-grade serous carcinomas are characterized by significant genomic instability and frequent amplifications and deletions [127]. Based on this

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phytopathogenic background, recent research proposes a twofold model of carcinogenesis composed of two sizable groups known as types I and II. Endometrioid type I cancers that are serious, mucinous, and low-grade frequently arise from well-characterized, genetically stable precursor lesions (mostly borderline tumors), manifest in the form of sizable adnexal masses in the early stages of the illness, and have a generally good prognosis [128]. On the other hand, serious, high-grade, mixed, and undifferentiated carcinomas originate from the adnexal epithelium de novo, frequently display chromosomal instability, and have aggressive biological behavior. P53 mutations are not common in low-grade cancer, but they are frequently present in high-grade serous carcinoma [129]. BRCA1/2 function loss may raise the risk of developing both spontaneous and hereditary high-grade serous carcinomas, according to mounting scientific evidence. The precise mechanism by which BRCA1/2 deficiency results in carcinogenesis is still unknown. It has been demonstrated that faulty BRCA1 cells exhibit transcription-coupled repair dysfunction, take longer to fix double-­stranded DNA breaks, and are more vulnerable to DNA-damaging substances [130]. It has been demonstrated that BRCA1 and p53 interact to promote the transcription of the Cyclin-dependent kinase inhibitor p21WAF/Cip1. Mostly women with a BRCA mutation or a history of ovarian or breast cancer have overexpressed levels of the mitotic phase regulating protein BTAK in their ovaries [131]. While KRAS or BRAF pathway mutations are typically seen in ovarian cancers that are serious and low-grade. RAS is a highly homologous and evolutionarily conserved gene that encodes the 21,000-kD GTPbinding protein that is frequently activated in low-grade ovarian serous carcinoma, mucinous ovarian cancer, and endometrioid ovarian cancer [132]. Three downstream effector pathways, PI-3K, RAF, and RAL-GEFs, are how RAS works. Studies of murine cells, which demonstrated that Raf is an effector employed by RAS to drive murine cell transformation, formed the basis of much of the existing understanding about these pathways [133]. The high incidence of KRAS and BRAF mutations seen in low-grade serous carcinomas suggests that the RAS-RAF signaling system is deregulated in this group of malignancies. Due to the high prevalence of p53 and BRCA1/2 mutations in high-grade serous carcinoma, these cancers most likely grow as a result of TP53 mutations and BRCA1 or BRCA2 malfunction [134]. Chemotherapeutic drug delivery has been improved because of the use of nanoparticles’ distinctive physical and chemical features [135]. Nanoparticlebased drugs play better role as they improve permeability and retention effect (EPR) to gather in tumors without any precise targeting because of leaky vasculature and accelerated absorption mechanisms of cancer cells (passive targeting) [136]. Nanoparticles containing encapsulated chemotherapeutics can provide enhanced dose delivery to the tumor environment in comparison to systemic dosing. Doxil, which is a pegylated liposomal doxorubicin formulation and is FDA approved for use in recurrent and platinum-resistant ovarian cancers, is the ultimate example of nanomedicine. Doxil is used often in combination with gemcitabine [137].

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6.4.8 Nanomedicines in Treatment of Prostate Cancer The urogenital sinus is the embryological source of the male sex gland known as the prostate [138]. In order to maintain spermatic health after ejaculation and to improve fertility, it adds nutrient-rich alkaline fluid to the semen as well as force to eject the sperm [139]. The gland has a greater rate of cancer than other urogenital tract structures, because it is extremely vulnerable to malignant transformation. Studies have revealed a close relationship between prostatic cancer and embryological organogenesis, as well as a significant dependence on testosterone [140]. As a carcinoma, prostate cancer is categorized as having a predominance in the epithelium. Subtypes of prostate cancer that are less common include lymphomas and sarcomas, which develop from mesenchyme [141]. Peripheral glandular tissue around the prostate frequently develops neoplastic changes [142]. Basal cells that produce the acinar basement membrane, which separates the epithelial acini from the prostatic stroma and is used to create fluid, surround them [143]. Activation of the AR by testosterone and dihydrotestosterone (DHT), which causes nuclear translocation of the receptor and subsequent binding to androgen response elements (AREs), is initially necessary for the growth and progression of prostate cancer and triggers transcription of genes that control cellular differentiation, proliferation, and apoptosis [144]. In order to maintain and ensure the survival of prostate luminal epithelial cells, AR stimulation is essential [145]. The HPG (hypothalamic–pituitary–gonadal) axis controls androgen synthesis. Luteinizing hormone (LH), which is secreted by the anterior pituitary gland, and gonadotropin-releasing hormone (GnRH) work together to control the primary production of androgens in the testes’ Leydig cells (GnRH) [146]. DHT is created from testosterone that is a potent ligand of androgen receptors [147]. PTEN is a tumor suppressor gene that inhibits cell growth by negatively affecting the PI3K-AKT-mTOR pathway and stopping the cell cycle at the G1 stage. Due to the increase in the PI3K-AKT-mTOR pathway and the impairment of normal AR regulation caused by PTEN loss, tumor cell development is accelerated by an increase in cellular proliferation, AR expression, and reduced apoptosis [148, 149]. The BIND-014 nanomedicine is used for the treatment of prostate cancer which encapsulates the drug Docetaxel [150]. Nanomedicines used in cancers have been tabulated in Table 6.1.

6.5 Drug Resistance in Cancer and Nanomedicines 6.5.1 Multidrug Resistance On multitreatments, the cancer becomes resistant not only to that drug but also to all the medicines of that class. The cross-resistant is a challenge for the oncologists to deal with; so nanotechnology is an emerging advancement in treating cancer [157]. Two mechanisms are involved in the multidrug resistance development. First, the ATP-binding cassette (ABC) superfamily is involved in increased drug efflux activity through the Efflux pump-­

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mediated (MDR) process. These molecules are expressed on the cellular vesicle membrane as well as the plasma membrane. These are employed to keep toxins and other foreign materials out of the cell. These proteins are transmembrane in structure and use ATP hydrolysis energy to transport substrates across the membrane. The gene that encodes for the P-glycoprotein amplifies in the drug-resistant cells and decreases the drug accumulation by pumping the drug outside. The doxorubicin and paclitaxel concentration greatly decreases due to this mechanism [158]. The nanomedicines are also in clinical trials for the treatment of resistant cancer as shown in the Table 6.2. The second pathway involved in developing multidrug resistance is the efflux pump-­ independent MDR. The influx of drugs is reduced, metabolic processes are altered, DNA repair is activated, and the expression of proteins linked to apoptosis and tumor suppressors, specifically the p53 mutation, is altered [159]. All of these mechanisms are employed to stop the spread of damaged DNA and stop the development of cancer and are shown in Fig.  6.3. Apoptosis begins to kill the damaged cells if any of these mechanisms fails. Anticancer treatments that cause DNA damage to cause cytotoxicity cause cell cycle arrests [160].

6.5.2 Intrinsic and Acquired Mutation Somatic mutation results in gain of function activation of the tyrosine domain kinase of EGFR in cohort of nonsmall cell lung cancer (NSCLC) were discovered in more than 35% of patients and showed significance response to the gefitinib drug. This resistance is associated with the secondary mutation in exon 20 that leads to substitution of methionine for threonine at position T790M in the kinase domain preventing the binding of most of the drugs, for example erlotinib [161]. Acquired mutation for example the mutation in the S492R in the EGFR ectodomain in the colorectal cancer inhibits the binding of Cetuximab. Together these mutations either intrinsic or acquired, they restrict the binding of the cytoTable 6.2  Nanomedicines for treating resistance developed cancer Nanomedicine Liposome containing pimonidazole

Active ingredient Pimonidazole

Tumor type Human melanoma cells

PLGA-chitosan

Carmustine, O-benzylgluanine

Glioblastoma

Nanoparticle Dithiazanine iodide Glioblastoma encapsulated with dithiazanine iodide Paclitaxel Human lung Micelleplexes adenocarcinoma

Mechanism of action DNA fragmentation and cross-linking sensitize for radiation damage Inhibition of methylguanine-DNA methyl transferase Cytotoxic effects toward brain cancer stem cells Inhibition of cell division

References [165]

[166]

[167]

[168]

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Fig. 6.3  Development of resistance by the cancer cells

toxic agents facilitating the progression of cancer. Nanodrugs are used in these both type of resistances to overcome these compensatory mechanisms. An antisense oligonucleotide is attached to the polymalic acid receptor that blocks EGFR and is effective in treating negative breast cancers [162].

6.5.3 The Contribution of Microenvironment in Multidrug Resistance The solid tumors are found within the microenvironment that are composed of cancer cells and stroma cells embedded in extracellular matrix. This stroma affects the malignant transformation and plays a role in tumor cell invasion and metastasis and also has effect on drug sensitivity. The tumor stroma has increased number of fibroblasts that synthesize the growth factors, chemokine, and adhesion molecules [163]. The interaction of the cancer cells with these factors affects the sensitivity of the cells to the apoptosis and response to chemotherapeutic drugs. This phenomenon is also known as cell adhesion-mediated drug resistance (CAM-DR).The adhesion of the myeloma cells to the fibronectin through B1 integrins, whose activation is known to influence apoptosis and cell growth resulting in CAM-DR. Due to the cell cycle arrest at G1phase and the inhibition of Cyclin A and E kinase activity brought on by this adhesion, the response to drugs is reduced [164]. The pH of the tumor environment can also affect a drug’s efficacy by preventing its transportation. The tumor has an acidic extracellular pH and a neutral to basic intracellular pH. Thus, weakly basic medications like doxorubicin are protonated and as a result, their cellular uptake is decreased. Drugs that are weakly acidic, like cyclophosphamide, frequently concentrate in extracellular matrix. Through physical and chemical networks, the tumor

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microenvironment helps cancer cells survive. Therefore, the physiological normalization of the tumor tissue and a decrease in the resistance to conventional chemotherapy may result from the blockage of the synthesis of the extracellular matrix protein that is specific to cancer. Consequently, altering the microenvironment is a successful treatment strategy [163].

6.6 Theranostic Nanomedicines Used in Cancer Tumor heterogenicity and its adaptive resistance is the newly emerging challenge in the treatment of the cancer. The theranostic drugs have the ability of both intrinsic function of diagnosis and therapy. The theranostic medicines are used for the diagnosis, treatment, and monitoring the response of therapy as well. The cellular phenotype of each tumor is first identified using molecular diagnosis by imaging, which then provides direction for its treatment. The simple cellular biopsy fails to recognize due to the heterogenicity of the tumor cells resulting in error in diagnosis and also fails to detect the metastasized cells to other locations [169]. All this detection is only possible through the full body imaging, so the nanotechnology has the advantage of detecting multiple tumor markers and delivers nanomedicine simultaneously for synergistic effect. The molecular analysis of the tumor is an important step during the therapy as well in order to modify the treatment according to the response of the tumor cells. The conventional chemotherapy is unable to differentiate between the normal cells and the cancer cells. Typically cisplastic acts by inhibiting the cross-linking of the DNA restricting the cellular division, but this targeting of the cisplastin is unspecified so its dosage and use is adjusted according to its systematic toxicity [170]. On the other hand, the nanotechnology provides specific and long-lasting effect of the medicines. Theranostic nanomedicines have specific mechanism of action through which they diagnose and initiate the apoptosis of the cancer cells as shown in Fig. 6.4. Recently, the agents that target molecular markers like monoclonal antibodies are also considered for treating the cancer. In theranostic applications, monoclonal antibodies or peptides can be attached to the nanoparticle exhibiting both effects simultaneously diagnosis and therapy, similar to how treatment with conventional herceptin medicine causes resistance over time in breast cancer patients who express the HER2 gene [169]. Codelivery of the imaging contrast agent and the chemotherapeutic agent is a real-time application in cancer. This approach can also provide early feedback of the therapy like the shrinkage of the tumor. The perflourocarbon-based nanobased particles of size 200 nm have been established as a vascular targeting system that will deliver drug molecules as well as ultrasound and MRI agent. Another recent study has revealed that developing multifunctioning polymeric micelle ≤100 nm with specific cancer targeting, ultra-sensitive MRI detection contrast agents and pH-sensitive release of drugs for cancer therapy [171]. The hydrophobic micelle core of the superparamagnetic iron oxide nanoparticle caused a dramatic increase in T2 relaxivity, which in turn reduced the MR detection limit to nanomolar particle concentration. This aids in the identification of 50,000 endothelial tumor cells that overex-

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Fig. 6.4  Mechanism of action of theranostic medicines

press the angiogenic tumor marker integrin. Until now, only a small number of clinically effective medications, including paclitaxel and doxorubicin, have been developed using nanotechnology [172, 173]. Another way to use the theranostic agents is in photothermal therapy for cancer in which detected cancer cells can be killed by heat from using desired nanoparticle with infrared light, magnetic field, and radio frequency. The gold nanoparticles are used in it mostly as they absorb light and convert photon energy efficiently to heat, about 150 antibodies individually can be conjugated to polyethylene glycol nanoshel [174]. Tumor cells are killed by a combination of light and a photosensitizer in photodynamic therapy. Under the proper dosage of the nanomedicine, these components produce cytotoxic singlet oxygen in addition to molecular oxygen in the tissue.. The carbon-based nanomedicine is used in cancer imagining as they can transfer the laser energy into acoustic signals and can show great photoluminescence [175]. For new inventions, the ­physicochemical properties are altreet of the therapeutic agents to be conjugated with the nanocarrier for theranostic application.

6.7 Conclusion In the past few years, nanoparticles have been developed to address the drawbacks of conventional therapies to fight against cancer. Compared to free chemotherapeutics, polymeric NPs have a better pharmacokinetic profile. Enhancing the permeability and penetration of the nanoparticles into the tumor by selectively targeting tumoral cells can reduce toxicity and prevent the negative consequences of extended treatment. In conclusion, even

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though much progress has been made, much work remains. Combined efforts from the scientific and biotechnology communities are required to accomplish this in order to hasten the advancement of this technology for cancer treatment. Take-Home Message

• Currently, many types of cancers are discovered with slight difference in their pathology. This overlapping pathology leads to the use of some similar therapeutic agents in each type of cancer. • Many therapeutic agents have been developed for treating cancer but the newly emerging approach is of using nanomedicines. • Nanomedicines can not only be used for treatment but also for diagnostic purpose for different types of cancer. • The nanomedicines work as targeted therapy so have minimal toxic effects and are more effective as compared to conventional medicines. • The use of multidrug therapy and many cellular adaptations has led to the development of cancer-resistant environment which can be overcome by using targeted nanomedicine therapy.

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7

Nanomedicine in the Treatment of Metabolic Diseases Sairah Hafeez Kamran

Contents 7.1  N  anomedicine  7.2  M  etabolic Diseases  7.3  O  besity  7.3.1  Pathophysiology of Obesity  7.3.2  Nanotherapeutics-Based Pharmacotherapy of Obesity  7.3.3  Synthetic Anti-obesity Drugs Modified with Nanotechnology  7.3.4  Herbal Nanomedicine for Obesity Treatment  7.4  Nanomedicine in Hyperlipidemias  7.4.1  Nanomedicine in Hyperlipidemias  7.5  Nanomedicine in Diabetes  7.5.1  Type 1 Diabetes Mellitus  7.5.2  Nanotechnology for the Development of Oral Insulin  7.5.3  Natural Nanomaterials for Insulin Delivery  7.5.4  Synthetic Nanomaterials for Insulin Encapsulation  7.5.5  Lipid Nanocarriers for Oral Insulin Delivery  7.5.6  Inorganic Nanocarriers for Oral Insulin Delivery  7.5.7  Insulin Oral Nanoformulations in Clinical Trials  7.5.8  Insulin Delivery Through Transdermal Route  7.5.9  Intranasal Delivery of Insulin 

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S. H. Kamran (*) Institute of Pharmacy, Faculty of Pharmaceutical and Allied Health Sciences, Lahore College for Women University, Lahore, Punjab, Pakistan e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 B. Akhtar et al. (eds.), Nanomedicine in Treatment of Diseases, Learning Materials in Biosciences, https://doi.org/10.1007/978-981-99-7626-3_7

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214 7.6  T  ype 2 Diabetes Mellitus  7.6.1  Antidiabetic Drugs Modified with Nanotechnology  7.6.2  Insulin Secretagogues Modified by Nanotechnology  7.6.3  Plant-Based Nanoformulations Investigated in Type 2 Diabetes  7.7  Nanomedicine in Nonalcoholic Fatty Liver Disease (NAFLD)  7.7.1  Pathophysiology of NAFLD  7.7.2  Nanomedicine in NAFLD  7.8  Endothelial Dysfunctions  7.8.1  Nanomedicine in Endothelial Dysfunctions  References 

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What You Will Learn from This Chapter

Nanotechnology employed in drug development has led to the origination of enhanced drug delivery systems targeted for the mitigation of metabolic diseases. Metabolic diseases customarily occur due to an imbalance in homeostatic mechanisms in the body. Nanomedicine has enhanced the bioavailability and augmented targeted delivery of drugs to their site of action, thereby reducing the disease burden on humankind. The surge of development of nanodrugs in the last decade has led to the emergence of formulations approved by the Food and Drug Administration (FDA). Treatments of diabetes, obesity, nonalcoholic fatty liver disease, and endothelial dysfunctions have been explored with nanotechnology to combat the sufferings.

7.1 Nanomedicine Nanomedicine is defined as the utilization of nanotechnology in the field of medicine. The Greek prefix “nano” means minute or very small and depicts “one billionth of a meter (10−9  m)”. The father of nanotechnology, an American physicist and Nobel Laureate, Richard Feynman introduced the concept in 1959. Nanomedicine employs the consumption of nanomaterials for the preparation of medicine, diagnostic tools, and biological devices. In the twenty-first century, many studies have highlighted nanotechnology’s potential role in the biomedicine field for the diagnosis of disease, drug delivery, molecular imaging, and therapeutics [1]. Nanomedicine formulated by loading drugs of interest into different nanomaterials such as natural or synthetic polymers and lipid-based and inorganic nanoparticles has shown more efficacy, better bioavailability, enhanced and targeted drug delivery, and reduced side effects compared to conventional drug formulations. During the past decade, many medicinal products produced by maneuvering nanomaterials have been approved by the Food and Drug Administration (FDA) and are available in the US market. These include nanocrystals, liposomal drugs, lipid-based nanoparticles, PEGylated polymeric nanodrugs, and metal- and protein-based nanoparticles [2].

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7.2 Metabolic Diseases Metabolic diseases encompass any disease that occurs due to dysregulation of metabolism at cellular levels. This leads to an imbalance in organ/tissue homeostasis. Over the past years, drastic change in the lifestyle of people has been observed due to escalated use of electronic gadgets. This has led to a sedentary lifestyle, thus leading to the development of lifestyle diseases. One of the most common factors is obesity which affects 650 million people around the globe. Obesity is one of the major factors associated with the development of hyperlipidemias, hypertension, nonalcoholic fatty liver disease, cardiovascular disorders like atherosclerosis, and diabetes. Another major contributing element is dysregulation in the immune system which favors chronic inflammation in peripheral tissues. This inflammation has also been associated with the development of insulin resistance leading to the progression of type 2 diabetes mellitus (T2DM) [3] (Fig. 7.1).

Fig. 7.1  Metabolic diseases and causes

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7.3 Obesity The metabolic syndrome includes the epidemic of obesity increasing day by day due to sedentary and unhealthy lifestyles. A major solution to control obesity is lifestyle modification which is difficult to adopt by many people due to trends in eating habits.

7.3.1 Pathophysiology of Obesity Metabolism in the cell entails all chemical reactions necessary for the cell to survive. These chemical reactions are focused on converting the absorbed dietary nutrients into energy required for multiple activities of the organ. The major nutrients obtained from diet are carbohydrates, proteins, and fats. The organs convert the dietary nutrients into energy, depending on the type of activity to be performed by the respective organ, for example, concentration of solutes to enhance glandular secretions, mechanical movement for muscle function, etc. The dietary intake and expenditure of the energy in the body must be balanced to maintain healthy lifestyle. The energy liberated by 1 g of carbohydrate is 4.1 calories, fat is 9.3 calories, and protein is 4.35 calories. Intra- and interindividual variations exist on a daily basis depending on the type of food consumed and activities performed. Moreover, the gastrointestinal tract absorbs the dietary substances in varied proportions [4]. The intake of food greater than the energy expenditure increases body weight and 1 g of fat is stored for every 9.3 excess calories. This leads to accumulation of fats in the adipocytes of the subcutaneous tissue, viscera of the abdomen, the liver, and lower parts of the body. Excessive adiposity leads to obesity and the impact of obesity on health increases particularly when excessive fats are stored in the visceral organs, thereby leading to increased risk of cardiovascular and liver disorders. In 2010, the worldwide prevalence of obesity was estimated to be 400 million, among which 1.6 billion were estimated to be adults [5]. The adipose tissue in humans is composed of two different types, namely, white and brown adipose tissue. The ratio of brown adipose tissue is high in infants and children, whereas adults comprise mainly white adipose tissue (WAT). WAT stores enormous triglycerides (TGs) formed or absorbed during an imbalance of energy intake and consumption. Excessive fats can cause increase in number and size of adipocytes leading to development of WAT dysfunction and obesity. The increase in size of WAT (adipogenesis) is also associated with the growth of new blood vessels, a process known as angiogenesis. WAT expresses adipokines which are cell signaling molecules in the adipose tissue and play a major role in energy metabolic status. WAT expresses more than 50 adipokines, of which clinically important are leptin and adiponectin. The endothelium of the vessels developing in the hypertrophic WAT expresses integrin and prohibitin (PHB), which are vascular biomarkers. PHB is a multifunctional protein secreted in the blood and involved

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Fig. 7.2  Structure of the adipose tissue and obesity

in the development of obesity and WAT remodeling. Targeting PHB expressed in the WAT vasculature caused ablation of white fat and reduced body weight. PHB was reported to be overexpressed in obesity, cancer, and diabetes and could serve as a potential biomarker for therapeutic intervention [5] (Fig. 7.2).

7.3.2 Nanotherapeutics-Based Pharmacotherapy of Obesity The conventional pharmacotherapy of obesity works in two ways subduing the appetite of suppressing the absorption of fats. Due to the appearance of unacceptable side effects and in some cases reduced efficacy, these therapies are used with limitations [1]. The side effects and limitations of the conventional anti-obesity treatment results in a decline in people opting for conventional treatment. As in the case of diet therapy, the main limitation is the short duration of adherence of the patient to the diet which results in erratic results and dissatisfaction with the therapy. The normal BMI of an adult is 18.5–24.9 and a BMI of 27–29.9 kg/m2 is associated with risks like hypertension, T2DM, sleep apnea, dyslipidemias, and myocardial infarction. FDA had approved many anti-obesity drugs in the last three decades like rimonabant, amphetamine, sibutramine, fenfluramine, and dexfenfluramine, most of which were removed from the market due to pharmacovigilance reports of psychiatric disorders and myocardial infarction. A 5-year Sibutramine Cardiovascular OUTcomes (SCOUT) trial conducted on the safety and efficacy of sibutramine provided evidence of increased risk of nonfatal stroke and myocardial infarction, so FDA removed the drug from the market on October 8, 2010. The individuals on anti-obesity medication orlistat also suffer from

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v­ itamin and mineral deficiencies, specifically those who are on long-term therapy. The surgical treatment of obesity like liposuction, bariatric surgery, etc. also presents some serious adverse effects. The adverse effects of conventional treatments have posed greater risks to human health and quality of life and made people shift toward alternative medicine or nanomedicine [6]. The delivery of nanoparticles for fat replacement takes place in three ways; the long-­ chain fatty acids in lipid-based formulations are replaced by small chains, and the absorption of fat and cholesterol is also reduced. In protein-based approaches, foods with reduced energy content are produced. The polysaccharide-based approaches have been employed to produce low-energy-density calorie compact foods [1].

7.3.3 Synthetic Anti-obesity Drugs Modified with Nanotechnology The binding specificity and targeting ability of nanoparticles to the adipose tissue are the most important in pharmacotherapy for obesity control. It has been reported that targeted delivery of nanoparticles in the white adipose tissue of obese individuals enhances permeability and retention effect. Orlistat, which is the only appetite-suppressant drug available on the market, inhibits lipase enzyme in the intestine to reduce the absorption of dietary fats. The drug causes gastrointestinal disturbances and requires three times administration with meals to reduce fat absorption. In 2016, Chen and coinvestigators developed a nanoformulation of orlistat with copolymer BTTPFN-g-PCL (poly (ε-caprolactone)). The copolymer was sensitive to pancreatic lipase and in the presence of pancreatic lipase released orlistat, and degradation of NPs was reduced as the levels of lipase decreased in the intestine. Overall, the efficacy of orlistat improved, and side effects were reduced [7]. The introduction of nano-derived food led to the manufacturing of eatables which are calorie binder with complete and better bioavailability of antioxidants and obesity-targeted drugs. Silica particles along with high-fat and sugar diet were investigated in mice for effects on body weight and fat composition, lipid profile, and blood glucose levels. The silica NPs sequestered pancreatic lipase, fats, and bile acids in the intestine and reduced the cholesterol, triglycerides, glucose, and body weight [8]. Gold is an inert material and gold nanoparticles have been patented in 2001. Gold NPs produce stable, targeted drug delivery systems with enhanced therapeutic action. WAT in obese animal rat model was targeted by functionalizing streptavidin-gold NPs with adipose homing peptide (AHP). Intravenously injected NPs escaped the uptake by the liver and widely accumulated in WAT and successfully delivered AHP in the tissue [9]. Anti-obesity nano-drugs targeting vascularization in WAT and inhibiting prohibitin (PHB) are also being investigated. Lipid-based NPs carrying KGGRAKD, a prohibitin-­ inhibiting peptide showed promising results in reducing WAT by initiating cell apoptosis. However, there are certain limitations in PHB-targeted treatment like development of chronic inflammation and insulin resistance in WAT due to PHB inhibition-induced hypoxic stress [10]. Various gold NPs conjugated with PHB inhibiting peptides were

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f­ ormulated and tested in vitro for targeted drug delivery in WAT vasculature, but further investigations are required for in vivo effects [11]. PHB-targeting peptide with PEG-lipid conjugate was formulated as NPs and to C57BL/6J and obese mice. The results demonstrated enhanced accumulation of the NPs by passive route at the targeted site in WAT and enhanced cellular uptake in the adipose endothelial cells inducing apoptosis. The NPs showed controlled release in WAT and reduced ectopic fat content by inducing adiponectin oxidation of fat in the liver and muscle [12]. The cerium oxide NPs were investigated in 3T3-LI preadipocytes and obese rats and showed significant reduction in body weight, leptin, and triglyceride levels [13]. The superparamagnetic iron oxide nanoparticles (SPIONs) were investigated by Sharifi and coinvestigators on two genes, of which one cluster was associated with high risk for obesity (22) and the other was linked to increased risk of T2DM (29). The SPIONs can play dual roles in the upregulation and downregulation of genes. These NPs downregulated most of the genes associated with T2DM risk but upregulated SLC30A8. SPIONs upregulated five genes associated with obesity; however, solid functions of these genes are still under investigation. SPIONs upregulated SEC16B gene which is associated with the phagocytosis of apoptotic cells; therefore, SPIONs can play crucial role in obesity [14]. SIPONs should be employed with caution due to unclear results. The brown adipose tissue has also been targeted to enhance energy expenditure and thermogenesis. Thermogenic inducers have been developed and modified by nanotechnology for treatment of obesity. Rosiglitazone and prostaglandin E2 analog (16,16-dimethyl PGE2) encapsulated in poly(lactic-co-glycolic acid)-b-poly (ethylene glycol) (PLGA-b-­ PEG) was successfully delivered to WAT in mice (IV administration) to promote browning of the tissue, angiogenesis, and upregulating brown adipose tissue markers. The NPs reduced weight gain, cholesterol, triglycerides, and glucose in the high-fat diet (HFD) animal model [15]. Zhang and coworkers developed degradable microneedle skin patches worked on an adipose browning agent/fat modulating agent and have applied for US patent in 2020. The nanoformulation of rosiglitazone-loaded dextran microneedle patches showed effective sustained release of drug and increased the browning of the inguinal WAT.  The brown adipocyte genes (Ucp1, Dio2, Elovl3, Cidea, Pgc-1α, Cox7a1, and Cox8b) involved in lipid utilization were upregulated concomitantly with downregulation of inflammatory genes (IL-6). The levels of adiponectin were not affected indicating sustained action on the thermogenesis. In obese mice, the microneedle patches reduced body weight and regulated the blood glucose levels. The patches restricted the browning of the tissue in the treated area [16, 17]. Conventional suction-assisted lipectomy (SAL) often results in severe side effects and variable therapeutic outcomes. NanoLipo, a nanotechnology-based weight loss procedure, is under investigation in which gold nanoparticles are injected in the fatty areas and the specific area is treated with laser (800 nm). The reaction between gold NPs and laser liberates triglycerides and reduces the content of WAT. The liquified fat is then removed with the needles. The NanoLipo shows many advantages over the conventional SAL. Bariatric

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surgery is recommended in obese people with BMI >40 kg/m2 or patients (BMI = 30–40 kg/m2) with at least one life-threatening risk associated with obesity [18].

7.3.4 Herbal Nanomedicine for Obesity Treatment Drugs effective in obesity among which obtained from natural sources have been extensively maneuvered using nanotechnology. Liposomal nanocarriers possess hydrophilic and hydrophobic ends demonstrating high incorporation of hydrophilic constituents in the aqueous phase and hydrophobic elements in the lipid part. Liposomes exemplified a promising nanocarrier for delivery of plant-based drugs with improved stability and efficacy and reduced side effects. Capsaicin, a phytoconstituent obtained from red peppers, along with appetite regulator oleoylethanolamide (OEA) was encapsulated in liposomes prepared with linseed. The liposomes were tested in vitro for the release of drug and in vivo for anti-obesity effects. The NPs showed controlled release revealing a biphasic pattern, thereby reducing the irritant effect of capsaicin on intestinal mucosa. The in vivo studies on mice demonstrated significant weight loss, decrease in appetite, improvement in lipid profile, and glucose homeostasis [19]. Resveratrol present in grapes, red wine, and berries has been investigated for its many pharmacological effects. The polyphenol compound was targeted to be delivered in adipose stromal cells (ASC) in subcutaneous WAT.  Resveratrol was loaded into N-(methylpolyoxyethylene oxycarbonyl)-1,2-distearoyl-sn-glycero-3-­­ phosphoethanolamine (DSPE-PEG5000-peptide conjugate) containing ASC-targeting peptide (GSWKYWFGEGGC), the Rnano, finally creating peptide ligand-coated R-Nano. The NPs targeted the ΔDCN receptors expressed on the ASC in WAT with minimal accumulation in the liver seen in C57BL/6J mice model. Significant increase in UCP-1 expression gene was observed in WAT along with improvement in lipid and glucose homeostasis. Trans-resveratrol and hesperetin (tRES-HESP) combination in a capsule (90  mg tRES, 120  mg HESP) has been evaluated clinically in HATFF randomized, double-blind, placebo-­controlled crossover trial involving 20 obese subjects. The combination showed improvement in dyslipidemias, blood pressure, and low-grade inflammation [20]. The bioavailability and efficacy of treatment can be enhanced by use of liposomal nanocarriers. Silibinin obtained from milk thistle exhibits anti-inflammatory effects and has been modulated with nanocarriers into an effective lipid-based nanoformulation. The lipid-­ based NPs consisted of pluronic F-68 (hydrophilic part) and 6% sesame oil, 4% Precirol ATO5, 1.5% soy phosphatidylcholine (phospholipon 80H), and 7.5% silibinin (hydrophobic part). The flavonolignan lipid NPs at 300 mg/kg were tested in male HFD SD rats with NASH and facilely penetrated the GI membranes and entered the lymphatic fluids, thereby limiting the first-pass effect. The NPs improved the pharmacological and pharmacokinetic profile in obesity-linked nonalcoholic fatty liver disease and showed much better results compared to invasive bariatric surgery.

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The phytosomal nanocarriers have been employed for the encapsulation of soybean and showed skin permeation by topical route and reduction in the obese tissue at the site of application. The phytoconstituent hydroxycitric acid obtained from Garcinia cambogia was formulated in solid-lipid nanocarriers. The NPs exhibited controlled release and higher bioavailability when compared with the microparticles of the same phytoconstituents [21]. Gold nanoparticles are believed to stand out among nanomaterials as they possess anti-­ inflammatory effects via various mechanisms. Gynostemma pentaphyllum gold nanoparticles (GP-AuNPs) were examined against obesity and obesity-induced inflammation. The GP-AUNPs significantly downregulated the genes of PPARγ, TNF-α, and CEPBα presenting anti-inflammatory and anti-obesity action. Gynostemma pentaphyllum is a traditional Chinese herbal medicine employed for the treatment of various diseases [22]. Cinnamomum verum J. (family: Lauraceae) gold NPs showed promising results in high-fat-fed mice by reducing the accumulation of fats in WAT, improving the lipid profile, glucose homeostasis, and increasing mRNA expression of UCP-1 genes involved in transformation of WAT to brown adipose tissue [23]. Similarly, many other herbal drugs like Smilax glabra, Salacia chinensis, and Poria cocos have been formulated in gold NPs for improved bioavailability and efficacy in obesity treatment. Some phytoconstituents like chlorogenic acid present in berries, apples, and vegetables like spinach, lettuce, and sweet potatoes have been formulated in chitosan NPs and decreased 46% WAT content and regulated leptin and insulin levels. Some nanocarriers like nanosized micelles which were exploited for the delivery of poorly water-soluble drugs have been investigated by Möschwitzer and coinvestigators. These NPs greatly can enhance the solubility and bioavailability of the hydrophobic phytoconstituents [24]. The alpha cyclodextrins (α-CD) can alter the microbiota of the intestine in obesity. α-CD complex with 4-methylthio-3-butenyl isothiocyanate (MTBI) was created and tested in obese mice model. The results showed that the complex can decrease liver fat and glucose absorption by intestinal flora and upregulated the gene expression of fat decomposing enzymes [25]. Among all nanomaterials recruited for obesity treatment, so far nanoliposomes have shown promising results for herbal drug delivery and gold NPs for the delivery of synthetic drugs. Even though many nanotechnology-based approaches have been explored preclinically to reduce obesity, successful clinical trials and marketing remain a challenge to combat this metabolic disease.

7.4 Nanomedicine in Hyperlipidemias A metabolic disorder that involves elevations in lipoproteins, triglycerides, and cholesterol can cause development of a variety of clinical diseases. Hyperlipidemias cause abnormal rise in triglyceride (TG) levels in association with irregular levels of other lipid biomarkers such as cholesterol, free fatty acids (FFAs), low-density lipoproteins (LDL), very-low-­

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density lipoproteins (VLDL), and high-density lipoproteins (HDL). The major clinical sequelae of hyperlipidemias are atherosclerosis and acute pancreatitis. The lipids absorbed from the gastrointestinal tract are transported in complexes termed as lipoproteins. Lipoproteins have a central hydrophobic core containing triglycerides and cholesteryl esters. The central core is surrounded by phospholipids, cholesterol, and apoproteins. The apoproteins exists in many forms, A, B, C, D, E, and H, and the type B proteins, the high molecular weight proteins, exist in two forms, B-100 and B-48. The apoprotein B-48 (apoB-48) is found in chylomicrons that are formed in the intestine and carry the unesterified cholesterol and dietary triglycerides into the lymphatic circulation to the plasma. The apo-B100 is manufactured by the liver and is carried in VLDL, intermediate-­density lipoproteins (IDL) and LDL. The lipoproteins containing B-100 and remnants of apoB-48 convey excessive lipids to the artery walls contributing to atherosclerosis development. The development of atherosclerotic plaque causes narrowing of arteries arising life-threatening conditions like stroke and myocardial infarction. Hypertriglyceridemia also contributes to the risk of coronary artery disease, hypertension, obesity, and insulin resistance. Hypertriglyceridemia’s transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins results in reduced HDL levels. HDL majorly contains apoprotein A with several hundreds of other lipoproteins. It mainly captures cholesterol and remnants of lipoproteins and is inversely related to atherosclerosis risk. The AHA/ACC 2018 guidelines recommend fasting and non-fasting triglycerides to be maintained below 150 mg/dL. The conventional hyperlipidemic therapy includes competitive inhibitors of HMG-­ CoA (3-hydroxy-3-methylglutaryl-coenzyme A), namely, atorvastatin, rosuvastatin, simvastatin, pravastatin (statins), PPAR-α ligands named fibric acid derivatives (gemfibrozil and fenofibrate), niacin, bile acid sequestrants (cholestyramine, colestipol), ezetimibe, lomitapide, mipomersen, and PCSK9 inhibitors (evolocumab, alirocumab). Some agents under development include cholesteryl ester transfer protein (CETP) inhibitor (torcetrapib, anacetrapib), AMP-kinase activators, and cyclodextrins.

7.4.1 Nanomedicine in Hyperlipidemias Nanotechnology implies the enhancement of the conventional therapy in terms of pharmacodynamics and kinetics. Chitosan that contains 1e4)-2-amino-2-deoxy-D-glucopyranosyl products deacetylated from chitin has proven to possess antihyperlipidemic activity, and the water-soluble chitosan has higher impact on lowering lipid levels [26]. Atorvastatin was conjugated with galactose-modified trimethyl chitosan (TMC) (GT), and nucleic acids siBaf60a and anti-miR-33 pDNA (pAnti-miR-33) were also included in the nanoformulation. The NPs were administered intravenously (0.2  mg/kg) or orally (2 mg/kg) to high-fat diet (HFD)-fed ApoE-knockout (ApoE-KO) mouse model of atherosclerosis. The orally administered NPs maintained their structural stability in in vitro and ex vivo experiments and effectively delivered the drug and nucleic acids to the liver and

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atherosclerotic plaques. The NPs effectively delivered the drug to atherosclerotic plaque lesions and reduced the cholesterol, LDL-C, and triglyceride levels and increased the HDL-C levels. The NPs also reduced macrophage distribution in the plaque and increased the collagen content, thus reducing plaque progression. The NPs also upregulated ABCA1 gene and decreased inflammatory burden by reducing cytokine secretion (MCP-1) and macrophage polarization [27]. Atorvastatin was formulated using nanostructured lipid carrier obtained from natural source. Olive oil has confirmed hypolipidemic activity and was used to carry atorvastatin, thus producing synergistic effect when administered to HFD-­ fed rats. The rats were administered 20 mg/kg NPs for 14 days, and significant reduction in lipid profile along with improved bioavailability and pharmacokinetic profile was documented [28]. The solubility and bioavailability of rosuvastatin was enhanced by encapsulating the drug in chitosan-coated mesoporous silica nanoparticles (CS-MSNs) [29] and in another study rosuvastatin was conjugated with polycaprolactone (PCL) and chitosan (CS) [30]. The nanoformulations showed sustained drug release behavior and targeted drug delivery in vitro. Nanosponges are cross-linked cyclodextrin polymers used to improve the stability and bioavailability of different drugs. Resveratrol, a polyphenolic compound, has shown potential antihyperlipidemic actions in various studies. The dissolution of resveratrol is limited due to hydrophobic nature. β-Cyclodextrin nanosponges of resveratrol were prepared and buccal and topical delivery was analyzed. The NPs showed good permeation in pig skin and better accumulation in rabbit mucosa [31]. Many plant-based nanoformulations have been extensively investigated for their antihyperlipidemic mechanisms. These include Curcuma longa (turmeric), Allium sativum (garlic), Ocimum basilicum (basil), Vaccinium myrtillus (blueberry), Taraxacum officinale (dandelion), Apium graveolens (celery), Trigonella foenum-graecum (fenugreek), Zingiber officinale (ginger), Nigella sativa, ginseng, evening primrose oil, eugenol, and psyllium. Various antihyperlipidemic mechanisms of these natural drugs have been elucidated and require attention to be formulated effectively to achieve therapeutic efficacy [32].

7.5 Nanomedicine in Diabetes Diabetes mellitus (DM) is a chronic metabolic disorder generally characterized by elevated blood glucose levels, polyuria, polydipsia, and polyphagia, all driven by insulin deficiency, insulin resistance, and in some cases both. DM is broadly classified into two types: type 1 DM (T1DM) occurs due to insulin deficiency and type 2 DM (T2DM) is related to insulin resistance. There are approximately 537 million adults living with diabetes globally; this number is predicted to increase to 643 million by 2030 and 783 million by 2045 (IDF). Among the affected ones, 1.2 million children and adolescents have T1DM. It has been estimated that DM causes 6.1 million deaths every year. T2DM constitutes for about 90% of diabetes in the developed world and this percentage is higher in the

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developing countries. Gestational diabetes mellitus (GDM) is another type of DM which is recognized as having higher glucose levels during pregnancy. It has been seen in many studies worldwide that GDM is increasing in parallel with the rise of T2DM. According to the American Diabetes Association (ADA), fasting glucose levels less than 150 mg/dL or glycosylated hemoglobin (HbA1c