Shape Memory Polymers for Biomedical Applications 9780857096982, 9780857097132, 9781845694708, 9780081019955, 9780081019962, 2472492502, 0857096982

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Related Titles Shape Memory Polymers for Biomedical Applications (ISBN: 9780857096982) Switchable and Responsive Surfaces and Materials for Biomedical Applications (ISBN: 9780857097132) Drug Device Combination Products (ISBN: 9781845694708)

Woodhead Publishing Series in Biomaterials

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications Advanced Nanocarriers for Therapeutics Volume 2

Edited by

Abdel Salam Hamdy Makhlouf Nedal Y. Abu-Thabit

An imprint of Elsevier

Woodhead Publishing is an imprint of Elsevier The Officers’ Mess Business Centre, Royston Road, Duxford, CB22 4QH, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, OX5 1GB, United Kingdom Copyright © 2019 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-08-101995-5 (print) ISBN: 978-0-08-101996-2 (online) For information on all Woodhead publications visit our website at https://www.elsevier.com/books-and-journals

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Contents

Contents for volume 1 xi List of contributors xix Preface xxv

Part One  Dual-Stimuli Responsive Polymers

1

1 Redox- and pH-responsive polymeric nanocarriers Peng Liu 1.1 Introduction 1.2 Polymer micelles 1.3 Polymer nanoparticles 1.4 Polymer nanoprodrugs 1.5 Perspectives References

3

2 Magnetic and pH-responsive magnetic nanocarriers Muhammad Nawaz, Yassine Sliman, Ismail Ercan, Michele K. Lima-Tenório, Ernandes T. Tenório-Neto, Chariya Kaewsaneha, Abdelhamid Elaissari 2.1 Introduction 2.2 Synthesis and magnetic properties of MNPs 2.3 pH-responsive MNPs (dual sensitivity) 2.4 Liposomes 2.5 Conclusion References Further Reading 3 Temperature and pH dual-stimuli responsive polymeric carriers for drug delivery Sara A. Abouelmagd, Noura Hassan Abd Ellah, Basma Nagy Abd El Hamid 3.1 Introduction 3.2 pH- and temperature-responsive polymers 3.3 Design of temperature and pH dual-stimuli responsive polymeric nanocarriers 3.4 Important considerations and challenges 3.5 Conclusions and future perspective References

3 4 15 25 29 31 37

37 40 48 55 73 75 85 87 87 89 92 102 105 105

viContents

4 Biomedical nanoparticle carriers with combined thermal and magnetic response Daniel Crístian Ferreira Soares, Marli Luiza Tebaldi 4.1 Introduction 4.2 Remote properties of nanomedicines and in vitro studies 4.3 Preclinical investigations 4.4 Future trends References Further Reading

111 111 112 122 125 126 129

Part Two  Multi-Stimuli Responsive Polymers

131

5 Multiresponsive polymeric carriers Peng Liu 5.1 Introduction 5.2 Tri-stimuli-responsive polymeric carriers 5.3 Quadruple-stimuli responsive polymeric carriers 5.4 Multiresponsive polymeric carriers with single stimulus 5.5 Conclusion and prospects References

133

6 Multistimuli-responsive magnetic assemblies Abdulhadi Baykal, Ayhan Bozkurt, Ravindran Jeremy, Sarah Mousa Maadi Asiri, Michele K. Lima-Tenório, Chariya Kaewsaneha, Abdelhamid Elaissari 6.1 Introduction 6.2 Multistimuli-responsive polymeric nanoparticles 6.3 Magnetic nanocarriers 6.4 Multistimuli-responsive magnetic assemblies 6.5 Multistimuli-responsive magnetoliposomes 6.6 Glucose-responsive MNPs 6.7 Conclusion References Further reading

155

Part Three  Stimuli Responsive Polymers for Theranostic Applications 7 Smart internal and external stimuli-responsive nanocarriers for image-guided drug delivery and therapy Gan Lin, Dan Huang, Huaping Zhang, Zihan Meng, Xixi Ai, Jing Liu, Peng Mi 7.1 Introduction

133 134 146 149 149 150

155 156 163 169 173 179 184 185 193

195 197 197

Contentsvii

7.2 Molecular imaging modalities 7.3 Image-guided drug delivery 7.4 Stimuli-responsive nanocarriers 7.5 Conclusion Acknowledgment References

198 199 200 214 214 214

8 Stimuli-responsive polymers for image-guided therapeutic applications 219 Rajeet Chandan, Ameya Prabhakar, Rinti Banerjee 8.1 Introduction 219 8.2 Photo-responsive polymers 220 8.3 pH-responsive polymers 226 8.4 MF-responsive polymers 229 8.5 US-responsive polymers 233 8.6 Enzyme-responsive polymers 235 8.7 Conclusion 238 References 238 Further reading 245

Part Four  Stimuli Responsive Drug Delivery Systems

247

9 Dual and multistimuli-responsive block copolymers for drug delivery applications 249 Renjith P. Johnson, Namitha K. Preman 9.1 Introduction 250 9.2 Dual/multistimuli triggered cell targeting 251 9.3 Dual/multistimuli-responsive drug release systems 251 9.4 Conclusions 264 Acknowledgment 265 References 265 10 Stimuli-responsive polymeric micelles for extracellular and intracellular drug delivery Can Sarisozen, Ujjwal Joshi, Livia Palmerston Mendes, Vladimir P. Torchilin 10.1 Introduction 10.2 Polymeric micelles 10.3 General concepts and delivery barriers in nanomedicine 10.4 Stimuli-responsive polymeric micelles 10.5 Concluding remarks References Further reading

269 269 270 274 278 297 299 304

viiiContents

11 Stimuli-responsive polymer-modified liposomes and their application to DDS Eiji Yuba 11.1 Introduction 11.2 Design of stimuli-sensitive liposomes 11.3 Temperature-sensitive liposomes for chemotherapy and diagnosis 11.4 pH-sensitive liposomes for cancer immunotherapy 11.5 Dual stimuli-responsive liposomes 11.6 Concluding remarks References Further reading 12 Stimuli-responsive carbon nanotubes for targeted drug delivery M. Saquib Hasnain, Syed Anees Ahmad, Mohammad Niyaz Hoda, Sanjay Rishishwar, Poonam Rishishwar, Amit Kumar Nayak 12.1 Introduction 12.2 Classification of CNTs 12.3 Designing of stimuli-responsive nanocarriers 12.4 Methodology for preparation of CNTs 12.5 Functionalization of CNTs 12.6 Characterization of CNTs 12.7 External regulation of drug delivery 12.8 Applications of CNTs 12.9 Absorption and transportation of CNTs 12.10 Toxicity consideration of CNTs 12.11 Regulatory considerations 12.12 Conclusions References 13 Stimuli-responsive polymersomes for drug delivery applications Mónica Cristina García 13.1 Introduction 13.2 Biological-stimuli-responsive polymersomes 13.3 Remarks and future perspectives References 14 Ionic-strength-responsive polymers for drug delivery applications Mónica Cristina García 14.1 Introduction 14.2 Stimuli-responsive polymers 14.3 Ionic-strength-responsive polymers 14.4 Comments and perspectives References

305 305 305 306 309 314 315 317 319 321 321 323 325 326 327 328 328 330 336 336 336 337 337 345 345 349 383 384 393 393 394 395 406 406

Contentsix

Part Five  Stimuli Responsive Polymers for Cancer Therapy 411 15 Stimuli-responsive polymersomes for cancer therapy Thavasyappan Thambi, Doo Sung Lee 15.1 Introduction 15.2 pH-responsive polymersomes 15.3 Enzyme-responsive polymersomes 15.4 Glucose-responsive polymersomes 15.5 Miscellaneous polymersomes 15.6 Conclusion and future perspectives Acknowledgment References 16 Responsive polymeric micelles for drug delivery applications/cancer therapy Panagiota G. Fragouli, Dimitra Stavroulaki, Panagiotis Christakopoulos, Varvara Athanasiou, Maria Kasimati, Katerina Mathianaki, Hermis Iatrou 16.1 Introduction 16.2 pH-responsive micelles 16.3 Temperature-responsive micelles 16.4 Redox-responsive micelles 16.5 Magnetic-responsive micelles 16.6 Multiresponsive micelles 16.7 Micelles bearing a surface ligand 16.8 Conclusions and future perspectives References

413 413 420 425 426 426 431 432 432 439

443 444 449 451 454 455 457 458 458

Part Six  Stimuli Responsive Polymers for Therapeutic Applications 461 17 Stimuli-responsive polymers for ocular therapy Gayatri C. Patel, Vijaykumar K. Parmar, Prigneshkumar S. Patel 17.1 Introduction 17.2 Thermosensitive polymers 17.3 Ion-sensitive polymers 17.4 pH-responsive polymers 17.5 Combination of polymers having different gelation mechanisms 17.6 Patents on stimuli-responsive polymer for ocular delivery 17.7 Conclusions and future trends Acknowledgment References Further reading

463 464 466 470 474 479 480 482 482 482 489

xContents

18 Stimuli-responsive polymers for treatment of diabetes mellitus Santanu Patra, Rashmi Madhuri, Prashant K. Sharma 18.1 Introduction 18.2 Commercially available drug delivery systems for insulin: Failure 18.3 Stimuli-responsive polymers: The hope 18.4 Some other efficient treatment process for diabetes 18.5 Conclusion and future scope Acknowledgments References

491

19 Stimuli-responsive polymers for oral insulin delivery Piyasi Mukhopadhyay, P.P. Kundu 19.1 Introduction 19.2 Stimuli-responsive polymers 19.3 Types/classification 19.4 pH-sensitive polymers in oral insulin delivery 19.5 Other stimuli-responsive polymers in insulin delivery 19.6 Conclusions and future prospective References Further reading

525

20 Stimuli-responsive polysaccharides for colon-targeted drug delivery Ankita Tiwari, Amit Verma, Pritish Kumar Panda, Shivani Saraf, Ankit Jain, Sanjay K. Jain 20.1 Introduction 20.2 Stimuli-sensitive colon targeting polysaccharides 20.3 Microflora-based colon targeting system 20.4 pH-sensitive colon-targeted delivery 20.5 Conclusion References

547

Part Seven  Future Trends and Challenges

567

21 Recent progress in responsive polymer-based drug delivery systems M. Saquib Hasnain, Amit Kumar Nayak 21.1 Introduction 21.2 Various responsive polymer-based systems in drug delivery 21.3 Challenges and future prospects 21.4 Conclusion References Further reading

569

491 493 494 516 516 518 518

525 528 529 530 539 540 540 546

547 552 552 558 562 562

570 571 584 587 587 595

Index 597

Contents for volume 1

Part One  Introduction 1 Historical development of drug delivery systems: From conventional macroscale to controlled, targeted, and responsive nanoscale systems Nedal Y. Abu-Thabit, Abdel Salam H. Makhlouf 1.1 Introduction 1.2 Mechanisms of controlled drug delivery 1.3 Historical development of drug delivery References Further reading

1 3 3 5 8 34 41

2 Stimuli-responsive polymers as smart drug delivery systems: Classifications based on carrier type and triggered-release mechanism 43 Sunaina Indermun, Mershen Govender, Pradeep Kumar, Yahya E. Choonara, Viness Pillay 2.1 Introduction 43 2.2 Internally responsive drug delivery 44 2.3 Externally responsive drug delivery 47 2.4 Dual-responsive or multiresponsive polymer systems 53 2.5 Future trends and conclusion 55 References 55 Further reading 58

Part Two  Endogenous and Exogenous Stimuli-Responsive Drug Delivery Systems 3 The smart chemistry of stimuli-responsive polymeric carriers for target drug delivery applications Tahir Rasheed, Muhammad Bilal, Nedal Y. Abu-Thabit, Hafiz M.N. Iqbal 3.1 Introduction 3.2 The smart chemistry of polymeric carriers

59 61 61 62

xii

Contents for volume 1

3.3 Stimuli-responsive micronanomaterials for control delivery 3.4 Concluding remarks and future perspectives Acknowledgment Declaration of Interest References Further reading 4 Enzyme-responsive polymers for drug delivery and molecular imaging Junqing Wang, Huaping Zhang, Fang Wang, Xixi Ai, Dan Huang, Gang Liu, Peng Mi 4.1 Introduction 4.2 Design strategies of developing enzyme-responsive polymers 4.3 Applications of enzyme-responsive polymers 4.4 Conclusion Acknowledgments References

64 86 86 86 86 94 101 101 102 103 115 115 115

5 pH-responsive polymers for drug delivery applications Elaref Ratemi 5.1 Introduction 5.2 The drug delivery system 5.3 pH-responsive polymer-based drug delivery scaffolds 5.4 Strategies for the design of pH-responsive polymer-based DDSs 5.5 Future prospective Acknowledgment References Further reading

121

6 Magnetically responsive polymers for drug delivery applications Eduardo Guisasola, Maria Vallet-Regí, Alejandro Baeza 6.1 Introduction 6.2 Magnetic nanoparticles: Properties and heating mechanism 6.3 Thermosensitive polymers: Action mechanism and types 6.4 Drug delivery and triggering mechanisms 6.5 Magnetic-responsive polymers in drug delivery applications 6.6 Conclusions References

143

Part Three  Polymeric Nanocarriers for Stimuli-Responsive Drug Delivery Systems 7 Responsive block copolymers for drug delivery applications. Part 1: Endogenous stimuli-responsive drug-release systems Renjith P. Johnson, Namitha K. Preman 7.1 Introduction 7.2 Endogenous stimuli-triggered cell targeting

121 121 123 128 136 137 137 141

143 145 148 152 155 162 163

169 171 172 173

Contents for volume 1

7.3 Endogenous stimuli-responsive drug-release systems 7.4 Conclusions Acknowledgment References Further reading 8 Responsive block copolymers for drug delivery applications. Part 2: Exogenous stimuli-responsive drug-release systems Renjith P. Johnson, Namitha K. Preman 8.1 Introduction 8.2 Exogenous stimuli-responsive cell targeting 8.3 Exogenous stimuli-responsive drug-release systems 8.4 Conclusions Acknowledgment References

xiii

175 210 210 210 220 221 222 223 225 242 242 242

9 Responsive polyelectrolyte multilayer nanofilms for drug delivery applications 247 Anandhakumar Sundaramurthy 9.1 Introduction 247 9.2 General aspects of polyelectrolytes and PEM films 249 9.3 Fabrication of responsive PEM films 250 9.4 Loading of drug or other biomolecules in the PEM film 252 9.5 Different methods of release from PEM films 254 9.6 Applications of PEM films 258 9.7 Conclusions 261 Acknowledgments 261 References 261 10 Responsive polyelectrolyte complexes based on natural polysaccharides for drug delivery applications Benjamin D. Emmanuel, Nedal Y. Abu-Thabit, Ndidi C. Ngwuluka 10.1 Introduction 10.2 Polysaccharides in drug delivery 10.3 Polyelectrolyte complexes 10.4 PECs based on natural polysaccharides 10.5 Polysaccharide-based PECs as a class of stimuli-responsive polymers for drug delivery 10.6 Underutilized polysaccharides for possible complexation 10.7 Future trends 10.8 Conclusion References 11 Responsive polymer nanoparticles for drug delivery applications Rajesh K. Saini, Laxmi P. Bagri, Anil K. Bajpai, Abhilasha Mishra 11.1 Introduction 11.2 Preparation of polymeric nanoparticles

267 267 268 269 271 274 280 281 282 282 289 289 290

xiv

Contents for volume 1

11.3 Properties of smart nanoparticles 11.4 Applications of smart nanocarriers in drug delivery 11.5 Obstacles and difficulties for smart nanodrug delivery systems in potential clinical applications 11.6 Conclusions and future directions References 12 Stimulus-responsive nanogels for drug delivery Mónica C. García, Julio C. Cuggino 12.1 Introduction 12.2 Crucial physicochemical properties of NGs for drug delivery in cancer therapy 12.3 Response to stimuli of the NGs for triggered drug delivery 12.4 Concluding remarks and perspectives References 13 Stimuli-responsive polymeric hydrogels and nanogels for drug delivery applications Nataly M. Siqueira, Maria F.R. Cirne, Maira F. Immich, Fernanda Poletto 13.1 Hydrogels 13.2 Hydrogel-based nanoparticles 13.3 Stimuli-responsive bulk hydrogels and nanogels: triggers and mechanisms 13.4 Final remarks References Further reading

Part Four  Biopolymer and Biodegradable Nanocarriers for Stimuli-Responsive Drug Delivery Systems 14 Bioinspired polymeric carriers for drug delivery applications Hafiz M.N. Iqbal, Tajalli Keshavarz 14.1 Introduction 14.2 Bioinspired polymers 14.3 Polymeric materials—notable potentialities 14.4 Drug delivery systems (DDS) 14.5 Bioinspired polymeric carriers: smart and innovative drug delivery systems 14.6 Miscellaneous biopolymers and their drug delivery exploitations 14.7 Concluding remarks and future perspectives Acknowledgment Declaration of interest References

296 302 310 311 312 321 321 323 327 338 338 343 343 352 355 366 366 374

375 377 377 378 383 383 391 394 396 397 397 397

Contents for volume 1

15 Stimuli-responsive biopolymer nanocarriers for drug delivery applications Eleni K. Efthimiadou, Maria Theodosiou, Gianluca Toniolo, Nedal Y. Abu-Thabit 15.1 Introduction 15.2 Natural biopolymers 15.3 Synthetic biopolymers 15.4 Stimuli-responsive biopolymer nanocarriers 15.5 Conclusion References 16 Responsive polymer-biomacromolecule conjugates for drug delivery Roberta Cassano, Silvia Mellace, Sonia Trombino 16.1 Introduction 16.2 Responsive polymer materials for drug delivery 16.3 Techniques for conjugating responsive polymers to biomacromolecules 16.4 Protein/peptide-polymer conjugation through covalent bindings (grafting to) 16.5 Protein/peptide-polymer conjugation through production of radicals on the biomacromolecules (grafting from) 16.6 Protein/peptide-polymer conjugation through polymerizable biomacromolecule 16.7 Attachment of responsive polymers to polysaccharides and nucleic acids 16.8 Applications of responsive polymer-biomacromolecules conjugates References Further reading

xv

405 405 405 409 411 426 426 433 434 434 436 437 440 442 443 444 447 452

17 Responsive biopolymer-based microgels/nanogels for drug delivery applications 453 Selin S. Suner, Mehtap Sahiner, Sultan B. Sengel, Daniel J. Rees, Wayne F. Reed, Nurettin Sahiner 17.1 Introduction 453 17.2 Biopolymer-based microgel/nanogel preparation 454 17.3 Drug loading and release systems 454 17.4 Biopolymer-based microgels/nanogels: Prepared from carbohydrates and polyphenols 455 17.5 Concluding remarks 492 References 492 18 Stimuli-responsive poly(ε-caprolactone)s for drug delivery applications 501 Katherine E. Washington, Ruvanthi N. Kularatne, Vasanthy Karmegam, Michael C. Biewer, Mihaela C. Stefan 18.1 Introduction 501 18.2 pH-responsive poly(caprolactone)s 502

xvi

Contents for volume 1

18.3 Temperature responsive polycaprolactones 18.4 Reduction responsive poly(caprolactone)s 18.5 Light responsive poly(caprolactone)s 18.6 Multiresponsive polycaprolactones 18.7 Conclusion References 19 Responsive polysaccharides and polysaccharides-based nanoparticles for drug delivery Ndidi C. Ngwuluka 19.1 Introduction 19.2 Nature and drug delivery 19.3 Polysaccharides 19.4 Nano-drug delivery 19.5 Polysaccharides in nano-drug delivery 19.6 Polysaccharide-based nanoparticles for specificity 19.7 Polysaccharide-based nanostructures for multifunctionality 19.8 Disease specificity 19.9 Future prospects 19.10 Conclusion References

508 514 519 520 524 524 531 531 532 532 536 536 542 548 549 549 550 550

20 Responsive cyclodextrins as polymeric carriers for drug delivery applications 555 Vijaykumar Parmar, Gayatri Patel, Nedal Y. Abu-Thabit 20.1 Introduction 556 20.2 Structure and properties of CDs for drug delivery 558 20.3 Functionalization of CD for stimuli-responsive property 562 20.4 Application of stimuli-responsive CD 564 20.5 Conclusions and future trends 573 References 573 Further reading 580 21 Chitosan as responsive polymer for drug delivery applications M Saquib Hasnain, Amit Kumar Nayak 21.1 Introduction 21.2 Responsive polymers 21.3 Chitosan 21.4 Chitosan-based responsive carrier systems for drug delivery 21.5 Conclusion References

581 581 582 585 586 596 596

Contents for volume 1

22 Biodegradable polyhydroxyalkanoates nanocarriers for drug delivery applications Zibiao Li, Janice Lim 22.1 Introduction 22.2 Raw PHA as a therapeutic delivery carrier 22.3 Modified PHA nanocarriers in therapeutic deliveries 22.4 Conclusion and future perspectives References 23 Biodegradable polymeric micelles for drug delivery applications Nimet Bölgen 23.1 Introduction 23.2 Polymeric micelles 23.3 Biodegradable polymeric micelles 23.4 Conclusion References

xvii

607 607 608 613 627 629 635 635 636 640 647 647

Index 653

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List of contributors

Sara A. Abouelmagd  Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt Syed Anees Ahmad  Department of Pathology, King George’s Medical University, Lucknow, India Xixi Ai Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China Sarah Mousa Maadi Asiri Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam, Saudi Arabia Varvara Athanasiou University of Athens, Department of Chemistry, Athens, Greece Rinti Banerjee  Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India Abdulhadi Baykal  Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam, Saudi Arabia Ayhan Bozkurt Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam, Saudi Arabia Rajeet Chandan Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India Panagiotis Christakopoulos University of Athens, Department of Chemistry, Athens, Greece Dan Huang  Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China Abdelhamid Elaissari  Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, Lyon, France

xx

List of contributors

Noura Hassan Abd Ellah Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt Ismail Ercan  Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Panagiota G. Fragouli Piraeus University of Applied Sciences, Department of Textile Engineering, Athens, Greece Mónica Cristina García  Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA)-CONICET-UNC, Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba, Argentina Basma Nagy Abd El Hamid  Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, Egypt M. Saquib Hasnain  Department of Pharmacy, Shri Venkateshwara University, Gajraula, India Mohammad Niyaz Hoda Department of Pharmacy, Hamdard University, New Delhi, India Hermis Iatrou University of Athens, Department of Chemistry, Athens, Greece Ankit Jain  Institute of Pharmaceutical Research, GLA University, Mathura (UP), India Sanjay K. Jain  Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar (MP), India Ravindran Jeremy  Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam, Saudi Arabia Renjith P. Johnson  Polymer Nanobiomaterial Research Laboratory, Yenepoya Research Centre, Yenepoya University, Mangalore, India Ujjwal Joshi  Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Chariya Kaewsaneha  Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR 5007, Lyon, France; School of Bio-Chemical Engineering and Technology, Sirindhorn International Institute of Technology (SIIT), Thammasat University, Pathum Thani, Thailand

List of contributorsxxi

Maria Kasimati University of Athens, Department of Chemistry, Athens, Greece P.P. Kundu Department of Polymer Science and Technology, University of Calcutta, Kolkata; Department of Chemical Engineering, Indian Institute of Technology, Roorkee, India Doo Sung Lee  School of Chemical Engineering, Theranostic Macromolecules Research Center, Sungkyunkwan University, Suwon, Republic of Korea Michele K. Lima-Tenório  Department of Chemistry, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil Gan Lin Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China; Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, VIC, Australia Peng Liu Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China Jing Liu  Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China Rashmi Madhuri Department of Applied Chemistry, Indian Institute of Technology (Indian School of Mines), Dhanbad, India Katerina Mathianaki  University of Athens, Department of Chemistry, Athens, Greece Livia Palmerston Mendes  Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Zihan Meng  Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China Peng Mi Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China Piyasi Mukhopadhyay Department of Polymer Science and Technology, University of Calcutta, Kolkata, India

xxii

List of contributors

Amit Kumar Nayak  Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj, India Muhammad Nawaz Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Pritish Kumar Panda Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar (MP), India Vijaykumar K. Parmar  Department of Pharmaceutical Sciences, Sardar Patel University, Vallabh Vidyanagar, Anand, India Gayatri C. Patel  Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology (CHARUSAT), Anand, India Prigneshkumar S. Patel Sun Pharmaceutical Industries Ltd., Vadodara, India Santanu Patra  Department of Applied Chemistry, Indian Institute of Technology (Indian School of Mines), Dhanbad, India Ameya Prabhakar Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India Namitha K. Preman  Polymer Nanobiomaterial Research Laboratory, Yenepoya Research Centre, Yenepoya University, Mangalore, India Sanjay Rishishwar  Department of Pharmacy, Shri Venkateshwara University, Gajraula, India Poonam Rishishwar  Department of Pharmacy, Shri Venkateshwara University, Gajraula, India Shivani Saraf  Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar (MP), India Can Sarisozen  Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Prashant K. Sharma Functional Nanomaterials Research Laboratory, Department of Applied Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad, India Yassine Sliman  Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

List of contributorsxxiii

Daniel Crístian Ferreira Soares  Universidade Federal de Itajubá-Campus Itabira, Itabira, Brazil Dimitra Stavroulaki University of Athens, Department of Chemistry, Athens, Greece Marli Luiza Tebaldi Universidade Federal de Itajubá-Campus Itabira, Itabira, Brazil Ernandes T. Tenório-Neto  Department of Chemistry, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil Thavasyappan Thambi  School of Chemical Engineering, Theranostic Macromolecules Research Center, Sungkyunkwan University, Suwon, Republic of Korea Ankita Tiwari  Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar (MP), India Vladimir P. Torchilin Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, United States Amit Verma  Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Vishwavidyalaya, Sagar (MP), India Eiji Yuba Graduate School of Engineering, Osaka Prefecture University, Osaka, Japan Huaping Zhang Department of Radiology, Center for Medical Imaging, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China

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Preface

This book is the second volume of the “Stimuli Responsive Polymeric Carriers for Drug Delivery Applications.” While the first volume focused on the types of responsive carriers and their triggering mechanisms, this volume is devoted to presenting the recent therapeutic, diagnostic, and theranostics applications of various responsive polymeric nanocarriers. This volume is divided into 7 parts and contains 21 chapters. Parts 1 and 2 discuss the dual-responsive and multiresponsive nanocarriers as advanced classes of stimuli-responsive polymers. Part 3 highlights the theranostics applications of ­stimuli-responsive polymers and presents deep discussion of image-guided therapeutic applications using internal and external stimulus-responsive nanocarriers. Part 4 discusses the innovative categories of stimuli-responsive drug delivery systems (DDSs) including dual- and multiresponsive block copolymers, responsive carbon nanotubes, ionic strength responsive nanocarriers; liposomes, micelles, and polymersomes as advanced stimuli-responsive DDSs. Part 5 discusses the applications of responsive nanocarriers for cancer therapy using polymersomes and polymeric micelles as responsive DDSs for tumor targeting. Responsive DDSs for different therapeutic applications are discussed in Part 6, which includes ocular therapy, treatment of diabetes mellitus, oral insulin delivery, and colon targeted delivery. The last part of the book (Part 7) addresses the future trends and challenges that need to be considered for DDSs based on stimuli-responsive nanocarriers.

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Part One Dual-Stimuli Responsive Polymers

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Redox- and pH-responsive polymeric nanocarriers

1

Peng Liu Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China

1.1 Introduction Tumor has become as one of the most deadly disease all over the world in the last decades. Nowadays, surgical operation is the most used therapy for cancer, usually followed with radiotherapy and chemotherapy as adjuvant therapy. Surgery and radiation therapy remove, kill, or damage cancer cells in a certain area, but chemo can work throughout the whole body. Although these anticancer drugs (chemotherapeutic agents) can kill cancer cells or stop them from multiplying, they would cause severe toxic side effect on the normal cells. So, it remains a challenge to precisely on-­demand deliver and releases the cytotoxic medicines in tumor site, but not in the normal tissues. Fortunately, the differences in the physiological parameters of tumor tissues from normal tissues provide a possibility, such as slight acidity, higher level of glutathione (GSH), abnormal temperature, etc. [1]. The nanocarriers, which respond to a variety of intrinsic cues afforded by the tumor microenvironment like low pH, elevated redox potential, overexpressed enzymes, and hyperthermia, have been developed to trigger site-specific drug release. Precisely, the extracellular pH value in tumor tissues ranges from 6.5 to 7.2, and the endosomal pH and lysosomal pH are about 4.5–6.5, while blood, body fluid, and normal tissue are neutral or slightly alkaline (pH 7.4) [2]. Besides the particularity of weak acidity in intracellular cancer cells, the remarkable distinction of redox potential between intracellular and extracellular sites also provides attractive chance for the enhancement of biodegradability of those drug delivery vehicles cross-linked with disulfide linkages. The concentration of GSH in intracellular compartments (3–10 mM) is maintained approximately three orders of magnitude higher than that in extracellular plasma (∼2.8 μM) [3], and the GSH concentration in some kinds of tumor cells is much higher than normal cells [4]. Nanocarriers are the ideal designs used in modern chemotherapy to minimize the systemic toxicity associated with most free anticancer drugs. These carriers can deliver the drugs preferentially to cancerous tissues by means of the enhanced permeability and retention (EPR) effect and bypass the multidrug resistance in the cell [5]. Especially, polymeric nanocarriers have attracted more and more interest as the outstanding smart drug delivery system (DDS) for tumor treatment, ­owing

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. https://doi.org/10.1016/B978-0-08-101995-5.00001-5 Copyright © 2019 Elsevier Ltd. All rights reserved.

4

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

to their flexibility of design and synthesis and the ease of modification and functionalization [6], which endow the polymeric nanocarriers higher drug-­loading capacity (DLC) and intelligent stimuli-responsiveness for precisely control of switching “on” and “off” at specific sites (cancer cells and some specific organelles) or correlative external stimulations, upon the stimuli such as acidity, highlevel reductant, and/or higher temperature in tumor tissues and tumor intracellular microenvironment [7]. Considering the synergetic site-specific effect of the two main stimuli-responsive factors for precisely controlled release of anticancer drugs [8], the redox- and pH-responsive polymeric nanocarriers have been widely studied to achieve more effective chemotherapy effect, especially the minimized toxic side effect on the normal cells. In this chapter, the recent progress in the preparation and application of redox and pH dual-responsive polymeric nanocarriers {polymer micelles [including CCL micelles and shell-cross-linked (SCL) micelles] and polymer nanoparticles [including core-shell nanoparticles, yolk-shell nanoparticles, and nanocapsules]} as well as polymer nanoprodrugs for controlled anticancer drug delivery is reviewed, with the emphasis on the relation between their structure design and controlled release performance. And, such understanding is expected favorable to the better design of on-­ demand DDS for tumor chemotherapy.

1.2 Polymer micelles Polymer micelles possess core/shell architecture and typically exhibit a narrow size distribution, with nanoscaled diameters. The choice of the core-forming segment is the major determinant for important properties of polymer micelles such as stability, DLC, and drug-release profile, while the hydrophilic shell of the micelle provides steric stability and minimizes nonspecific uptake of nanoparticles by the reticuloendothelial system (RES), resulting in prolonged circulation time in the body. Generally, higher hydrophobicity and molecular weight lead to a lower critical micelle concentration (CMC), thus, higher stability [9]. In addition, the size of polymer micelles can be easily controlled by varying the hydrophobic block of the amphiphilic copolymer. This size range also permits for evasion of renal filtration, while allowing for increased tumor penetration as compared with liposomes [10].

1.2.1 Self-assembled polymer micelles Chen et al. designed and synthesized a novel copolymer based on poly(ethylene glycol) (PEG) and reducible poly(β-amino ester)s (RPAE), containing disulfide bonds in the backbone of poly(β-amino ester)s. This copolymer can self-assemble into stable sub-100 nm micelles in a physiological environment, with the RPAE constituting the core and the PEG as the shell. They showed rapid intracellular release of doxorubicin (DOX) through demicellizing rapidly at high levels of reducing reagents and in an acidic environment [11].

Redox- and pH-responsive polymeric nanocarriers5

Bahadur et  al. designed a novel poly[2-(pyridin-2-yldisulfanyl)ethyl acrylate] (PDS) based micelle as delivery system to mimic the clinic dosing pattern, initially administering high loading dose and then low maintenance dose [12]. After conjugating PEG and cyclo(Arg-Gly-Asp-d-Phe-Cys) (cRGD) peptide through thiol disulfide exchange reaction for the purpose of enhanced the cellular uptake and nuclear localization and encapsulation of DOX via intermolecular hydrophobic interaction resulted from π-π interaction, the PEG and cRGD conjugated PDS (RPDSG)/DOX nanoparticle of 50.13 ± 0.5 nm was obtained, which was stable in physiological condition while quickly releasing DOX with the trigger of acidic pH and redox potential, and displaying significantly higher anticancer efficacy than that of free DOX at concentrations higher than 5 μM. Zhong group developed redox and pH dual-responsive biodegradable micelles based on poly(ethylene glycol)-SS-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-SS-PTMBPEC) copolymer and investigated for intracellular doxorubicin (DOX) release (Scheme 1.1) [13]. The PEG-SS-PTMBPEC copolymer with a Mn of 5.0–4.1 kg/mol formed micellar particles with an average diameter of 140 nm and a low polydispersity of 0.12. The DOX-loaded micelles with decent drug-loading content of 11.3 wt% released only ca. 24.5% DOX under physiological conditions in 21 h. The drug release was further boosted under 10 mM GSH and pH 5.0 conditions, with 94.2% of DOX released in 10 h. Cheng et  al. designed poly(BAC-AMPD)-g-PEG-g-CE by conjugating PEG and cholesterol (CE) onto the linear poly(amido amine)s via Michael addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BACy) (Scheme 1.2) [14]. The copolymer formed micelles with an average hydrodynamic diameter of 135.7 ± 13.6 nm in aqueous solution. The DOX-loaded micelles with loading capacity of 5.4% showed pH- and redox-responsive release of DOX, due to the high solubility of the protonated DOX in acidic media and dithiothreitol (DTT)-induced degradation of hydrophobic cores. Cai et  al. fabricated the pH- and redox-responsive mixed micelles by solvent evaporating of the amphiphilic copolymer mixture of poly(epsilon-­caprolactone)b-poly(2-(diethylamino) ethyl methacrylate) (PCL-PDEA) and disulfide-linked

O

O

O O O

O O

n

N H

S

S

H N

S O

O

O

O O

Scheme 1.1  Poly(ethylene glycol)-SS-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PEG-SS-PTMBPEC).

O m

6

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

H2N

NH

+

O S

N H

S

O

O N

S

N H

H N

S

O

H N

S

x

O S

N H

N O

H N

S

O

O

N

1-x

O

S

N H

N

S

N H

N

O HN

HN

O

H2N

H N

H N

S

x

O

O HN

O N

N H

SS

H N O

O

N 1-x-y

O O

N

N H

SS

H N O

O

N

x

O

O N

N H

SS

H N O

x

O

Scheme 1.2  Synthesis of poly(BAC-AMPD)-g-PEG-g-CE.

poly(ethyl glycol)-poly(epsilon-caprolactone) (mPEG-SS-PCL) [15]. In  vitro drug release showed that drug-loaded mixed micelles (mass ratio 5:5) could achieve above 90% of drug release under low pH and reducing condition within 10 h. They also synthesized amphiphilic poly(epsilon-caprolactone)-SS-poly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3-sulfopropyl)-N-methacrylate-N,N-diethylammonium-­ betaine) (PCL-SS-PDEASB) for the pH and redox dually responsive micelles, with zwitterionic sulfobetaines as hydrophilic shell, 2-(diethylamino) ethyl methacrylate (DEA) as pH-sensitive content, and disulfide as redox-responsive linkage [15a]. PCLSS-PDEASB1 and PCL-SS-PDEASB2 were obtained and their sulfobetaine unit numbers were 3 and 7 (Scheme 1.3), with CMC of 1.48 and 2.75 mg/L, respectively. After loading of DOX, their micelle diameters were about 190 and 173 nm, with DLC of 8.1% and 5.0%. A total of 13.8% drug release for PCL-SS-PDEASB1/DOX and 21.5% drug release for PCL-SS-PDEASB2/DOX at pH 7.4 and without DTT in 12 h, while 53.3% and 84.6% of the drug released from PCL-SS-PDEASB1/DOX and PCLSS-PDEASB2/DOX, respectively, at the condition of the synergistic effect of low pH and redox. Chu et al. reported novel pH and reduction dual-sensitive biodegradable polymeric micelles for an efficient intracellular delivery of anticancer drugs, based on a block copolymer of methyloxy-poly(ethylene glycol)-b-poly[(benzyl-l-aspartate)-co-(N-(3aminopropyl) imidazole-l-aspartamide)] [mPEG-SS-P(BLA-co-APILA)] synthesized by a combination of ring-opening polymerization and side-chain reaction (Scheme 1.4) [16]. The polymeric micelles and DOX-loaded micelles could be prepared simply by adjusting the pH of the polymer solution without the use of any organic solvents. A release of about 50% of the entrapped DOX was achieved within 8 h in phosphate buffered saline (PBS) at pH 7.4, while >90% DOX released in the first 4 h in the ­presence

Redox- and pH-responsive polymeric nanocarriers7

HO

S

S

OH

O

+ Br

HO

Br

S

O O

HO

O

O

n

Br

O

O

S

S

S

Br

O

O O HO

O

O

n

S

O

S

O

n O

O

O N

O HO

O

O

n

S

O

S

O

y O

x O

O

O

O

N

N

SO3

Scheme 1.3  Synthetic line to PCL-SS-PDEASB.

O

O

m

OH

N

+

O N

N

N

O

O

O

O

m

O O

O

O

m

S

N H

NH2

S

O O O

O

O

m

S

N H

S

O

O

O m

O

N H

S

n

O

O

H N

S N

O N

O

H N

O

O

H N

N H x H N

H n-x

O

Scheme 1.4  Methyloxy-poly(ethylene glycol)-b-poly[(benzyl-l-aspartate)-co-(N-(3aminopropyl) imidazole-l-aspartamide)] [mPEG-SS-P(BLA-co-APILA)].

N

N

8

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

of 10 mM DTT. However, there was insignificant difference between the rates of DOX released in PBS at 7.4 with DTT and in PBS at 5.0 with DTT. The possible explanations are given by the authors as follows: the reduction-triggered cleavage of the disulfide bond in the block junction of the hydrophilic and hydrophobic moieties leads to the complete loss of micelle stability, as a result, almost all the encapsulated drug diffused out in the presence of DTT almost independent of pH from 5.0 to 7.4. Bui et  al. synthesized a redox- and pH-sensitive poly(beta-amino ester)-grafted ­disulfide methylene oxide poly(ethylene glycol) (PAE-g-SWEG), which showed not only a sharp pH-dependent assembly-disassembly transition but also a quick shell shading in a high concentration of reducing agent by Michael addition polymerization (Scheme 1.5) [17]. The micelles with CMC of 0.4 mg/L were used for the controlled release of DOX. The DOX-loaded micelles with DLC of 4.96% released DOX rapidly in an acidic environment (pH 6.4) with the presence of reducing agent DTT, and up to 91.7% of DOX was released after 4 h. In comparison with single-trigger conditions (pH 6.4 or pH 7.4 + DTT), DOX-loaded polymeric micelles (PMs) in pH 6.4 + DTT showed a two times higher cumulative percentage, which suggests that the release rate of DOX from PMs can be highly enhanced under cotriggered conditions. For physiological conditions (pH 7.4), the release of DOX was slower than that under triggered conditions. The same group developed a new type of redox and pH dual-responsive biodegradable polypeptide micelle based on the disulfide-linked methoxy poly(ethylene glycol)-b-poly[2-(dibutylamino) ethylamine-l-glutamate] (mPEG-SS-PNLG) copolymer, which was synthesized by a combination of ring-opening polymerization using mPEG-cystamine as a macroinitiator and a side-chain aminolysis reaction, as an efficient and intelligent carrier to rapidly trigger the intracellular release of DOX [18]. The cumulative release profile of the DOX-loaded mPEG-SS-PNLG micelles ­indicated a low level of drug release (approximately 25 wt% within 24 h) at pH 7.4, which was O O

O

114

O

O 114

O

O O

O

O O

OH + O

O

O N

O O

O

N

O

O 114

HN

N

OH

114

O O

O

O

6O

O

NH O

O

O O

O x N

S

N H

O

6O

O O

O

y

S S O N H

Scheme 1.5  Synthesis of PAE-g-DSMPEG.

O O

O 114

S

NH2

Redox- and pH-responsive polymeric nanocarriers9

S

HO

OH

S

O

+ O

N

S

O

S

O

Br O

S

OH

O COCl

n

OH

O

S

O

O

HO N

O OH

O O

O

OH S

S

O

Redox-sensitive

Hydrophilicity

OH

N

OH

O

m HO

S

S

O

N O

pH-sensitive

O

Fluorescence probe

n

O O

O

Scheme 1.6  Synthetic route of pH- and redox-sensitive RPHA and RPHA-g-coumarin polymers.

significantly accelerated at a lower pH of 5.0 and a higher reducing environment (over 95 wt% in 24 h), demonstrating unambiguous redox/pH dual-­responsive controlled drug-release capability. Li et al. reported a facile method to construct pH- and redox-responsive micelles from a novel reducible poly(β-hydroxyl amine)s (RPHA), in which a large number of hydroxyl groups gave rise to good hydrophilicity to stable micelles in aqueous solutions, and the abundant disulfide bonds embedded in the core and tertiary amines located in the shell provided the stimulative responsibility for the micelles (Scheme 1.6) [19]. The CMC of RPHA micelles with Dh of 185 nm was ca. 1.17 mg/L. After DOX loading with DLC of 9.1%, the in vitro experiments showed a burst DOX release in the first 2 h (24.1%), and then the release ratio sharply rose into 62.6% after 24 h in the presence of 10 mM DTT in PBS at pH 7.4. Notably, the fastest and almost completely DOX release (96.9%) was observed at pH 5.0 in the presence of 10 mM DTT. Yan et  al. developed glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-­ caprolactone) copolymer (PCL-SS-CTS-GA) micelles for the codelivery of DOX and curcumin (CCM) to hepatoma cells, in which glycyrrhetinic acid (GA) was used as a targeting unit to ensure specific delivery. The coencapsulation of DOX and CCM was facilitated by the incorporation of poly(ε-caprolactone) (PCL) groups, with DLC of 19.8% and 8.9% (w/w), respectively [20]. The PCL-SS-CTS-GA micelles presented a spherical or ellipsoidal geometry with a mean diameter of approximately 110 nm. The surface charge of the micelles changed from negative to positive, when the pH value of the solution decreased from 7.4 to 6.8. Meanwhile, they exhibited a character of redox-responsive drug release and GA/pH-mediated endocytosis in vitro. In simulated body fluid with 10 mM glutathione, the release rate in 12 h was 80.6% and 67.2% for DOX and CCM, respectively.

10

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Chen et  al. reported dually pH/reduction-responsive novel micelles based on self-assembly of carboxymethyl chitosan-cysteamine-N-acetyl histidine (CMCHSS-NA) and DOX, to generate precise spatiotemporal responsiveness of intracellular drug release with minimalized undesired release at surrounding normal tissues [21]. The DOX/CMCH-SS-NA micelles with DLC of 22.3% and Dh of 141 nm were prepared via a dialysis method. DOX was released slowly in the presence of pH 7.4 PBS, with an accumulated release of 41% ± 2% within 24 h. However, the accumulated release ratio was as high as 89% ± 2% in both acidic and reducing environments, suggesting that rapid DOX release could be triggered by intracellular stimuli. Gong et  al. developed a pH and redox dual-responsive drug carrier based on poly(aspartic acid) through ring-opening reactions of polysuccinimide (PSI), then chains were grafted onto the polyaspartamide backbone via redox-responsive disulfide linkages, providing a sheddable shell for the polymeric micelles in a reductive environment. Phenyl groups were introduced into the polyaspartamide backbone via the aminolysis reaction of PSI to serve as the hydrophobic segment of micelles. The polyaspartamide scaffold was also functionalized with N-(3-aminopropyl)-imidazole to obtain the pH-responsiveness manifesting as a swelling of the core of micelles at a low pH [22]. The DOX-loaded polymeric micelles exhibited accelerated drug-release behaviors in an acidic and reductive environment due to the swelling of hydrophobic cores and the shedding of PEG shells. Jia et al. synthesized novel multifunctional copolymer, methoxy poly(ethylene glycol)N′-cystamine carbamate-poly[2-(diethylamino) ethylmethacrylate-co-N′-rhodamine 6G-ethylacrylamide] [PEG-Cys-P(DEAEMA-co-Rh6GEAm)] via reversible additionfragmentation chain transfer (RAFT) polymerization, in which the PDEAEMA segment was hydrophilic in acidic media and hydrophobic in neutral or alkaline solution (Scheme 1.7) [23]. Its positively charged characteristic could be used for drug-loading and pH-responsive controlled release. DOX was loaded into the PEGCys-P(DEAEMA-co-Rh6GEAm) micelles by facile micellization of the c­ opolymer O

O

O

O

OH 42 H N

O 42

O O

O

+

S

O

Cl

O

O

S

H N O

O

O

O

42

NO2

O O

H N

O

O

NH2

O 42

O

NO2

S

O

S

N H

S

S S

O S

S

N H

S O

O

O

N

O

S S

NH

N

11

NH

O NH

Scheme 1.7  Synthesis of the PEG-Cys-P(DEAEMA-co-Rh6GEAm) block copolymer by RAFT polymerization.

11

Redox- and pH-responsive polymeric nanocarriers11

in water without any organic solvent, in the presence of DOX. With a high DLC of 39.2%, the Dh of the DOX-loaded micelles was about 330 nm. In the pH 7.4 releasing media with lower reductant level (10 μM) as the stimulated physiological medium, the cumulative release ratio increased to 18.2%, slightly higher than the corresponding releasing media without DTT or GSH. As for the pH 5.0 releasing media with high reductant level (10 mM GSH or DTT) mimicking the tumor microenvironment, the release ratio of DOX increased dramatically to 89.6% and 86.4% within 60 h, respectively. Furthermore, the fluorescence intensity of the micelles increased with the decrease of the solution pH value, meanwhile, the solution transformed from colorless to pink in the daylight, and changed from colorless to yellow under the ultraviolet (UV) lamp at the wavelength of 365 nm. All these results stated that the fluorescent reduction/pH dual stimuli-responsive micelles possessed highly promising potential as a multifunctional theranostic platform for the tumor microenvironment-responsive targeted intracellular delivery of hydrophobic chemotherapeutics and real-time fluorescent imaging of tumor tissues.

1.2.2 CCL micelles Amphiphilic block copolymers containing both hydrophilic and hydrophobic blocks can be self-assembled into micelles as vehicles for hydrophobic drugs. However, in further applications for anticancer drug delivery, the performance of the self-­assembled micelles might be limited by suffering from low structural stability and tending to be disrupted upon large dilution. The dissociation of self-assembly at low concentrations (below its CMC) in blood circulation indeed accelerates the premature drug release at normal tissues or organs and thus only low extent of vehicle dosage could reach the target disease sites [24], and the premature drug release usually leads to serious side effects. To resolve the stability issue, conventional chemical cross-linking of micelles has been used as powerful approach to hold the self-assembled architecture [25]. However, the cross-linked shell might limit the intracellular drug release. To satisfy the requirement, the degradable linkages have been utilized as promising approach for the cross-linking of micelles [26]. Liu et al. synthesized genipin cross-linked polyionic complex (PIC) micelles by mixing a pH-sensitive/disulfide-based polymer, poly(DTPA-co-cysam), which was synthesized by copolymerization of diethylenetriaminepentaacetic (DTPA) dianhydride with cystamine, and a pH-sensitive copolymer, polyethylene glycol-block-poly(l-lysine) (PEG-b-PLL), with the aid of metal ion and subsequent cross-link [27]. Their size and colloidal property were found to be determined by mixing weight percentage, polymer molecular weight, and metal ion. Upon genipin cross-link, the cross-linked compound not only stabilizes the assembled nanostructures but also induces red fluorescence, which is promising as a fluorescent probe for cell imaging. These genipin cross-linked PIC micelles were found to be biocompatible toward fibroblast 3T3 cells and exhibited noticeable pH-sensitive and glutathione-cleavable behavior based on DOX release experiments, suggesting that they are promising stimuli-responsive drug vehicles. Le et al. designed redox-responsive CCL micelles via self-assembly of poly(ethylene oxide)-b-poly(furfuryl methacrylate) (PEO-b-PFMA) block copolymers which

12

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

were synthesized by the RAFT polymerization, following with cross-linking by the Diels-Alder click-type reaction using dithiobismaleimidoethane at 60°C without any catalyst [28]. The CCL micelles showed fine spherical distribution with hydrodynamic diameter of 68 ± 2.9 nm. With DLC of 10.7%, the cumulative release of DOX from the CCL micelles was 18.6% at pH 7.4 after 96 h. However, it was improved and reached to 28.3% at pH 5.0 after 96 h due to the good solubility of DOX in the acidic environment. Furthermore, there was a burst release of DOX at pH 5.0 in the presence of the thiol-containing reagent, 10 mM DTT, and the amount of DOX release reached 52.2% of the initial loading value after 96 h. Zhang et al. synthesized amphiphilic diblock copolymers, in which the hydrophilic segment was PEG and the hydrophobic segment contained a hydrophobic moiety [n-butyl methacrylate (nMBA)] and carboxylic acid groups [methacrylic acid (MAA)] [29]. The core of each micelle was cross-linked using disulfide bonds. High loading capacities were achieved at high feed ratios, owing to the ionic bonding interactions that can occur between the amino group of DOX and the carboxylic group of the poly(methacrylic acid) (PMAA) unit, and the hydrophobic effect between the hydrophobic moieties of DOX and the PnBMA unit. Interestingly, the DOX release profiles for the cross-linked micelles in medium that mimicked the intracellular environment (e.g., pH 5 and 15 mM GSH) were similar to those obtained for noncross-linked micelles in the same medium. Yi et al. designed pH and redox dual-sensitive CCL/SS micelles by cross-linking the micelles of amphiphilic block copolymer poly(ethylene glycol)-poly(2,4,6-tri-­ methoxybenzylidene-pentaerythritol carbonate-co-5-methyl-5-propargyl-1,3-dioxan2-one), that is, PEG-P (TMBPEC-co-MPMC) with pendant reactive alkynyl groups as well as pH-sensitive acetal groups, with bis(azido-ethyl) disulfide via azide-alkyne click chemistry [30]. The hydrodynamic size of the CCL/SS micelles was 80.45 nm polydispersity index (PDI = 0.089) at pH 7.4. DOX was loaded with DLC of 10.9%. The release of DOX from the CCL/SS micelles was approximately 35.8% at pH 7.4 without DTT, while an accelerated release rate was observed in the presence of 10 mM DTT at pH 7.4. Furthermore, the release profile of DOX for the CCL/SS micelles at pH 5.0 with 10 mM DTT was similar to that of the uncross-linked (UCL) micelles at pH 5.0 in the absence of DTT, that is, almost all of the drugs (∼92%) were released within 48 h. Tian et al. established novel approach for the CCL micelles via in situ atom transfer radical polymerization (ATRP) technique. The CCL micelles were in situ synthesized via ATRP of tert-butyl acrylate (tBA) and N,N′-bis(acryloyl)cystamine (BACy) with folate-functionalized macroinitiator (FA-PEG-PtBA-Br). After the hydrolysis of the tBA units in the CCL micelles into acrylic acid units, the hydrolyzed CCL (HCCL) micelles were obtained with Dh of 260 nm (Scheme 1.8) [31]. The HCCL micelles remained stable for >36 h in the stimulated physiological medium (pH 7.4 + 10 μM GSH), while degraded after 5 h at pH 5.0 releasing media with high reductant level (10 mM GSH) mimicking the tumor microenvironment. A high DLC of 27.8% was achieved for DOX owing to the plentiful carboxyl groups in the HCCL micelles. Under pH 7.4 media with 10 μM GSH or DTT, the DOX cumulative release rates were 9.6% and 7.0% within initial 10 h, respectively. The final cumulative release rates came to only 13.4% and 10.7% within 36 h. Under acidic condition (pH = 5.0), drug release with 10 mM GSH was more efficient than that without GSH. Within first 10 h,

Redox- and pH-responsive polymeric nanocarriers13 O HN H2 N

O

N

N

N

N H

H

COOH

H N

O O

Br

O n

m

O

O

O

FA-PEG-PtBA-Br

ATRP Crosslinking

CCL Hydrolysis

DOX-loaded HCCL

HCCL

Scheme 1.8  Structure of FA-PEG-PtBA-Br and the synthesis of the HCCL micelles.

the former gave a higher DOX cumulative release (57.6%) while only 9.5% for the latter, and these data reached 78.7% and 18.8% within 36 h, respectively. Furthermore, the group used the multifunctional amphiphilic linear-hyperbranched copolymer, which was synthesized via the self-condensing vinyl copolymerization (SCVCP) of tBA and p-chloromethylstyrene (CMS) from a PEG-based initiator (mPEG-Br) (Scheme 1.9), as a macroinitiator for the ATRP of tBA and BACy to ­fabricate a reduction-responsive CCL micelles [32]. After hydrolysis, a DLC of 18.4% was achieved for DOX. They could release DOX on the tumor microenvironment, while less leakage in normal tissue microenvironment.

14

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications O O

4

nO

H3C

X

O O

X

10

CH2X (Cl, Br )

Scheme 1.9  Structure of the multifunctional amphiphilic linear-hyperbranched copolymer.

1.2.3 SCL micelles The shells of micelles could also be cross-linked to stabilize the micelles on large dilution. It was reported that the micelles and SCL micelles could be internalized by caveolae-mediated endocytosis while clathrin-mediated endocytosis did not play a noticeable role. However, a considerable difference was found in the exocytosis of both particles. While the micelle was lodged inside the cell for an extended period of time with  LCST; polymer chains collapse, squeezing drug out

Reference [56]

[63]

PNIPAM/37°C

At temperature > LCST; polymer chains collapse, squeezing drug out

[64]

PNIPAM/42°C

At temperature > LCST; polymer chains collapse, squeezing drug out

[58]

Pluronic F-127/37°C

At temperature > LCST; polymer chains are shrunken, resulting in drug release At temperature > LCST; polymer chains are shrunken, resulting in drug release

[73]

At temperature > LCST; polymer chains are shrunken, resulting in drug release At temperature > LCST; polymer chains are shrunken, resulting in drug release At temperature > LCST; polymer shrinks, releasing the DOX Also, rate of hydrolysis of imine bond is faster further enhancing DOX release

[60]

PNIPAM/40°C

PNIPAM/32°C of skin

Polymer is protonated, releasing DOX via electrostatic repulsion.

PNVCL/43°C of hyperthermia

Imine bond hydrolysis at acidic pH results in release of DOX

P(DEGMAco-PEGMA) and Imine bond/50°C of hyperthermia

[7]

[70]

[55]

Continued

98

Table 3.2 

Response to stimuli

Drug release and size change

Size change

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Continued Dual-responsive polymeric system

Targeted location

pH-sensitive component/ Triggering pH level

Cisplatin-loaded nanogel

Tumor

Cleavable bond between cisplatin (Pt) and MAA-COOH/pH  LCST, polymer shrinks protecting the cisplatin-polymer bond from chloride ions in medium, delivering intact nanogel to tumor Dehydration of oligo(ethylene glycol) units of MD, decreasing water solubility of the polymer and increasing drug release

[65]

At mildly acidic pH, LCST decreases and polymer shrinks, decreasing NPs size to 130 nm promoting cellular uptake Lactic acid side groups hydrolysis is accelerated in micelle core, allowing DOX to be released

[66]

At mildly acidic pH, LCST decreases to 34°C and polymer shrinks, decreasing NPs size and promoting cellular uptake

[75]

[61]

[59]

100

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Room temperature (25°C)

Physically loaded drug

(A)

Body temperature (37°C)

Hyperthermia (38–42°C)

T< LCST Polymer expanded, drug is retained

T> LCST Polymer shrinks, squeezing drug out

T< LCST Polymer expanded, acting as diffusion barrier, drug is retained

T> LCST Polymer shrinks, allowing drug release

Drug is loaded inside the core (mesoporous silica, liposomes)

(B)

Chemically conjugated drug

(C)

T< LCST Polymer expanded

T> LCST Polymer shrinks, shielding drug from environment

Fig. 3.4  Effect of temperature on drug release from thermoresponsive polymeric nanocarriers; (A) polymer shrinkage at T>LCST leading to carrier collapse and drug release, (B) polymer shrinkage at T>LCST allowing drug release from carrier core, and (C) polymer shrinkage at T>LCST resulting in a more condense carrier with minimum drug release.

often occurs due to polymer shrinkage/expansion while releasing the drug, yet in these systems the size change is not of therapeutic significance [72]. Alternatively, in many reports, the change in particle size is intended, favoring cellular uptake and tissue extravasation and improving carrier’s in vivo performance [7,61,68,77]. In a previously mentioned example, Chen et al. developed polymeric mixed micelles that undergo changes in both drug release and particle diameter [61]. A mixture of poly(N(2-hydroxypropyl) methacrylamide lactate-co-histidine) and PEG-b-poly(lactic acid) was used to form DOX-loaded micelles. At condition similar to that of the circulation (neutral pH and 37°C), micelles had particle size of 50 nm. By lowering the pH to mimic that of the tumor tissue, micelles size gradually increased, reaching 140 nm at pH 5. The increase in size favored retention of the micelles in the tumor tissue and limited their extravasation back into the circulation. Additionally, DOX release was shown to be pH dependent. At 37°C and pH 7.4, only 15% of the drug was released after 5 h, increasing to 66% at pH 5.4. This was explained by the hydrolysis of lactic acid side groups in the micelles, allowing more DOX to leave the micelles. When tested in vivo, dual-responsive micelles had superior tumor growth suppression than that of free doxorubicin in Balb-c/nude mice bearing HeLa subcutaneous tumor xenografts [61]. In another report, poly(NIPAM-AA) nanogels experienced size reduction in response to pH decrease and hyperthermia [68]. At 40°C and pH 6.8, dual-responsive nanogel encountered phase transition from hydrophilic state into the hydrophobic state resulting in a smaller particle size (130 nm).

Temperature and pH dual-stimuli responsive polymeric carriers for drug delivery101

3.3.3 Relationship between temperature and pH responses within nanocarrier systems Conventionally, pH and temperature responsiveness arise from independent and different functionalities within the polymeric carriers [66,67]. Occasionally, the same functionality may respond to both pH and temperature [57]. Additionally, in many cases there is an interaction between pH and temperature responsiveness; the thermoresponsive action of the polymer is contingent upon certain pH level or the other way around. This is explained with examples in the following section.

3.3.3.1 pH-dependent thermoresponsiveness Generally, the thermoresponsiveness of a polymer is dependent on its characteristic LCST, which can be easily increased or decreased through incorporation of hydrophilic or hydrophobic components [73]. In pH-dependent thermoresponsiveness, the resultant copolymers have pH-dependent LCST, that is, respond to temperature stimulus only in the presence of the suitable pH. In one example, a star-shaped copolymer of hydrophobic PMAA arm and three hydrophilic P(NIPAM-co-DMAEMA) arms was synthesized [81]. This copolymer assembled into polymeric micelles of PMAA core and P(NIPAM-co-DMAEMA) shell for oral delivery of methotrexate and exhibited pH-dependent thermo-responsiveness (Fig. 3.5). Copolymer’s LCST was found to be 32°C, 36.6°C, and 39.5°C at pH 9, 7.4, and 5, respectively. Methotrexate release from the micelles was pH- and temperaturedependent; at pH 7.4, ~70% of drug was released after 48 h at 40°C (>LCST) in ­comparison to only ~25% at 25°C ( LCST

(D)

ON

OFF

Fig. 4.4  Release concepts from a thermosensitive polymeric nanosystem triggered in different LCST (A) Release of hydrophilic drug incorporated into a swollen gel. (B) Diffusion of hydrophobic drug from the collapsed gel. (C) Swollen gel blocks: diffusion and convection flow through porous membranes. (D) Above the LCST, the amphipathic agent incorporated at the gel phase is arranged in dense layers allowing the core to remain swollen. Reproduced with permission from L.E. Bromberg, E.S. Ron, Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery, Adv. Drug Deliv. Rev. 31 (1998) 197–221, https://doi.org/10.1016/S0169-409X(97)00121-X.

a swollen gel. After adequate heating, the temperature reaches values below the LCST and the hydrophilic agent can be released through an increased diffusion mechanism. In (B a hydrophobic agent can be released after the temperature reaches values above the LCST. In (C) swollen gel blocks both diffusion and convection flow through the pores, and allows permeation when collapsed. Finally, in (D) above the LCST temperature, the amphipathic agent, incorporated at the gel phase, is arranged in dense layers allowing the core to remain swollen. To date, polyethyleneglycol (PEG) or dextran is the most biocompatible agent used to cover SPIONs, as evidenced in numerous works found in the literature. However, the use of the polymeric covering approach can significantly reduce the action of many enzymes or proteins over the system. Due to the dense covering process, the release of the agent requires a diffusional mechanism, thus strongly reducing or delaying the

Biomedical nanoparticle carriers with combined thermal and magnetic response119

therapeutic effects. The use of thermosensitive polymers can allow drug release through heating, where different mechanisms such as swelling or shrinkage induce drug delivery, thus avoiding the problems observed in the diffusional process. In the past 5 years, many researchers have given attention to using Pluronic as a thermosensitive coating polymer. This compound is a nonionic triblock copolymer composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene and was invented and patented by Irving Schmolka (Basf Company), in 1973 [40]. This polymer is also known by the trade names Synperonics, Pluronics, and Kolliphor. Chiper et al. [41] covered SPIONs with the triblock copolymer Pluronic aiming to develop a new system capable of combining magnetic and thermal-sensitive properties simultaneously. Pluronic can form many types of micellar structures with PPG (core) and PEG (on exterior) giving good stability in an aqueous environment, allowing the incorporation of agents in the nonpolar region of the micellar structure, maintaining almost the same original magnetic properties of SPIONs [41]. The same authors prepared SPIONs covered with Pluronic (F68) and PEG, and evaluated the stability and thermosensitivity of the system. According to the authors, SPIONPEG-F68-FA has a critical temperature around 37°C, presenting optimal characteristics for in vivo applications. Upon heating, the colloidal nanosystem begins to shrink due to reorganization of its chains after dehydration, significantly reducing the polydispersity index obtaining a very narrow size distribution. The authors claimed thermosensitivity, stability, and biological interaction characteristics due to the presence of the Pluronic-F68 polymer and adequate modification (10 million people are suffering from cancer all over the world. With the quickly increasing numbers of cancerous patients as well as types, cancer diagnosis and therapy have attracted more and more attention of chemical, biological, medical, and pharmaceutical researchers. Nowadays, various treatment protocols have been developed for cancer treatment, in which the main three methods, surgery, radiotherapy, and chemotherapy, have been widely used in the clinical treatment of cancer. Chemotherapy has become a mainstream cancer therapy, after more than a century of development. Benefiting from achievements in the development of antitumor drugs, satisfactory effects have been achieved in stopping or slowing the growth of cancer cells. Unfortunately, conventional chemotherapy mainly relies on small molecule anticancer drugs, leading to indiscriminate killing of both cancerous and healthy tissues/cells [1]. Furthermore, it still remains as a challenge to enhance the anticancer efficiency of chemotherapy with small molecule drugs, such as low solubility, poor pharmacokinetics, undesirable biodistribution, inefficient cellular uptake, and an inability to target desired locations [2]. Additionally, the new biological drugs (such as proteins, antibodies, and nucleic acids) may be deactivated or degraded during blood circulation before they get to the target sites [3]. Such undesired toxic and side effects largely decreased the therapeutic efficacy, and one of the possible outcomes, multidrug resistance to certain types of cancer cells, might further decrease the therapeutic efficacy. Moreover, both systemic and cellular barriers will further hinder the efficient delivery of conventional small molecule drugs to target sites. In order to overcome these limitations, polymeric carriers have been developed for the targeting transport and follow-up site-specific controlled drug/gene release [4–8], responding to the tumor microenvironment and intracellular signals {including acidity, redox potential [glutathione (GSH)], specific enzymes, reactive oxygen species (ROS), hypoxia, and adenosine-5′-triphosphate [ATP]} [9] or external stimuli (such as photo-, electro-, magnetic-, or ultrasound field) [10]. Recently, more precise on-demand drug/gene delivery has been achieved by the combination of more than one stimulus, either intracellular signal or external field, as dual-responsive or multiresponsive delivery systems. Among them, the dual-­responsive delivery systems for drugs or genes have been extensively developed, especially the pH and redox dual-responsive delivery systems [11]. In this chapter, the recent d­ evelopment Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. https://doi.org/10.1016/B978-0-08-101995-5.00005-2 Copyright © 2019 Elsevier Ltd. All rights reserved.

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in the multiresponsive delivery systems based on the tri-stimuli and quadruple-stimuli responsive polymeric carriers (also containing polymer-based composites and hybrids) for cancer therapy is reviewed with particular emphasis on the design of such polymeric carriers, from the point of view of a chemist. Future perspectives and challenges in the field toward the development of more intelligent polymeric drug-delivery systems (DDSs) for diagnosis and treatment of cancer are also discussed.

5.2 Tri-stimuli-responsive polymeric carriers 5.2.1 Polymeric carriers 5.2.1.1 Copolymer micelles Copolymer-based micellar nanoparticles (NPs) are the currently most studied tri-­stimuliresponsive polymeric carriers for cancer chemotherapy, which could be self-­assembled with single kind of copolymer or mixed copolymers. Comparatively speaking, the copolymers for mixed micelles are easy to synthesis, because it is not necessary to integrate all triggering factor in one macromolecule. Similar as the micelles formed with single copolymer, in which the composition would affect the particle size and stimuli-­responsive properties, the micelles formed with mixed copolymers are usually controlled by the composition of the copolymers, as well as their feeding ratio. Zhao et al. designed two-disulfide-functionalized 5-arm AB2C2 star terpolymers (PEG(PCL)2(PNIPAM)2 and PEG(PCL)2(PAA)2) (Scheme 1), and their aggregates formed by a single star or mixed stars were used for loading and release of doxorubicin (DOX) upon dual and triple stimuli [12]. The micelles of PEG(PCL)2(PNIPAM)2 or PEG(PCL)2(PAA)2 expressed temperature/reduction or pH/reduction dual-responsive O

O

O N N N

O

O O

OH

O

O

m

O

CN S

O l

S

R

O

S

n

O O

O O

N N N

OH

O

O O

m

O

CN S

S

S

O

R

S S

O

n

PEG(PCL)2(PNIPAM)2: R = CONHCH(CH3)2 PEG(PCL)2(PAA)2: R = COOH

Scheme 1  Chemical structure of the two-disulfide-functionalized 5-arm AB2C2 star terpolymer.

Multiresponsive polymeric carriers135

characteristics, respectively. As for the mixed micelles of the two 5-arm AB2C2 star terpolymers, temperature/pH/reduction triply stimuli-responsive controlled release of DOX was achieved. Compared with the dually sensitive micelles formed from a single star terpolymer, the triply stimuli-responsive mixed micelles are expected to be more promising as controlled delivery vehicles since the drug-release properties can be potentially adjusted by various external stimuli and composition of star terpolymers. The same group recently reported the preparation and properties of multistimuliresponsive NPs through the coassembly of a 3-arm star quaterpolymer (Scheme 2) with a near-infrared (NIR) photothermal agent and chemotherapeutic compound [13]. The NPs can exhibit NIR light/pH/reduction-responsive drug release and intracellular drug translocation in cancer cells, which further integrate photo-induced hyperthermia for synergistic anticancer efficiency, thereby leading to tumor ablation without tumor regrowth. Wang et  al. prepared photo-, temperature-, and pH-responsive polymers by the quaternization of poly(dimethylaminoethyl methacrylate) (PDMAEMA) with 1-­(bromomethyl)pyrene (Scheme 3). It could assemble into micellar NPs of approximately 60–100 nm, which could be photocleaved under UV irradiation, shrunk to smaller ones above the lower critical solution temperature (LCST) or at high pH, and swollen/dissociated at low pH. The changes in nanostructures endowed the NP great

O HO

CN

O O

S

O

44

O

O

N

O N

O

S

O

S

1−X

O X NH

n

S

N

N

O

O

O

45

Scheme 2  Chemical structure of the 3-arm star quaterpolymer. CH3

H2 C

CH2 C

C Ox

C O y

O

O

CH2

CH2

CH2 N H3C

CH3 C

CH2 Br

CH3 H3C

N CH3

Scheme 3  Chemical structure of the photo-, temperature-, and pH-responsive polymer.

136

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications CH3 CH2 C

C Ox

CH3

H2 C

CH2 C

C Ox

C C O

NH

O

O

CH2

CH2

CH3

O

O

CH2

N

CH3 H3C

H3C

y

CH2 Cl

N

CH2 CH3

C C O

CH2

y

O

CH H3C

CH3

CH3

H2 C

N N O

NO2

O

NO2

P(DMAEMA-SP)

poly(NIPAM-co-SP)

Scheme 4  Chemical structure of the spiropyran-based amphiphilic random copolymer poly(NIPAM-co-SP) and P(DMAEMA-SP).

potential as a sensitive nanocontainer for controlled release under the stimulation by UV light, temperature, and pH, especially under UV light and low pH where the loaded guest molecules, such as Nile Red (NR) and DOX could be released dramatically [14]. The same group designed series of spiropyran-based amphiphilic random copolymers [poly(NIPAM-co-SP and P(DMAEMA-SP)] (Scheme 4). They could self-­ assemble into photo-, pH-, and thermo-responsive micellar NPs. The micellar NPs could be swollen at lower pH, shrunk at higher pH or higher temperature, and dissembled upon UV light. Using coumarin 102 as a model drug, highly efficient controlled release from the NPs under stimulation of UV light, acid, and the combined stimuli could be realized [15,16]. Huang et al. synthesized an ABA-type triblock copolymer containing GSH-sensitive disulfide bond, acid and hydrogen peroxide-disrupted peroxalate ester, and triazole units for pH-responsive hydrogen bonds in its backbone (Scheme 5) [17]. It could be self-assembled into intracellular pH, GSH, and ROS-responsive NPs for the effective

O

PEG2000 N N N

N H

S NH BOC

S

BOC NH H N O

N N N

O O

O N N N

O O

n

NH BOC S

O

N N

PEG2000 N

N H

N H

S NH BOC

Scheme 5  Chemical structure of the ABA-type triblock copolymer.

Multiresponsive polymeric carriers137 X

H2 C

H CH

C O

O mS

S O

S

O O

H O n

NH

Scheme 6  Chemical structure of the triple-stimuli-responsive polymer PNiPAAm-S-S-PXCL.

intracellular DOX delivery. Its average diameter, size distribution, and morphology greatly changed upon adding GSH/H2O2 or modulating the media pH value. In vitro drug-release profiles showed that DOX was quickly released from DOX-loaded NPs by addition of 10 mM GSH, or 10 mM H2O2 or under acidic conditions rather than under physiological conditions. Lee et al. designed triple-stimuli-responsive polymer PNiPAAm-S-S-PXCL containing a disulfide (SS) bond as a junction point between hydrophilic and hydrophobic chains through ring-opening polymerization (ROP) and nucleophilic substitution (Scheme 6). It could self-assemble into micellar NPs with mean hydrodynamic diameter (Dh) of 5 h), the different type and different percentage of HPMC prolonging the process due to swelling of polymer (until about 8 h). These results evidenced that the compression-coated mini tablets, coated with various types of Eudragit enteric polymers are a assuring system for colonic delivery of active drugs [71]. The colon-targeted pH-sensitive microspheres containing the drug capecitabine (CPB) were formulated for the treatment of colorectal cancer. The microspheres formulation showed better patient compliance and also reduced the frequency of dosing. The microspheres were formulating by emulsion solvent diffusion method and showed 53.28%–93.76% entrapment efficiency. Different drug to polymer ratio (1:2 to 1:6) were employed for the formulation of microspheres and characterized for various parameters. The microspheres were spherical in shape, smooth surface (determined by SEM) and displayed good flow properties. The in vitro release study was performed in various simulated GI fluids firstly in SGF (simulated gastric fluid) (pH 1.2) for 2 h, secondly in SIF (simulated intestinal fluid) (pH 6.8) for 2 h, and then in SCF (simulated colonic fluid) (pH 7.4) for 24 h. The results of in vitro release studies showed that microspheres avoided the drug release in stomach and small intestine but showed ­excellent drug release in colon (99.39%). These results proved the therapeutic potential of pH-sensitive microspheres for the treatment of colorectal cancer [72].

Stimuli-responsive polysaccharides for colon-targeted drug delivery561

The pH-responsive polymeric system was formulated with the help of various polysaccharides CT, nanocellulose (NC), and sodium alginate (Na-Alg) for the delivery of dual drug 5-fluorouracil and levamisole hydrochloride. First, carboxylated NC-CT composite was prepared and then coated with Na-Alg and the coated composite was further altered with vinyl monomers for rendering them pH sensitivity. The effect of temperature, time, and pH on swelling behavior was studied. In vitro release studies of dual drug were performed in simulated gastric and intestinal media and the data were analyzed using the Peppas kinetic equation. The cytotoxicity studies were conducted against the HEK293 cells and HT29 colon cancer cells. Apoptosis and reactive oxygen species studies results showed selective irreparable destruction of cancerous cells. Polysaccharides CT was employed for colon-targeted drug delivery due to selective enzymatic degradation by colonic microbial agents at the site of action. Na-Alg was the biodegradable polysaccharide used for imparting pH sensitivity. Na-Alg-coated polymeric system avoids the drug release in gastric pH [18]. The pH sensitive bipolymeric beads were formulated using guar gum or derivative of guar gum (guar gum succinate) and Na-Alg for colon-specific delivery. Na-Alg was utilized to impart pH sensitivity and it is also biocompatible, mucoadhesive, and biodegradable in nature. The formulation showed pH-responsive swelling and release. Guar gum succinate was hydrophilic in nature, retarded the drug release, and showed degradation in presence of microbial agents in large intestine. The in vitro release and swelling studies revealed that drug (ibuprofen) release and degree of swelling were higher at pH 7.4 as compared to pH 1.2 (Fig. 20.3).

Fig. 20.3  Drug-release mechanism from pH sensitive bipolymeric beads.

562

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

20.5 Conclusion Polysaccharides possess versatile properties, such as low biotoxicity, gelling ability, flexibility for chemical modifications and biodegradability, which make them suitable choice for drug delivery. CT, chondroitin sulfate, dextrans, cyclodextrins, guar gum, pectin, and inulin have been explored widely for stimuli-responsive colon-­specific drug delivery based on microflora and pH-responsive approaches. This chapter summarized all such approaches using various drug delivery systems, such as microspheres, NPs, hydrogels, matrices, and beads. However, there is a need of warranted drug delivery to colon in terms of safety and efficacy. With advancing nanotechnology, multifaceted approaches having more than one feature of targeting should be employed for better outcomes.

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Part Seven Future Trends and Challenges

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Recent progress in responsive polymer-based drug delivery systems

21

M. Saquib Hasnain⁎, Amit Kumar Nayak† ⁎ Department of Pharmacy, Shri Venkateshwara University, Gajraula, India, †Department of Pharmaceutics, Seemanta Institute of Pharmaceutical Sciences, Mayurbhanj, India

Abbreviations CAD chitosan-g-PNIPAM dextran-g-PNPAM-co-NNDEAM DOX DTX Fe2O3 GSH IPN LCST MDR PAA PAM PCL PDEAM PDLA-co-PEG PEG PEG-b-PLA PEG-b-PLy-b-PLpa PEG-DA PEG-Fe2O3 PEI PELG PGA PLGA PLGA-mPEG PLLA PMMA PMVE PNBA PNIPAM

cis-aconityl-doxorubicin chitosan-grafted poly(N-isopropylacrylamide) dextran-g-poly(N-isopropylacrylamide-co-N, N-dimethylacrylamide) doxorubicin docetaxel magnetite glutathione interpenetrated polymeric networking lower critical solution temperature multidrug resistant polyacrylic acid polyacrylamide poly(caprolactone) poly(N,N-diethyl acrylamide) poly(d,l-lactide)-co-polyethylene glycol poly(ethylene glycol) poly(ethylene glycol)-b-poly(lactic acid) poly(ethylene glycol)-b-poly(l-lysine)b-poly(l-phenylalanine) poly(ethylene glycol) diacrylate poly(ethylene glycol)‑iron oxide polyethylenimine poly(l-lysine)-poly(l-glutamic acid) polyglycolic acid poly(d,l-lactide-co-glycolide) poly(d,l-lactide-co-glycolide)-methoxy poly(ethylene glycol) poly(l-lactic acid) poly(methacrylic acid) poly(methyl vinyl ether) poly(2-nitrobenzyl acrylate) poly(N-isopropyl acrylamide)

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. https://doi.org/10.1016/B978-0-08-101995-5.00024-6 Copyright © 2019 Elsevier Ltd. All rights reserved.

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PNVCL PTX PVA PVP-co-DMMA Red-Ox Sn(Oct)2 UCST

poly(N-vinyl caprolactam) paclitaxel poly(vinyl alcohol) poly(vinyl pyrrolidone-co-dimethyl maleic anhydride) reduction-oxidation stannous caprylate upper critical solution temperature

21.1 Introduction With the advancements in the discovery of numerous newer as well as more potent drug molecules, a parallel growth in research in more advanced systems for optimal drug release becomes mandatory. Since the past few decades, a huge number of drug candidates have arrived in the market to enhance the therapeutics and diagnostics for different diseases. For the effective delivery of different drug candidates, numerous kinds of drug delivery systems are being researched and developed to deliver drugs through various routes of administration [1–22]. The majority of these drug-releasing systems have been formulated using various biocompatible and biodegradable polymers [15, 20, 23–38]. However, the shortcomings of therapeutic efficacy are always bothersome for the drug delivery scientists and formulators because of their nonspecific targeting potentials and faster rate of blood excretion [39]. The current drug delivery approaches have advanced their characteristics varying from the controlled drug release to the targeting approaches of various loaded drugs [40]. These characteristics transform the simple and conventional drug delivery systems. In recent years, numerous remedies have been researched and developed for imparting smarter drug releasing/targeting attributes to the dosage forms. The well-accepted approach for the attainment of drug targeting can be made through incorporating and/or embedding numerous kinds of drug candidates in macromolecular structures called polymers with especial abilities for the effectual and optimal modulating or moderating of drug releases by the response of a stimulus [39, 40] and such polymers are commonly known as “responsive polymers” or “stimuli-responsive polymers” [41]. Responsive polymers are known as smart polymeric materials and these are able to alter the physicochemical characteristics under the exposure of various external stimuli, for example, pH, temperature, enzyme, light irradiations, electrical fields, magnetic fields, ultrasound, ionic strength, etc. [41–43]. These “smart” polymers exhibit a sharper transition phenomenon in various physicochemical characteristics even under a minute alteration in the environmental condition(s) (i.e., stimuli) [44]. However, the responsive polymeric systems return to the initial condition when the employed trigger is withdrawn. Responsive polymers also result from the surface modifications of various polymeric matrices through the linking of responsive chains to generate responsive interfaces exhibiting several characters in response to slight alterations in the environmental factors [41]. Surfaces may alter from the hydrophobic character to the hydrophilic character [45] or show a variation in pore size [46]. It is feasible to design effective responsive polymeric systems, whose physicochemical ­characteristics like rheological properties as well as surface topographical properties change in r­ esponse

Recent progress in responsive polymer-based drug delivery systems571

to specific stimuli [47]. The responsive polymeric gel systems also facilitate the prospective economic substitutions to the conventional separation procedures for use in various industrial applications [42, 48]. In current years, a variety of systems made of numerous effectual responsive polymer candidates have been synthesized and evaluated for biomedical applications including cell and gene encapsulations, drug deliveries, tissue regenerations, smart biocoatings, biosensings, etc. [42, 44, 49]. In drug delivery applications, various responsive polymer-based carrier systems have been exploited for triggering the release of loaded/encapsulated drugs and targeting drug delivery carriers to advance therapeutics through decreasing related side effects [41]. The responsive polymer-based carrier systems improve the versatility of numerous drug releases and render effective drug targeting to treat several kinds of diseases [48, 50]. During the past few years, numerous responsive polymeric nanosystems have been researched and developed for use in the targeted delivery of various drugs to treat a variety of diseases [51–54]. The current chapter reviews the state-of-the art in various responsive polymer-based systems for drug delivery applications.

21.2 Various responsive polymer-based systems in drug delivery Various responsive polymers imitate biological systems in a simple manner where the exposure of stimulus produces changes in the physicochemical as well as functional properties [41]. This may result in changes in conformations, solubility pattern, hydrophilic/hydrophobic balance, and release of loaded/encapsulated drugs, etc. [55]. Responsive polymers and responsive polymeric systems are capable of showing their response characteristics within biological systems [41, 56]. The chemical as well as biochemical stimuli of internal origins compromise the difference in cell temperature, pH shifting, and overexpression of enzymes in various pathological conditions of the specific tissues. In recent years, numerous internal stimuli-responsive nanocarriers are being investigated as novel drug delivery as well as drug-targeting vehicles on the basis of their intrinsic properties. The intrinsic characteristics are the fundamental points in the designing of numerous internal stimuli-responsive nanocarrier systems with the broad emphasis on different internal stimuli such as pH, concentration of glutathione (GSH), enzyme specificity, overexpression, etc. [51, 56]. The design strategies of stimuli-responsive nanocarriers are presented in Fig. 21.1 [51].

21.2.1 Temperature-responsive polymer-based systems Temperature is one of the most important and extensively employed stimuli in a variety of bio-inspired responsive systems in biomedical applications [56]. Various temperature-responsive polymers display a volume phase transition at the definite temperature and, thereby, hasty alterations in the salvation condition [57]. The most important quality of different temperature-sensitive polymers is the critical solution temperature at which the polymers alter phase. If the polymer experiences phase ­transition from the soluble condition (i.e., monophasic) to the insoluble condition

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Extracellular stimuli (pH, enzyme, temperature)

Intracellular stimuli (pH, enzyme, GSH)

Internalization

Endosomal escape

Nucleus Endocytosis Endosome

Nanoformulations

Normal tissue

Blood vessel

EPR effect

Tumor tissue

Fig. 21.1  Design strategies of internal stimuli-responsive drug nanocarriers. From M. Liu, H. Du, W. Zhang, G. Zhai, Internal stimuli-responsive nanocarriers for drug delivery: design strategies and applications, Mater. Sci. Eng. C 71 (2017) 1267–1280; Copyright 2016 Elsevier B.V.

(i.e., biphasic) above the critical temperature, it is described as possessing a lower critical solution temperature (LCST) with the increments of temperatures. If the polymer transition results from an insoluble condition to a soluble condition with the increment of temperature, it possesses an upper critical solution temperature (UCST) [56, 58]. Some common examples of LCST polymers are poly(N-­isopropyl acrylamide) [PNIPAM], poly(N,N-diethyl acrylamide) [PDEAM], poly(methyl vinyl ether) [PMVE], poly(N-vinyl caprolactam) [PNVCL], etc. [57]. An important example of an UCST polymeric system is interpenetrated polymeric networking of polyacrylic acid [PAA] and polyacrylamide [PAM] [56]. Both the UCST and LCST systems are not limited to an aqueous milieu. However, in the biopolymer research area, only aqueous systems are employed extensively. The approximate adjustment of LCST to the body temperature is also important, particularly for use in drug-­ releasing applications [39, 59]. Temperature-sensitive polymers are exploited for biomedical uses, including drug delivery, gene and cell deliveries, tissue regenerations, biosensings, etc. [56–58, 60]. Curcio et  al. [61] formulated diclofenac sodium-loaded temperature-responsive microspheres of PNIPAM grafted with gelatin. These temperature-responsive microspheres suffered from the shortcomings of an LCST value of 32°C (low). Therefore, with the intention of increasing the LCST closer to the body temperature, the PNIPAM was grafted onto a natural polymer, gelatin. The LCST value of the polymer was increased and a slow, sustained, drug-releasing pattern for these temperature-responsive microspheres of diclofenac sodium was attained. Thus, the pharmacological efficacy

Recent progress in responsive polymer-based drug delivery systems573

of diclofenac sodium was improved through the exploitation of these temperature-­ responsive microspheres. Meenach et al. [62] synthesized poly(ethylene glycol)‑iron oxide [PEG-Fe2O3] hydrogels for use in the fabrication of temperature-responsive drug delivery systems. In this work, the behaviors of PEG-Fe2O3 hydrogels were researched for the combined paclitaxel (PTX) delivery to the tumorous cells (in  vitro). Breast carcinoma (MDA-MB-231) cell lines, lung adenocarcinoma (A549) cell lines, and glioblastoma (M059K) cell lines were exposed to PTX, individually, hyperthermia individually, and also, hyperthermia and PTX combination to assess whether any cytotoxic result would occur synergistically. A cytotoxicity synergism phenomenon was noticed for the lung adenocarcinoma cell lines; but, the glioblastoma and breast carcinoma cell lines did not demonstrate similar results. The uses of temperature-responsive drug-releasing systems have been ­explored for ocular therapeutics. In an investigation, Derwent and Mieler [63] ­developed hydrogel-based temperature-responsive systems for use in the ocular deliv­ ery of an antiVEGF agent. These hydrogel-based systems were prepared using a ­temperature-responsive polymer, PNIPAM, which was cross-linked with poly(ethylene glycol) diacrylate [PEG-DA]. It was seen that with the use of a cross-linker, the hydrogel-based temperature-responsive systems possessed homogenous porous structures and also found to have enhanced temperature-responsive properties. The higher the cross-linking density, the smaller the pore sizes and therefore, the drug release was found to be sustained over a longer period. Lou et al. [64] developed an in situ gel-based temperature-responsive system containing Pluronic F68, Pluronic F127, and albumin nanoparticles loaded with curcumin. The albumin nanoparticle gel loaded with curcumin exhibited temperature-responsive character. Therefore, because of the transformations of this formulation into a gelled state on exposure to the ocular temperature, it can be used as ophthalmic drops. The temperature of sol-gel transition was dependent on the concentrations of Pluronic F68 and Pluronic F127; an increment in the amount of Pluronic F127 was found to reduce the sol-gel transition temperature of the gel-based system, while the increments in the contents of Pluronic F68 showed a rise in the sol-gel transition temperature. The albumin nanoparticle gel loaded with curcumin could improve the ocular bioavailability of curcumin in the rabbit eye with decreased administration frequency. In a very recent research by Luckanagul et al. [65], chitosan-based polymeric hybrid systems for temperature-responsive nanosized hydrogels (nanogels) of curcumin were synthesized and evaluated. These temperature-responsive nanogels of curcumin were developed to overcome the insolubility, instability, and lower absorption of curcumin. The schematic design of these chitosan-based nanogel systems is presented in Fig.  21.2. Chitosan-grafted poly(N-isopropylacrylamide) [chitosan-g-PNIPAM] nanogels were prepared via the sonication technique. In these nanogel systems, chitosan was utilized as the structural material grafted with PNIPAM via the EDC/NHS coupling reaction procedure. The curcumin loading within these chitosan-g-PNIPAM nanogel systems was attained through the incubation methodology. A CellTiter-Blue cell viability testing was carried out using HeLa and NIH-3T3 cells to measure the safety profile while MTT assay testing was performed using Caco-2, MDA-231,

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Incubation

Sonication

pNIPAM-grafted CS {CS-g-pN x}

Assembled pNIPAMgrafted CS (CS-g-pN xyy) Polymer backbone

T > LCST

Curcumin-loaded gel (CUR-CS-g-pN xyy)

pNIPAM branch

Drug release

Curcumin

Fig. 21.2  Schematic representation of chitosan-g-PNIPAM nanogel assembly and drug release. From J.A. Luckanagul, C. Pitakchatwong, P.R.N. Bhuket, C. Muangnoi, P. Rojsitthisak, S. Chirachanchai, Q. Wang, P. Rojsitthisak, Chitosan-based polymer hybrids for thermoresponsive nanogel delivery of curcumin, Carbohydr. Polym. 181 (2018) 1119–1127; Copyright 2017 Elsevier Ltd.

HT-29, and HepG2 cells to reveal the cytotoxic profiles. The results demonstrated that chitosan-g-PNIPAM (degree of modification, 3%–60%) was assembled into spherically shaped nanogel hybrid particles of submicron size range, in which curcumin was loaded. The temperature responsiveness of chitosan-g-PNIPAM nanogels differed because of the length and density of grafted PNIPAM. The chitosan-g-PNIPAM nanogels were found nontoxic toward the HeLa and NIH-3T3 cells. All these curcuminloaded chitosan-g-PNIPAM nanogels exhibited dose-dependent cytotoxic effects against the HeLa and NIH-3T3 cell lines.

21.2.2 pH-responsive polymer-based systems The values of pH significantly vary in various organs or tissues in the diseased conditions [66]. pH is also considered as one of the important signals that can be addressed by the pH-sensitive polymers. Various polymers, which are ionizable in between 3 and 10 pKa, are common examples of the pH-responsive materials and these polymers are also being used in the development of various effective pH-responsive polymerbased systems for biomedical uses [56, 67]. pH-sensitive polymers comprise either polyacids and/or polybases. These are responsive polymeric systems, whose volumes, aqueous solubilities, chain conformations, etc., can be controlled through variations in pH, cosolvents, electrolytes, etc. The pH values at the systemic sites of various infections and also, the primary as well as metastasized tumors are comparatively lesser than the pH values of the normal body tissues [68]. This pH-responsive property is currently being exploited for the designing and development of numerous pH-responsive polymeric systems for the delivery of various drugs, proteins, genes, cells, etc. [69]. The use of various pH-responsive polymers offers the opportunity in designing effective “smart” functional polymer-based carrier systems, which are tailorable. In recent years, these polymers have been identified for several prospective commercial uses, including drug delivery applications. The pH-sensitive ­polymers

Recent progress in responsive polymer-based drug delivery systems575

comprise ­pendant acidic and/or basic groups that can either receive or discharge protons due to the alterations in the varying environmental pH values [42, 44]. The characteristic examples of pH-responsive polymers possessing anionic groups are PAA, poly(methacrylic acid) [PMMA], poly(propylacrylic acid), poly(ethylacrylic acid), etc. [39, 70]. Recently, pH-responsive polymers have been investigated for the preparations of effective gastrointestinal drug-releasing dosage forms. Kendall et al. [71] formulated prednisolone-loaded microparticles made of different grades of Eudragits (like Eudragit S, Eudragit L, and Eudragit L55). Because of the small particle sizes and dissolution profiles of Eudragit L at the alkaline pH (pH 6.8), the drug release was found to be more rapid in comparison with that noticed at lower pH (acidic pH, where only 8% of the drug was found to be released after 2 h of dissolution). Again, because of the comparatively larger sizing of microparticles made by Eudragit S, the drug release was found lesser in comparison with that of the microparticles made by Eudragit L at the acidic pH. The microparticles made of Eudragit L55 were formed as aggregates in the drug-releasing medium and the drug release was found to be slower as the pH of the system was altered from 1.2 to 6.8 (acidic to alkaline pH). Likewise, capsules containing mesalazine were formulated by Schellekens et al. [72], which were prepared using Eudragit S and a disintegrant, Ac-di-Sol. Lin et  al. [73] formulated chitosan-based nanoparticles loaded with heparin and also investigated these nanoparticles against the infection caused by Helicobacter pylori. These heparin-loaded chitosan-based nanoparticles were found enough stable at the acidic pH. In the gastric region, these nanoparticles may possibly come in contact with the infection caused by H. pylori and there, the chitosan molecules may deprotonate. This occurrence may possibly weaken the electrostatic interactions and, thereby, this may promote the collapsing of these chitosan-based nanoparticles. This also can cause further releasing of heparin from these chitosan-based nanoparticles. The overall results of this investigation demonstrated that the chitosan-based nanoparticles can be employed as protective pH-responsive drug-releasing systems against the H. pylori infections. Various anticancer drug molecules can be conjugated to the polymeric molecules possessing pH responsiveness by utilizing the acidic milieu of the tumorous sites. The occurrence of the acid-responsive spacers between the drugs and polymers allows the drug release either in comparatively acidic-natured extra-cellular fluids or, after endocytosis in lysosomes and/or endosomes present in the tumorous cells. In a study, Kamada et al. [74] developed a pH-responsive polymer-based system, where the poly(vinyl pyrrolidone-co-dimethyl maleic anhydride) [PVP-co-DMMA] was conjugated to an anticancer drug, doxorubicin (DOX). From these pH-responsive polymer-based systems made of PVP-co-DMMA, free DOX was found to be released slowly due to the pH-responsive polymeric system tested on the basis of pH alterations from near-neutral pH to faintly acidic pH (∼7.0 to ∼6.0). The results of this study indicated an improved anticancer effect of PVP-co-DMMA/DOX conjugates, which might be due to controlled DOX releasing and higher degree of tumor accumulations of the released DOX.

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Ulbrich et  al. [75] prepared and evaluated antibody targeted pH-responsive polymer/DOX conjugate systems. In these polymer/DOX conjugates, DOX was tagged to an aqueous soluble polymer-based system through a simple hydrolytically labile linker containing hydrazone bondings and these bondings hydrolytically controlled the release of DOX from the pH-responsive polymer/DOX conjugate carrier system. In addition, it was activated after the transfer of conjugates (polymer/ DOX) from the systemic circulation. Unlike the classical drug conjugates, these pH-­responsive polymer/DOX conjugates did not need the lysosomal enzymes for efficient performance. Bae et al. [76] investigated intracellular pH-responsive polymeric micelles releasing DOX, which responded to the acidic pH in lysosomes (pH 4–5) as well as endosomes (pH 5–6). This occurrence improved the DOX releasing capability to the tissues of the tumorous sites. In other research, Na et al. [77] modified an aqueous soluble polymer, pullulan for use in the preparation of a pH-responsive drug delivery carrier. In this work, modification of pullulan with a pH-responsive functional group (i.e., a weak acid of sulfonamide) was carried out to prepare self-assembled nanoparticles loaded with adriamycin. These pullulan acetate-sulfonamide conjugate nanoparticles of adriamycin exhibited improved drug release through interactions with and/or internalization into the diseased cells at the tumor pH. The combination of various multiple pH-responsive materials, for example, ­acid-cleavable linkers as well as polymers having ionic groups, through a variety of mechanisms has been investigated with the intention of achieving a higher drug targeting efficiency, in particular, pH-responsive systems based on the charge conversion shielding mechanism [51, 78]. A newer pH-dependent charge conversion shielding mechanism-based system was developed via the binding of cis-aconityl-doxorubicin [CAD] with polyethylenimine [PEI]-poly(l-lysine)-poly(l-glutamic acid) [PELG], electrostatically. In this investigation, DOX was modified by the cis-aconityl linkage to generate the acid-responsive CAD; afterwards, this was adsorbed by the cationic PEI [78]. The PEI/CAD complexes were consequently shielded with the charge conversions of PELG in response to the pH. In the healthy tissues, the pH-responsive PELG/PEI/CAD complexes were found in anionic nature. Again, in the tissues of acidic tumorous sites, the shielding of PELG was found to be cationic in nature, which was disconnected from the PELG/PEI/CAD complexes. On the other hand, the cationic-natured PEI/CAD complexes were exposed and also, endocytosed. CAD was observed to be cleaved in the intracellular acidic milieu in the lysosomes as well as endosomes. Finally, it was transformed into the DOX. In addition, the charge conversion of PELG/PEI/CAD complexes was analyzed through performing the zeta potential analyses at various pH values. In addition, the DOX release was found to be enhanced with the lowering of pH values. Most prominently, this pH-­responsive drug-releasing system exhibited significant cytotoxic actions against cancerous cells. Thus, the outcomes of the study demonstrated that the pH-­responsive charge conversion shielding mechanism with the pH-responsive release of drugs, in combination, can be the prospective system in cancer therapy. The design mechanism of the pH-responsive charge conversion system for the release of DOX is shown in Fig. 21.3.

Recent progress in responsive polymer-based drug delivery systems577

PEI

pH-sensitive PELG

Tumor

Normal pH

Acidic pH

CA DOX

CAD

PEI/CAD PELG/PEI/CAD

CA Cis-acotonic anhydride

Nucleus

DOX

CAD

PEI

PELG

Endo/lysosome

Fig. 21.3  The mechanism of a pH-responsive charge conversion system for the release of DOX. From X. Guan, Y. Li, Z. Jiao, J. Chen, Z. Guo, H. Tian, X. Chen, A pH-sensitive chargeconversion system for doxorubicin delivery, Acta Biomater. 9 (2013) 7672–7678; Copyright 2013 Acta Materialia Inc. Published by Elsevier Ltd.

21.2.3 Red-Ox-responsive polymer-based systems Reduction-oxidation (Red-Ox) reactions are described by the electron transferring process among chemical species [79, 80]. The electrons are accountable to form covalent bondings and the transferring of the electrons simultaneously breaks the existing bondings while forming newer ones. Various areas of the living body and a variety of intracellular compartments possess several Red-Ox states [79]. These characteristics of Red-Ox reactions make these an excellent target to design smart (responsive) drug delivery carriers. For instance, if Red-Ox-sensitive chemical groups are exploited as the effective linker for drug candidates, they should be stable enough when the Red-Ox status is neutral. And, this occurrence prevents hasty drug release. Numerous Red-Ox responsive polymers have been synthesized and exploited in the designing of various devices for the controlled release of drugs [81]. By selecting an effective linker, which is responsible for cleavage in the particular Red-Ox state in the target tissues, the drug release can also be localized there. Various Red-Ox responsive drug-releasing systems have gained a great deal of importance as these contain Red-Ox responsive polymers with higher Red-Ox potential differences of 100–1000 folds in-between the decreased intracellular gap and the oxidizing extracellular gap [80]. Recently, Red-Ox-responsive biodegradable polymers and conjugates are being developed and evaluated as sophisticated biomaterials, which can be used in the designing of smart drug-releasing systems for the effective release of low molecular weight drugs and other biotherapeutic agents (such as, siRNA, pDNA, proteins, peptides, etc.) [82].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Disulfide-linked nanovehicle

s-

-s-

-s-

s-

-s-s-

GSH

GSSG

-

-sh -sh s -s-

-

-ss

s -s-

-

-ss

s -s-

-

-s-s-

-sh

-s-s-

-

Disulfide cleavage Endocytosis

-sh

-sh

s-s-

sh

s-

-s-

-sh

-s-s-

Drug release

Fig. 21.4  The mechanism of Red-Ox-responsive nanocarriers for intracellular drug delivery. From M. Liu, H. Du, W. Zhang, G. Zhai, Internal stimuli-responsive nanocarriers for drug delivery: design strategies and applications, Mater. Sci. Eng. C 71 (2017) 1267–1280; Copyright 2016 Elsevier B.V.

A variety of Red-Ox-responsive nanoparticulate systems have been prepared for the delivery of numerous drug candidates. In recent years, disulfide bonding has been employed as a Red-Ox responsive linker to design Red-Ox responsive nanosystems [83]. Generally, the disulfide bondings in various nanosystems in the external milieu have been found stable enough with lower levels of reductions and the disulfide bondings have been reduced to thiol moieties through higher GSH concentration inside the cells, leading to rupture as well as cleavage of nanosystems in the triggered drug release [51]. The mechanism of these Red-Ox-responsive nanocarrier systems for use in intracellular drug release is described in Fig. 21.4. Wang et al. [84] designed a newer Red-Ox-responsive amphiphilic polyanhydride copolymeric material, which contained disulfide bonds in-between the hydrophobic and hydrophilic parts. The copolymeric material was capable of self-assembling into stable polymeric micelles. The disassembling performances of these polymeric micelles were triggered by GSH. Analysis of in vitro cytotoxicity profile revealed that the Red-Ox-responsive polymeric micelles containing curcumin possess effectual therapeutic potential to artificial solid tumors in comparison with the Red-Ox-irresponsive polymeric micelles. Thus, this investigation highlighted a new spotlight onto the uses of polyanhydride-based polymeric systems in Red-Ox-responsive drug-releasing applications.

Recent progress in responsive polymer-based drug delivery systems579

In an investigation, Song et al. [80] prepared polymeric nanoparticle systems made of a Red-Ox-responsive polymer, poly(ethylene glycol)-b-poly(lactic acid) [PEG-bPLA]. The PEG-b-PLA nanoparticles were prepared to deliver an anticancer drug, PTX, which was GSH-controlled. The PEG-b-PLA nanoparticles of PTX were designed by an optimized oil/water emulsification-solvent evaporation technique. The drug-releasing results demonstrated that approximately 90% of PTX released over 4 days, when the GSH controlling demonstrated at the intracellular contents, whereas only the little content of PTX was found to be released at the plasma-GSH levels. The obtained results of the MTT test presented that the polymeric nanoparticles produced concentration- as well as time-controlling transforms in cell viability. These nanoparticles were tested for in vitro endocytosis and the results of the test exhibited a faster penetration as well as intracellular accumulations of these PTX-loaded PEG-bPLA nanoparticles. On the whole, the obtained results indicated that the PTX-loaded nanoparticles made of synthesized Red-Ox-responsive polymer, PEG-b-PLA, can be employed as a drug-releasing system for anticancer drugs. In a study by Koo et al. [85], core-shell-corona polymeric micelles made of RedOx-sensitive shell-specific cross-linking was designed and examined for the release of docetaxel (DTX) in cancer therapy. The Red-Ox-responsive polymeric micelles of poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-phenylalanine) [PEG-b-PLy-bPLpa] in the aqueous milieu facilitated three different functional parts: (i) a PEGbased external corona for prolonged systemic circulations, (ii) a PLy-based middle shell for the cross-linking of disulfide, and (iii) a PLpa-based internal core for the entrapment of DTX. The DTX release from these DTX-loaded disulfide cross-linked micelles was found to be controlled through the rising of GSH concentrations. At an intracellular level of GSH concentrations, the DTX release was facilitated because of the reductive cleavage of the disulfide cross-linking in the shell parts. The results of noninvasive real-time optical imaging investigation demonstrated that the disulfide cross-linked micelles containing DTX showed prospective tumor specificity because of the prolonged stable systemic circulation and improved permeation and retention effects in comparison with the noncross-linked micelles containing DTX. The disulfide cross-linked micelles containing DTX demonstrated a greater therapeutic potential in tumor bearing mice as compared to noncross-linked micelles containing DTX and free DTX.

21.2.4 Enzyme-responsive polymer-based systems The enzyme-responsive polymer-based systems use the higher specificity of enzymes and this behavior guarantees that the cross-linkings are divided only by the action of the definite enzyme ensuing in the site-specific release of various drugs [86, 87]. Enzymes are selectively responsive in nature and also, they are capable of showing reactivity in mild environments, even in in vivo conditions. These are known as important constituents in numerous biological pathways [87]. These are also engaged in several metabolic procedures, even at the molecular level [86]. Enzyme-responsive polymeric systems are characteristically made of an enzyme-responsive substrate. The catalytic action of the enzymes on their selective substrates can alter the s­ upramolecular

580

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

p­ olymeric architectures, swelling and/or collapsing of the polymeric gels, or the transformations of surface characteristics [87]. Important examples of enzyme-responsive polymers are dextran, poly(caprolactone) [PCL], etc. [88]. In another study, arabinoxylane-loaded Eudragit FS 30 D acrylic polymeric films were developed. These polymeric films exhibited a significant weight loss after immersing in buffer solutions contained an enzyme, Pectinex 3X-L [89]. The incorporation of arabinoxylane in the film formula was thought to produce more susceptibility for undergoing enzymatic degradation, which added the responses to these newly developed films. These arabinoxylane-loaded Eudragit FS 30 D acrylic polymeric films can be used as an interesting enzymatic responsive system for use in colon-specific drug deliveries.

21.2.5 Magneto-responsive polymer-based systems Magnetism is a property that is capable of producing significant responsiveness by living organisms. Hemoglobin present in the blood is an iron-containing protein and therefore, it is magnetic in nature [90, 91]. It is an accepted fact that magnetic agents/ substances and magnetism have an important role in various biological as well as healthcare applications [42, 92, 93]. Incorporation/encapsulation of different magnetic particles with/within biocompatible polymers (naturally originated or synthetic biopolymers) is considered as the easiest and traditional process to design a variety of magneto-responsive systems for biomedical uses, including drug delivery. The development of emulsified polymerizations like the conventional emulsified polymerization method, miniemulsion- as well as microemulsion-based polymerizations, and soap-free emulsified polymerization, have led to the design of newer methodologies to prepare a variety of magneto-responsive systems for drug release to the specific sites [94, 95]. Zhang and Misra [93] developed a new kind of drug-targeting magnetic carrier systems, in which magnetic nanoparticles were encapsulated with smart polymeric materials for the use in controlled drug release. The developed magnetic carrier systems contained DOX (anticancer therapeutic agent), functionalized magnetite (Fe3O4) nanoparticles, and a smart polymeric material (temperature responsive). DOX and magnetic nanoparticles were encapsulated using a temperature-responsive polymer, for example, dextran-g-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [dextran-g-PNPAM-co-NNDEAM]. Actually, DOX was attached to magnetic nanoparticles (made of functionalized Fe3O4) by an acid-labile hydrazone bonding, produced via the reaction between the hydrazide groups and the CO groups of DOX. A preliminary faster drug release followed by controlled drug release was observed. This kind of drug-releasing pattern can be attributed due to the collapsing of the temperature responsive and the splitting of the acid-labile hydrazone linkages. These magneto-responsive systems can be employed for magneto-targeting drug release with extended circulation period, decreased adverse effects, and also, controlled pattern of drug release by the influence of external temperature. Hu et  al. [96] synthesized tamoxifen-loaded composite nanoparticles made of Fe3O4 and poly(l-lactic acid) [PLLA]. The in vitro anticancer action of Fe3O4/PLLA­

Recent progress in responsive polymer-based drug delivery systems581

composite nanoparticles containing tamoxifen was evaluated. The cytotoxicity ­evaluation results demonstrated no significant cytotoxic actions against the MCF-7 breast cancer cells, when treated by the Fe3O4/PLLA composite nanoparticles containing tamoxifen. In this study, approximately 80% of MCF-7 breast cancer cells were found to be killed after incubation for a period of 4 days. Ren et  al. [97] synthesized several block copolymers of poly(d,l-lactide)-co-­ polyethylene glycol [PDLA-co-PEG] by the ring opening polymerization reaction using a catalyst, stannous caprylate [Sn(Oct)2]. The composite particulate system made of PDLA-co-PEG copolymers and Fe3O4 were developed via the phase separation technique. The synthesized PLLA-co-PEG composite particles with magneto-­ responsive characteristics and biodegradability may facilitate controlled drug release as well as drug targeting application.

21.2.6 Electrically responsive polymer-based systems Electrically responsive carriers are designed by using polyelectrolyte-based materials (biopolymeric biomaterials containing a comparatively higher concentration of ionizable groups alongside the polymeric chains) [42]. In response to an electric field, electrically responsive hydrogel systems generally experience deswelling or bending, according to the shape as well as orientations of the gel structure. A gel system bends when it occurs parallel to the electrodes, while, deswelling of the gel-structure is experienced as the hydrogel structure positions perpendicular to the electrodes [42, 98]. In a research by Ramanathan and Block [99], the exploitation of chitosan-based gels as the potential carrier systems for electrically responsive deliveries of various drugs was studied. In the electrification evaluations, the drug-releasing patterns for cationic (lidocaine HCl), anionic (benzoic acid), and neutral (hydrocortisone) drug molecules from the hydrated chitosan-based gel systems were controlled and d­ ependent on the milliampere (mA) currents against time. Similarly, in other research, chondroitin4-sulfate hydrogel systems were designed and evaluated by Lensen et al. [98] for use as prospective electrically responsive matrices to deliver proteins and peptides. In another research, an interpenetrated polymeric networking (IPN) hydrogel made of poly(vinyl alcohol) [PVA] and chitosan was synthesized and evaluated by Kim et al. [100]. These IPN-based hydrogels were responsive under electrical fields. The swollen PVA/chitosan IPN hydrogels was placed in-between the electrode pair as well as bending characteristics due to the influence of applied electric fields were evaluated and analyzed. The bending angle as well as the bending rate of PVA/chitosan IPNbased hydrogels were augmented with the rising of voltage applied and concentration of sodium chloride in aqueous solutions.

21.2.7 Light-responsive polymer-based systems Light is considered as an important and effective external stimulus for use in drug delivery since it is easily controlled and economical. Light-responsive molecules switch a reversibly controlled biomolecular activity, which can facilitate newer possibilities to deliver drug molecules for use in therapeutics as well as diagnostics [101].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Different light-sensitive functional moieties on repeating units make polymers light responsive and these light-responsive polymers are utilized in a variety of biomedical purposes, including drug delivery [102]. On photo-irradiation, different light-responsive polymeric materials alter their characteristics reversibly, physically, and/or chemically (e.g., pH, solubility, shape, conformation, wetting surfaces, membrane characteristics, sol-gel transition temperature, phase separation temperature, etc. [101, 102]). The light-­ responsive units are also being tagged/joined/incorporated to biopolymeric systems in response to light and/or dark situations presenting the reversible alterations of the polymeric structural arrangements [103]. In general, these light-responsive polymeric systems contains light-responsive materials (i.e., photochromic molecules like chromophores, etc.), which capture optical signals and also transfer these to physico-chemical signals, and subsequent functional materials (e.g., protein domains) that sense the physicochemical responses to show newer outputs. In general, the absorbed light triggers chemical transformations in the chromophores (e.g., photoisomerization), which afterward control the conformation and/or the assemblage of the nearby molecules [104]. All these characteristics demonstrated that light-responsive polymers can be employed as proper biomaterials for the designing and preparation of improved drug delivery carrier systems. Most of the light-responsive polymers are generally dependent on the photoisomerizations of azobenzene groups and these azobenzene groups usually experience “cis-trans” isomerization(s) as the incoming wavelength alters. This occurs due to the significant differences in the polarity of isomers and the isomerization promotes the transition(s) from “cis” (polar or hydrophilic) forms to “trans” (less-polar or hydrophobic) forms [102]. In another study, Feng et al. [105] designed novel kinds of polymeric nanoparticulate systems having a hydrophobic core of acrylate units ­containing azobenzene and a hydrophilic shell structure made of acrylic acid units from a pH- and light-sensitive amphiphilic random azobenzene copolymer system. Upon ­ultraviolet light irradiation, the “trans” form of azobenzene is altered to the “cis” form and therefore, the contact angle of water as well as the water absorption of the polymeric film could be altered, while the lesser influence on the nanoparticle morphology was noticed, though the polarity of the nanoparticle core raised. Adjusting the pH of nanoparticle-containing solutions could produce a stronger influence on nanoparticle morphology. The controlled release of Nile Red from these polymeric nanoparticulate systems under pH and light responsiveness was revealed. Song et al. [106] prepared and studied a newer kind of light-responsive plasmonic vesicular system to deliver the anticancer payloads to the specific cancerous cells and also, to facilitate the personalized drug release regulated by external light irradiation responses. The results of this investigation exhibited that the amphiphilic gold nanoparticles bearing PEG (hydrophilic material) and poly(2-nitrobenzyl acrylate) [PNBA] (light responsive hydrophobic material) could be capable of assembling to the plasmonic vesicles with the gold nanoparticles embedded in the shell made of PNBA that can be transformed into PAA (hydrophilic in nature) upon light exposure. Wang and Kim [107] prepared light- and temperature-sensitive liposomal vesicles through immobilizing the cinnamoyl Pluronic F127 on the egg phosphatidyl choline liposome surface. The cinnamoyl group of cinnamoyl Pluronic F127 was dimerized by using ultra-violet light irradiation (6 W, 254 nm). The cinnamoyl Pluronic F127

Recent progress in responsive polymer-based drug delivery systems583

reduced the zeta potential values of these liposomes. This could be due to the shifting of the hydrodynamic plane away from the egg phosphatidyl choline liposome surface. Calcein was released from these liposomes due to the influence of ultra-violet irradiation. This could possibly be due to the photo-dimerization of the cinnamoyl group perturbing the liposomal membrane. In addition, these liposomes released the dye due to the response to the temperature alteration, which could possibly because of the phase transition of the Pluronic F127 layer on the liposomal surface or the hydrophobic interactions of the polymer(s) with the liposomal membrane.

21.2.8 Ultrasound-responsive polymer-based systems Ultrasound is also a widely employed local stimulus to trigger drug release at the desired tissue site [108, 109]. In recent years, ultrasound-responsive systems for drug release have attracted the spotlight in healthcare research, mainly in targeted therapeutics [110]. The high-intensity focused ultrasound technology is currently recognized as an effectual means to deliver drugs and other therapeutic agents in a controlled manner to the localized sites of the body [88, 108], thus, harnessing the ultrasound energy as a localized energy trigger to control the targeting of therapeutics to the desired sites, and this currently leads the designing of different kinds of systems for drug delivery applications [108, 110]. A variety of polymeric systems have been exploited for ultrasound responsive drugreleasing systems. In general, polymeric systems impermeable to various drugs are considered as being preferred for ultrasound responsive drug release, which can deliver the drugs only at the desired sites within the desired time [88]. Both bioerodible as well as nonerodible polymeric systems can be utilized as drug carrier matrices in the designing of ultrasound responsive systems for drug delivery. These bioerodible polymeric systems are mainly made of PLA, polyglycolic acid [PGA], poly [bis(p-carboxyphenoxy) alkane] anhydrides and their copolymers with sebacic acid [110]. The concept of the ultrasound responsive systems for use in delivery and targeting drugs is based upon the accumulation of dosage on the desired site, where the drugs are released/targeted via the local influence of ultrasound as external stimulus. Once the dosage system-structure is disrupted, the effectual release of incorporating drugs is achieved [108]. When the ultrasound stimulus is employed in biological systems, it is capable of inducing cavitations, heating of local tissue, and radiation force, which can be employed to instigate localized drug releasing, enhancement of the permeability through the membranes, and the improvement of drug diffusivity, respectively, only at the sonication sites to regulate the localized deliveries of numerous drugs [111]. In a study, Enayati et  al. [112] encapsulated estradiol within poly(d,l-lactide-co-­ glycolide) [PLGA] particulates. They studied the influence of different ultrasound exposure issues on the estradiol releasing rates. A positive correlation between the drug release and all of the ultrasound factors was studied with the output power exhibiting significant influence upon both the particulate morphologies and the drug-releasing rates. Du et al. [113] prepared a new kind of ultrasound-sensitive nanoparticle carriers loaded with DOX for use in cancer therapeutics. The polymeric micelles containing DOX made of poly(d,l-lactide-co-glycolide)-methoxy poly(ethylene glycol) [PLGAmPEG] was prepared. After the incorporation of DOX with perfluoropentane, the

584

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

prepared polymeric micelles containing DOX were transformed into the nanodroplet structure. At the 35°C temperature, these transformed nanodroplets were further transformed into nanobubbles and lesser amount of drug was released, if no ultrasound was applied. These nanosystems loaded with DOX exhibited the ultrasound triggered release of the loaded DOX with pH alterations. In addition, these nanodroplets demonstrated less toxicity, as compared to free DOX. A polymer-based ultrasound contrast loaded with DOX within the shell was developed by Eisenbrey et al. [114]. These agents were found responsive to the ultrasound in the in vitro studies and also exhibited dramatic reductions of their sizes. The results of the in vivo evaluation demonstrated that the combination of these ultrasound contrast agents and ultrasound results were found to show approximately 50% of lesser drug releasing to the nontargeted tissues and an enhancement of 110% of DOX delivery to the peripheral tumor tissues. The results of this research demonstrated how the ultrasound responsive destruction of anticancer drug loaded polymer-based ultrasound contrast agents can be effectively employed for sustained release potential. The influence of high-frequency ultrasound power on DOX release from Pluronic micelles and intracellular DOX uptake was investigated for the treatment of ovarian carcinoma, breast cancers, promyelocytic leukemia, multidrug resistant (MDR) cases, etc. [115]. The cavitation occurrences started by the high frequency ultrasound power were evidenced through employing a radical trapping procedure. The commencement of transient cavitation and the DOX release from these Pluronic micelles were noticed at elevated ultrasound frequency in comparison with that at the lower ultrasound frequency. Yet, a very short exposure to the higher frequency ultrasound was found to significantly augment the intracellular uptake of DOX through the delivery of Pluronic micelles as an effective means of ultrasound-responsive drug delivery systems. Some other responsive polymer-based drug delivery systems are presented in Table 21.1.

21.3 Challenges and future prospects The situation of the development of new approaches for the fabrication of various polymeric drug-releasing systems is not practically easy. There is also a strong requirement of judging several issues that produce obstacles for the practical as well as regulatory approvals of these drug-releasing systems to be participating in therapeutics. Among these, some important recognized issues are biodegradability and biocompatibility of the drug-releasing devices, in vivo competence, chances of adverse effects, cost-effectiveness, FDA and other regulatory approvals, etc. Only after the examinations of these important issues, can successful polymeric systems for drug delivery be selected and accepted for the use in therapeutics. Drug release at a programmed rate over a specific period to the desired target tissues has been the principle requirement in the designing of advanced drug delivery systems with favorable pharmacokinetics as well as pharmacodynamic parameters. In recent years, the need for polymeric carrier systems exhibiting oscillatory performances of drug release has also come forward with a variety of noteworthy difficulties.

Recent progress in responsive polymer-based drug delivery systems585

Table 21.1 

Some responsive polymer-based drug delivery systems

Responsive polymer-based drug delivery systems Temperature sensitive hydrogels of PNIPAM and chitosan Temperature-responsive chitosan-g-PNIPAM nanocarrier for drug delivery Bioresponsive nanohydrogels based on copolymer of PNIPAM, N-hydroxyethylacrylamide and tert-butyl 2-acrylamidoethyl carbamate for poorly soluble drugs delivery Temperature-responsive hollow silica microgels for controlled drug release Novel pH- and temperature-responsive blend hydrogel microspheres of sodium alginate and PNIPAM grafted-guar gum pH- and temperature-responsive poly(aspartic acid)-l-PNIPAM co-network hydrogel pH- and temperature-responsive polymeric nanocarriers for drug delivery to treat solid tumors pH responsive nanoparticles made of PLGA/ Eudragit S-100 for the prevention of HIV transmission Dendronized heparin/DOX conjugate based nanoparticles as pH responsive drug delivery system for cancer therapy pH- and temperature-responsive carboxymethyl chitosan/PNIPAM semi-IPN hydrogel for oral drug delivery Glucose and pH dual responsive concanavalin A based microhydrogels Red-Ox/pH dual stimuli responsive biodegradable nanohydrogels Magnetic and pH dual responsive system consisting of Fe3O4@SiO2 nanoparticles coated with mPEG-poly(l-asparagine) Self-assembling peptide amphiphile-based nanofiber gel for bioresponsive drug delivery Water soluble pH sensitive nanocarriers for drug delivery Cyclodextrin derived pH responsive nanoparticles for drug delivery Red-Ox sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery Core-shell corona micelles with shell specific Red-Ox responsive cross-links Microbubbles for ultrasound triggered drug delivery

Drugs

References

Cisplatin and carboplatin Curcumin

[116]

Paclitaxel

[118]

Rhodamine B

[119]

Isoniazid

[120]

Diclofenac sodium

[121]

DOX

[122]

Tenofovir

[123]

DOX

[124]

Coenzyme A (CoA)

[125]

Insulin

[126]

DOX

[81]

DOX

[127]

Cisplatin

[128]

DOX

[129]

Paclitaxel

[130]

Paclitaxel

[131]

Docetaxel

[85]

DOX

[132]

[117]

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

The conventional dosage forms like pills and intravenous (i.v.) or subcutaneous (s.c.) injections are still employed as the principal drug administration routes. Nevertheless, pills and injectable present restricted control over the drug-releasing rate within the body; generally, these are related to the immediate release of drugs. As a result, the initial drug concentration within the body should be higher to reach the therapeutic level to extend over the period producing a desired peak of plasma-drug concentration, which slowly lessens over the period to an ineffective level. Thus, the period of the therapeutic outcome depends on the half-life of drugs as well as the dosing frequency. Therefore, the designing of an effective drug delivery system with optimal action in the specific conditions must produce these following advantages: (i) Optimal delivery of drugs and improved effectiveness (ii) Targeted drug deliveries with minimal side effect occurrences (iii) Assurances of safer settings (iv) Interfacing as well as pacing with modern drug delivery procedures (v) Ease of fabrication as well as application

These advantages may be realized through adopting the approaches and procedures, which essentially entail the well thought-out combinations of different highly specific biodegradable as well as biocompatible monomers/polymers of natural, synthetic, and semisynthetic origins. The utilizations of smart polymeric substances in the designing of responsive drug delivery systems should not only to focus on the potential medical advantages but also should judge the economic aspect. A reasonable concern of the bright viewpoints for responsive polymer-based controlled releasing drug delivery presents the prospective applications and thus, more efforts need to be invested in their development as well as expansion in view of the fact that responsive polymers comprise the definite means of operability and also are prone to characteristic experimental circumstances. Thus, there is a huge possibility for the use of synthetic polymer chemistry to design and develop a variety of multiresponsive drug delivery carrier systems. In addition, an enormous effort on the synthesis of different, novel, tailor-made stimuli-responsive biomacromolecules by employing synthetic polymer chemistry for use in the designing of effective responsive polymer-based drug delivery systems must be made. Regardless of the remarkable research contributions that have been employed to accomplish the advanced and sophisticated technologies, several important features still stay behind to be worked on: (i) Designing and development of polymeric systems for drug delivery with multiple stimuliresponsive potentials (ii) Designing of more localized drug delivery systems made of responsive polymers with stimuli-responsive potentials (iii) Searching and development of more accurate synthetic routes to construct responsive polymeric materials with better sensitivity of responsiveness (iv) Guarantee of economic feasibility in order to popularize the drug delivery devices on a large commercial as well as population scale

Although much progress has been displayed by the constant endeavors of drug delivery researchers and scientists worldwide, still there are several potential challenges that need to be resolved. Furthermore, the area of controlled drug release through

Recent progress in responsive polymer-based drug delivery systems587

responsive polymer-based drug delivery systems offers a broad possibility and future perspective to develop an updated technology with higher levels of performances, cost-effectiveness, and potential competence.

21.4 Conclusion Different responsive polymer-based carrier systems for drug delivery applications are able to regulate and target drug release in response to external and/or internal stimuli. In recent years, a variety of polymer-based drug delivery/targeting approaches have been investigated and developed, where an extensive amount of studies has been dedicated in the designing and development of responsive polymer-based systems. And, various stimuli-responsive polymeric macromolecules (i.e., smart polymers) have been synthesized to formulate most of these responsive polymeric systems for use in smart drug delivery with responsive controlling. These stimuli-responsive polymeric macromolecules (i.e., smart polymers) not only improve different important drug characteristics like solubility, extended circulation period, and bioavailability, but also can be made to selectively release the loaded drugs at the preferred site for therapeutic actions. A variety of responsive polymeric systems have already been designed and developed for triggering the drug release in response to different effectual stimuli like temperature, pH, Red-Ox potential, light, enzymes, ultrasound, magnetic fields, etc. Even upon small changes in environmental conditions, these responsive polymers are capable of exhibiting a sharp alteration in characteristics. During the past few years, a lot of remarkable biomedical applications in the area of drug delivery, gene delivery, protein and peptide delivery, tissue engineering, diagnostics, biosensing, etc., have been planned and investigated for the potential use of different responsive polymerbased systems. Although, a few important factors like biocompatibility and toxicology, their capability to present the requisite levels of drugs, and also, addressing required formulation issues in the designing of dosage forms (e.g., shelf life, reproducibility, sterilization, etc.) are to be taken under consideration in the designing and development of responsive polymer-based drug delivery systems.

References [1] T.  Ansari, Farheen, M.S.  Hasnain, M.N.  Hoda, A.K.  Nayak, Microencapsulation of pharmaceuticals by solvent evaporation technique: a review, Elixir Pharm. 47 (2012) 8821–8827. [2] S. Beg, A.K. Nayak, K. Kohli, S.K. Swain, M.S. Hasnain, Antibacterial activity assessment of a time-dependent release bilayer matrix tablet containing amoxicillin trihydrate, Braz. J. Pharm. Sci. 48 (2012) 265–272. [3] A.K.  Behera, A.K.  Nayak, B.  Mohanty, B.B.  Barik, Formulation and optimization of losartan potassium tablets, Int. J. Appl. Pharm. 2 (2010) 15–19.

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[113] L. Du, Y. Jin, W. Zhou, J. Zhao, Ultrasound-triggered drug release and enhanced anticancer effect of doxorubicin-loaded poly (D,L-lactide-co-glycolide)-methoxypoly(ethylene glycol) nanodroplets, Ultrasound Med. Biol. 37 (2011) 1252–1258. [114] J.R.  Eisenbrey, M.C.  Soulen, M.A.  Wheatley, Delivery of encapsulated doxorubicin by ultrasound-mediated size reduction of drug-loaded polymer contrast agents, IEEE Trans. Biomed. Eng. 57 (2010) 24–28. [115] A.  Marin, H.  Sun, G.A.  Husseini, W.G.  Pitt, D.A.  Christensen, N.Y.  Rapoport, Drug delivery in pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake, J. Control. Release 84 (2002) 39–47. [116] J.Y. Fang, J.P. Chen, Y.L. Leu, J.W. Hu, The delivery of platinum drugs from thermosensitive hydrogels containing different ratios of chitosan, Drug Deliv. 15 (2008) 235–243. [117] N.S. Rejinold, P.R. Sreerekha, K.P. Chennazhi, S.V. Nair, R. Jayakumar, Biocompatible, biodegradable and thermo-sensitive chitosan-g-poly (N-isopropylacrylamide) nanocarrier for curcumin drug delivery, Int. J. Biol. Macromol. 49 (2011) 161–172. [118] E. Pérez, A. Martínez, C. Teijón, J.M. Teijon, M.D. Blanco, Bioresponsive nanohydrogels based on HEAA and NIPA for poorly soluble drugs delivery, Int. J. Pharm. 470 (2014) 107–119. [119] G. Liu, C. Zhu, J. Xu, Y. Xin, T. Yang, J. Li, L. Shi, Z. Guo, W. Liu, Thermo-responsive hollow silica microgels with controlled drug release properties, Colloids Surf. B Biointerfaces 111 (2013) 7–14. [120] P.B. Kajjari, L.S. Manjeshwar, T.M. Aminabhavi, Novel pH- and temperature responsive blend hydrogel microspheres of sodium alginate and PNIPAAm-g-GG for controlled release of isoniazid, AAPS Pharm. Sci. Tech. 13 (2012) 1147–1157. [121] A. Némethya, K. Solti, L. Kiss, B. Gyarmati, M.A. Deli, E. Csanyi, A. Szilagyi, pH- and temperature-responsive poly(aspartic acid)-l-poly(N-isopropylacrylamide) conetwork hydrogel, Eur. Polym. J. 49 (2013) 2392–2403. [122] C.-Y. Chen, T.H. Kim, W.-C. Wu, pH-dependent, thermosensitive polymeric nanocarriers for drug delivery to solid tumors, Biomaterials 34 (2013) 4501–4509. [123] T. Zhang, T.F. Sturgis, B.B. Youan, pH-responsive nanoparticles releasing tenofovir intended for the prevention of HIV transmission, Eur. J. Pharm. Biopharm. 79 (2011) 526–536. [124] W.  She, N.  Li, K.  Luo, C.  Guo, G.  Wang, Y.  Geng, Z.  Gu, Dendronized heparin-­ doxorubicin conjugate based nanoparticles as pH-responsive drug delivery system for cancer therapy, Biomaterials 34 (2013) 2252–2264. [125] B.-L. Guo, Q.-Y. Gao, Preparation and properties of a pH/temperature-responsive carboxymethyl chitosan/poly(N-isopropylacrylamide)semi-IPN hydrogel for oral delivery of drugs, Carbohydr. Res. 342 (2007) 2416–2422. [126] R. Yin, Z. Tong, D. Yang, J. Nie, Glucose and pH dual-responsive concanavalin A based microhydrogels for insulin delivery, Int. J. Biol. Macromol. 49 (2011) 1137–1142. [127] S. Yu, G. Wu, X. Gu, J. Wang, Y. Wang, H. Gao, J. Ma, Magnetic and pH-sensitive nanoparticles for antitumor drug delivery, Colloids Surf. B Biointerfaces 103 (2013) 15–22. [128] J.-K.  Kim, J.  Anderson, H.-W.  Jun, M.A.  Repka, S.  Jo, Self-assembling peptide ­amphiphile-based nanofiber gel for bioresponsive cisplatin delivery, Mol. Pharm. 6 (2009) 978–985. [129] M.H. Dufresne, D.L. Garrec, V. Sant, J.C. Leroux, M. Ranger, Preparation and characterization of water-soluble pH-sensitive nanocarriers for drug delivery, Int. J. Pharm. 277 (2004) 81–90. [130] H. He, S. Chen, J. Zhou, Y. Dou, L. Song, L. Che, X. Zhou, X. Chen, Y. Jia, J. Zhang, S.  Li, X.  Li, Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel, Biomaterials 34 (2013) 5344–5358.

Recent progress in responsive polymer-based drug delivery systems595

[131] J.  Li, M.  Huo, J.  Wang, J.  Zhou, J.M.  Mohammad, Y.  Zhang, Q.  Zhu, A.Y.  Waddad, Q.  Zhang, Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel, Biomaterials 33 (2012) 2310–2320. [132] I. Lentacker, B. Geers, J. Demeester, S.C. De Smedt, N.N. Sanders, Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved, Mol. Ther. 18 (2010) 101–108.

Further reading [133] J.J. Khandare, S. Jayant, A. Singh, P. Chandna, Y. Wang, N. Vorsa, T. Minko, Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of paclitaxel, Bioconjug. Chem. 17 (2006) 1464–1472.

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Index Note: Page numbers followed by f indicate figures, t indicate tables and s indicate scheme. A ABA-type triblock copolymer, 136–137, 136s Acid-responsive linkers, 420–422 Active targeting, 222, 276–277, 282 Adjuvant functions, 312–313 Afrezza, 493–494 Agar, 548–551t Alginate, 405–406 Alginate/poly-l-lysine/alginate (APA), 330–331 Alginic acid, 396–399t, 548–551t Alternating magnetic field (AMF), 113–114, 113–114f, 119, 179 4-(Aminomethyl)piperidine (AMPD), 5 Amino-PEG-3-maleimidobenzoic acid, 457–458 Amphiphilic block copolymers, 11, 353–355 Amphiphilic diblock copolymers, 12 Anionic polymers, 474 Antiferromagnetic material, 37, 38f Antiferromagnetism, 46t Arabino galactan, 548–551t Archea, 555–557 3-Arm star quaterpolymer, 135, 135s Atomic magnetic moments, 37, 38f Atomic transfer radical polymerization (ATRP), 12–13, 116 Au-vesicle-polymer complexes, 222 Avastin, 478 Azademethylcolchicine, 205 Azithromycin, 400 Azobenzene, 226 Azobenzene-triazole-glutamate (ATG), 226 AZO-containing polyacrylate, 376 Azo-SS-Azo dimer, 146, 147s B β-cyclodextrins (β-CD), 183–184 Beta-cyclodextrin-poly[(2-(2methoxyethoxy)ethylmethacrylate)co-oligo(ethylene glycol) methacrylate] [beta-CD-P(MEO2MAco-OEGMA)], 144–146, 145s

Biochemical stimuli, 325 Biological stimuli, 348, 529, 530f Biomedical nanoparticle carriers combination between heat and magnetism in knowledge frontier, 112–116 combination of thermal and magnetic properties, 116–122 Biopolymers, 332–333 Bioreducible polymersomes, 415–420 N,N-Bis(acryloyl)-cystamine (BACy), 5, 138–139 Blood glucose levels (BGLs), 526 BM@NCP(DSP)-PEG, 143–144 Boron dipyrromethene (BODIPY) conjugates, 203, 204f Boronic esters, 360 BR14 microbubbles (MBs), 233 Brownian relation mode, 113 C Calcium channel blockers (CCB), 328–329 Camptothecin (CPT), 27, 258–259, 416–417, 420, 425–426 Camptothecin (CPT)-loaded pH-sensitive micelles, 281–282 Cancer, 133, 179 Cancer theranostics, 167, 169f Cancer therapy dual-responsive polymers, 416–417, 417f micelles magnetic-responsive, 454–455 multiresponsive, 455–457 pH-response, 444–449 redox-responsive, 451–454 surface ligand, 457–458 thermo-responsive, 449–451 polymersomes drug delivery to cancer cells, 418, 419f dual drug-loaded, 416–417, 417f enzyme-responsive, 425–426 glucose-responsive, 426 light-responsive, 426–428, 429f

598Index

Cancer therapy (Continued) magnetic field-response, 431 PEG-b-PAA-b-PDEA synthesis, 418–420, 421f pH-responsive, 420–423 properties, 413–414 stimuli-responses, 414, 415f tumor-targeting characteristics, 414f ultrasound response, 431 voltage responsiveness, 429–431 Capecitabine (CPB), 553–554t, 560 Carbohydrates, 231 Carbomer, 396–399t, 400 gelation mechanism, 475 mucoadhesion property, 475 in ocular drug delivery, 475–477 regulatory status, 475 Carbon nanohorns (CNHs), 323 Carbon nanotubes (CNTs), 223–224, 321 absorption and transportation, 336 brain targeting, 331–332 cancer targeting, 332 characterization, 328 classification multiwalled, 323 single-walled, 323 in controlled drug delivery, 332–333 functionalization covalent, 328 noncovalent, 327 in gene delivery, 335 lymphatic targeting, 331 nanotube-based antibody therapy, 331 ocular drug targeting, 332 preparation chemical vapor deposition, 326 electric arc discharge, 326 laser ablation technique, 327 as quantum dots for therapeutic purpose, 334–335 regulatory considerations, 336–337 shapes, 321–322 in solubility enhancement, 334 toxicity consideration, 336 in transdermal drug delivery, 334 in vaccine delivery, 335 Carboxylated polyglycidols, 310, 311f Carboxymethyl cellulose (CMC), 138–139, 396–399t

Carboxymethyl chitosan-cysteamine-Nacetyl histidine (CMCH-SS-NA), 10 Carboxymethyl dextran (CMD), 231 Carboxymethyl hexanoyl chitosan (CHC)/ superparamagnetic iron oxide (SPIO) (CHC/SPIO-MBs), 234–235 Carboxymethyl-starch, 396–399t Carrageenan, 396–399t, 405 Cathepsins, 236 Cathepsin B, 364, 425 Cationic pH-responsive polymers, 474–475 Cationic polypeptides, 355 Cell penetrating peptide (CPP)protoporphyrin complex, 236–237 Cellulose gelation mechanism, 469 ocular drug delivery, 469–470 structure, 473f Cellulose sulfate, 396–399t Chemical stimuli, 325, 529, 530f Chemical vapor deposition, 326 Chemotherapy, 133, 306–309 CHEMS. See Cholesteryl-hemisuccinate (CHEMS) Chimeric polymersomes, 423 Chitin, 548–551t Chitlac, 157–158 Chitosan, 66–68, 92, 396–399t based nanogel systems, 573–574, 574f colon-targeted drug delivery, 547, 553–554t gelation mechanisms, 477–478 insulin delivery system glucose responsive, 500–501 pH-responsive, 507–511 in ocular drug delivery, 478–479 oral insulin delivery, 535–538, 535f Chitosan@Fe3O4 NPs, 49 Chitosan-graft-poly(N-vinyl caprolactam) NPs, 141–142 Chitosan@magneto-liposomes, 66–70, 67–69f Chlorin e6-encapsulated nanospheres (Ce6-Ns), 20–21, 139–140 Cholesteryl-hemisuccinate (CHEMS), 63–64, 64f, 305–306 Ciprofloxacin, 400–401, 401f Cisplatin, 334–335

Index599

N-Citraconyl dioleoyl phosphatidyl ethanolamine (C-DOPE), 64–65 N-Citraconyl dioleoyl phosphatidylserine (C-DOPS), 64–65 CNTs. See Carbon nanotubes (CNTs) Cobalt-molybdenum catalytic (CoMoCat) process, 327 CoFe2O4 coated with meso-2,3dimercaptosuccinic acid (CoFe2O4@ DMSA), 51 Colon-targeted drug delivery microflora-activated system aim, 552–555 enzymes, 552–555, 556t pectin matrices, 557–558 tablet formation and drug-release, 557f natural polysaccharides, 547, 548–551t pH-sensitive system bipolymeric beads, drug-release mechanism, 561, 561f Eudragit, 559–560 hydroxypropyl methylcellulose acetate succinate, 558–559 microspheres with capecitabine, 560 poly(lactide-co-glycolide) acid, 558 stimuli-responsive polysaccharides, 552, 552f, 553–554t Concanavalin A (Con A), 140, 497 Confocal laser scanning microscopy (CLSM), 228–229 Conjugated polyelectrolyte (CPE) polymers, 220, 225 Controlled drug delivery, carbon nanotubes in, 332–333 Coordination polymer (CP) encapsulated polydopamine (PDA) nanocomplex, 231–232 Copolymer micelles, 134–137 Copolymer microspheres, 137–140 Copper sulfide-doped periodic mesoporous organosilica NPs (CuS@PMOs), 143 Coprecipitation, 41 Core-cross-linked (CCL) micelles, 11–13 Core-shell-corona micelles, 15, 16s Core-shell nanoparticles, 22–23 CO2-responsive polymersomes, 367, 368f Coumarin 102, 136 Covalent functionalization, carbon nanotubes, 328

c-PDP, 146, 148s CPT. See Camptothecin (CPT) Cremophor, 269–270 Critical micelle concentration (CMC), 4, 90, 273 Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), 18–19 Curcumin (CUR), 9, 160–163, 162f, 256–257, 558 Curdlan, 313–314 Cyanine dye (Ce6)-loaded GO, 223–224 Cyclodextrins (CDs) properties, 181, 182t structures, 181, 182f voltage-response, 382 cis-1,2-Cyclohexanedicarboxylic acid (CCA), 251 Cytotoxic singlet oxygen (1O2), 207–209 D DCs. See Dendritic cells (DCs) Deacetylase gellan gum, 404–405 Dendrimeric macromolecules, 170–171 Dendritic cells (DCs), 72, 310–312 Dendronized polymer (DP), 400–401, 401f Dextran, 313, 548–551t Dextran-b-poly(ε-caprolactone) di-block copolymer (Dex-SS-PCL), 296 Dextran sulfate (DEXS), 142–143, 396–399t Dextran vesicular approach, 362–363, 363f Diabetes mellitus treatment glucose-responsive insulin delivery ARS-loaded nanogel, 503–504, 504f bio-based capsules, 506 hydrogels, 504–505 implant biocompatibility evaluation, 502f layer-by-layer assembly, 500–501, 503f micelles, 505 microneedles, working principle, 497–500, 499f organoboronic acids, 505 PBA-grafted chitosan, 504 phenylborate derivative, 506 poly(NIPAM/MAA) nanoparticles, 500–501, 501f releasing mechanism, 497–500, 498f swelling and degradation mechanism, 496–497, 497f

600Index

Diabetes mellitus treatment (Continued) gold stud fabrication, 516, 517f insulin delivery system, 493–494 dual-responsive polymers, 514–515 electrochemical responsive, 513–514 pH-responsive polymers, 507–511 redox stimulus, 512–513 thermoresponsive polymers, 511–512, 513f metformin, 516 mobile sensing in diabetic mice, 516, 518f salmon calcitonin, 516 Diacetylenic phosphatidyl ethanolamine (DAPE), 63–64 Diamagnetic materials, 37, 38f Diamagnetism, 46t Diarylethene, 226 2-(N,N-Dimethylaminoethyl)methacrylate (DMAEMA), 26 2,3-Dimethylmaleic anhydride (DMMA), 201 Dioleoyl phosphatidyl ethanolamine (DOPE), 63–64, 64f, 305–306 Dipalmitoylphosphatidylcholine (DPPC), 305–306 Distillation-precipitation polymerization (DPP), 15–17 Dithiolated dimethylaminoethyl methacrylate polymer (DDMP), 222 Dithiothreitol (DTT), 229, 251 Divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA), 26 Docetaxel (DTX), 203, 204f DOPE. See Dioleoyl phosphatidyl ethanolamine (DOPE) Double redox strategy (DRS), 143 Double-walled nanotubes (DWNTs), 323 DOX. See Doxorubicin (DOX) DOX-HS-PMs, 294 Dox-loaded nanoparticles (DOX-NPs), 257–258 DOX-loaded PRDSP (PRDSP@DOX), 18–19 Dox-loaded RPAE-PEG copolymeric micelles dissociation, 251–252, 253f DOX-loaded supramolecular magnetic nanoparticles (DoxSMNPs), 210–211 DOX-loaded temperature-sensitive liposome (TSLDOX), 220–222 DOX-loaded thiolated complementary DNA, 222

Doxorubicin (DOX), 4, 119–122, 134–135, 138, 144, 160–163, 162f, 220–222, 251 Doxorubicin-encapsulated supramolecular MNPs (Dox⊂SMNPs), 53, 54f Dried rehydrated vesicles (DRV) method, 62 Drug-loading capacity (DLC), 3–4 DTX-magnetic-hydrogel, 122 Dual/multistimuli triggered cell targeting, 251 Dual-responsive polymers cancer therapy, 416–417, 417f insulin delivery, 514–515 Dual stimuli, 529, 530f Dual stimuli-responsive liposomes HPG-based, 314 methacrylic acid-based, 314–315 Dual temperature- and pH-responsive polymeric nanocarriers, 96–98t modes of response, 94–100, 94f poly(N-isopropylacrylamide), 93 poly(N-vinylcaprolactam), 93 triggered change in nanocarrier size, 95–100 triggered drug release, 94–95 types, 93–94, 93f E Electric arc discharge, 326 Electro-responsive polymers, 329–330 EMF. See External magnetic field (EMF) Endogenous stimuli pH-responsive system, 201–203, 202f redox-responsive system, 203, 204f Enhanced permeability and retention (EPR) effect, 3–4, 174–175, 197, 274–276 Enzymes, 205, 235–236, 288 Enzyme-responsive image-guided therapeutics, 235–236, 236f Enzyme responsive polymers, 235–238, 579–580 Enzyme-responsive polymersomes for cancer therapy, 425–426 drug delivery applications, 361–364 Enzyme-sensitive polymeric micelles, 288–291 Epidermal growth factor (EGF), 334–335 EPR. See Enhanced permeability and retention (EPR) effect 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide·HCl (EDC·HCl), 140 Eudragit, 396–399t, 401

Index601

Exogenous stimuli light-triggered system, 205–209 magnetic field-triggered system, 210–211 photodynamic triggered system, 207–209 photothermal-triggered system, 207 US-triggered system, 211–212 External magnetic field (EMF), 37, 39–40 External stimuli, 219, 348 F FA and rhodamine 6G modified hyaluronic acid (HA) (FA-HA-Rh 6G), 21 FA conjugated poly(ethyleneimine)-coated superparamagnetic iron oxide (FAPEI-Fe3O4), 166–167 FA- 2,3-dimethylmaleic anhydride terpolymer, 455, 456f FA-PEG-b-P[(PTX-SS-CL)-co-CL, 27–28 FA-PEG-PtBA-Br, 12–13, 13s FA-PLL(DCA)-PLC, 20, 20s 18 F-BODIPY dye, 236–237 Fe3O4@DMSA/DOX, 158 Fe3O4@PMAA nanoparticles, 22, 23s Fe3O4@PMAA@PNIPAM NPs, 141, 141s Fe3O4@SiO2 core-shell nanocomposites, 183 Feridex, 49, 50f Ferrimagnetic material, 37, 38–39f Ferrimagnetism, 46t Ferromagnetic materials, 37, 38f, 40f Ferromagnetism, 46t Film rehydration, 347 FITC-labeled bovine serum albumin (BSA) (FITC-BSA), 257 FITC-labeled cytochrome C (CC) (FITC-CC), 257 3-Fluoro-4-carboxyphenylboronic acid (FPBA), 237 Folate-decorated bovine serum albumin (FABSA), 49, 50f 4-Formylphenyl acrylate (FPA), 29 Functionalized partitioning, 334 G Gadobenate dimeglumine (Gd-BOPTA), 212, 213f Gadolinium, 200 Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), 49, 50f

Gadolinium-diethylene triamine pentaacetic acid-bis methyl acid (GdDTPABMA), 73 Gadolinium-doped silica nanoparticles (GaSi-NP), 44 Gas-responsive polymersomes, 366–369 Gellan gum, 404–405 colon-targeted drug delivery, 548–551t gelation mechanism, 471 in ocular drug delivery, 471–472 regulatory status, 471 Gelrite, 471–472 Gemcitabine (GEM), 205, 206f, 330–331 Genipin cross-linked polyionic complex (PIC) micelles, 11 Gestational diabetes, 491 Gibbs equation, 90 Glucagon-like peptide 1 (GLP-1), 526, 538 Glucose, 180 Glucose oxidase (GOx), 180–181, 496–497 Glucose-responsive MNPs, 180–181 Glucose-responsive polymer, 539 Glucose-responsive polymersomes for cancer therapy, 426 insulin delivery, 364–366 Glucose transporter (GLUT-1), 179 l-Glutamic acid (E) polypeptides, 140, 140s Glutathione (GSH), 3, 203, 294 Glycol chitosan (GC-NBSC), 258–259, 259f Glycyrrhetinic acid (GA), 9 Glycyrrhetinic acid-modified chitosancystamine-poly(ε-caprolactone) copolymer (PCL-SS-CTS-GA), 9 Gly-Phe-Leu-Gly (GFLG), 364 Gold nanoparticle-polypyrrolenanobiocomposite, 539–540 Gold nanoparticles (Au-NPs), 220–222 GO/mesoporous silica sandwich-like nanocomposites (rGO@MS), 146 Graphene, 321–322 Graphene oxide (GO), 223 GSH. See Glutathione (GSH) GSPIONs-CHIGP-PEI-DOX, 124 Guar Gum, 548–551t H Hafnium (Hf), 143–144 Heat shock protein (Hsp90), 210–211 1,6-Hexanediammonium (HDA), 144

602Index

Hexanoyl glycol chitosan (HGC), 478–479 High-intensity focused ultrasound (HIFU), 200 High-pressure carbon monoxide (HiPCO) disproportionation process, 327 Hollow mesoporous silica nanoparticles (HMSNs) with PDEAEMA (HMSNsPDEAEMA), 142, 142s Hollow microcapsules, 142 Homogeneous precipitation, 41 Hyaluronic acid, 396–399t, 548–551t Hyaluronidase (HAase), 205 Hybrid inorganic/organic capsules, 142–143 Hydrazine-modified bovine serum albumin (BSA-HyNic), 158–160 Hydrogels glucose-responsive insulin delivery, 504–505 oral insulin delivery, 531–535, 532–533f Hydrolyzed core-cross-linked (HCCL) micelles, 12–13, 13s Hydrophilic blocks, 270–272 Hydrophilic-lipophilic balance (HLB), 24–25 Hydrophilic volume fraction, 346 Hydrophobic blocks, 270–272 Hydrothermal synthesis, 41–42, 43f Hydroxyethyl methacrylate (HEMA), 322 Hydroxypropyl cellulose (HPC), 286 Hydroxypropyl methylcellulose (HPMC), 406, 469 Hydroxypropyl methylcellulose acetate succinate (HPMCAS), 558–559 Hydroxypropyl methylcellulose phthalate (HPMCP), 507–511 Hyperbranched polyacylhydrazone (HPAH), 228–229 Hyperbranched polyglycidol (HPG), 26, 310 Hyperthermia, 88, 179 Hypoxia/H2O2 dual-sensitive polymersomes, 360, 362f Hypoxia-inducible factor-1 (HIF-1), 291 Hypoxia-sensitive polymeric micelles, 291–294, 292f I ICG. See Indocyanine green (ICG) ICG-loaded polydopamine-rGO (ICG-PDArGO), 223–224 Image-guided drug delivery, 199–200

Indocyanine green (ICG), 207, 208f, 220–222 Indomethacin (IND), 286–287 In situ gel-forming polymers, 404–406 Insulin (INS), 526–527 chemical structure, 491–492, 492f colon-specific drug targeting, 548–551t oral insulin delivery, 493, 494f structure, 527f Intelligent intraocular implant, 480 Intelligent polymer, 525, 528–529 Internal stimuli, 219 Inverse nanoprecipitation method, 26 Ion-activated ketotifen ophthalmic delivery system, 404–405 Ionic cross-linking method, 141–142 Ionic strength, 395–396, 399, 406 Ionic-strength-responsive polymers in situ gel-forming polymers, 404–406 polyelectrolytes-based delivery systems, 396–403, 396–399t IONPs@mSiO2, 51, 51f Iron carbide, 116 Iron oxide-hydrogel, 122 Iron oxide nanoparticles (IONPs), 37–39, 42, 140–141 J Juvenile diabetes, 526 Juvenile onset diabetes, 491 K Ketalized linear polyethyleneimine (KLPEI), 282 Kinetic stability, 273–274 L Lactoferrin, 228–229 Lactoferrin-hyaluronic acid-DOX prodrug (LF-HA-DOX), 228–229 Laser ablation technique, 327 Lauryl succinyl chitosan (LSC), 535–538 Layer-by-layer (LBL) assembly, 142, 500–501, 503f LCST. See Lower critical solution temperature (LCST) Light, 373–374 Light-responsive image-guided therapeutic systems, 220, 221f

Index603

Light responsive polymers, 581–583 Light-responsive polymersomes for cancer therapy, 426–428, 429f drug delivery applications, 373–378 Lipids, 232 Liposomes, 173–175 advantages and disadvantages, 56t sensitive, 55–56 structure, 55f tumor accumulation of, 307–308, 309f Lower critical solution temperature (LCST), 89–90, 89f, 116–118, 283, 511–512 l-PDP, 146, 148s d-Luciferin, 225 Lymphatic targeting, 331 l-Lysine (K) polypeptides, 140, 140s M MAA-co-NIPAM-co-mPEGMA block copolymer, 95 Maghemite (γ-Fe2O3), 173 Magnetically responsive polymers, 330 Magnetic dipole-dipole interactions, 169–170 Magnetic field (MF)-responsive polymers natural polymers, 230–232 synthetic polymers, 232–233 Magnetic field (MF)-responsive polymersomes, 378–380 Magnetic fluid hyperthermia (MFH), 112–113, 119 Magnetic hyperthermia, 210–211, 210f Magnetic nanoparticles (MNPs), 37–39, 88, 454 β-cyclodextrins multiresponsive of, 183–184 coprecipitation, 41 in drug delivery, 163–167, 166f, 168t glucose-responsive, 180–181 hydrothermal synthesis, 41–42, 43f liposomes advantages and disadvantages, 56t structure, 55f magneto-liposomes dried rehydrated vesicles method, 62 pH-sensitive, 60–61, 63, 64f synthesis and properties, 62 traditional film method, 62–63 microemulsion, 44, 44f pH-responsive

in drug delivery, 50–53, 51f, 53–54f in magnetic resonance imaging, 48–49, 50f pH-sensitive magneto-liposomes contain cage lipid derivatives, 64–65 as drug delivery systems, 70–72, 71f in magnetic resonance imaging, 72–73 with pH-sensitive polymers, 66–70, 67–69f polymorphic lipids, 63–64, 64f synthetic fusogenic peptides/proteins, 65–66 polyol process, 45 sol-gel, 45 solvothermal synthesis, 42–44 in theranostic application, 167–169 Magnetic resonance imaging (MRI), 199, 307–308 pH-responsive magnetic nanoparticles, 48–49, 50f pH-sensitive magneto-liposomes, 72–73 Magnetic targeting, 163, 166f Magnetite (Fe2O3), 173 Magnetization (M), 37 Magneto-liposomes, 174, 174f dried rehydrated vesicles method, 62 pH-sensitive combine polymorphic lipids, 63–64, 64f contain cage lipid derivatives, 64–65 as drug delivery systems, 70–72, 71f in magnetic resonance imaging, 72–73 with pH-sensitive polymers, 66–70, 67–69f synthetic fusogenic peptides/proteins, 65–66 synthesis and properties, 62 traditional film method, 62–63 Matrix metalloproteinases (MMPs), 205, 288 Mesoporous silica nanoparticles (MSNs), 142 Metal-organic frameworks (MOFs), 144 Metformin, 516 Methacrylic acid (MAA), 138, 314–315 p-(Methacryloxyethoxy) benzaldehyde (MAEBA), 26 Methotrexate (MTX), 22, 175 Methotrexate-based thermosensitive magnetoliposomes (MTX-MagTSLs), 175–177, 176f, 178f

604Index

2-(2-Methoxyethoxy) ethyl methacrylate (MEO2MA), 286 Methoxy poly(ethylene glycol)-blockpoly(methacrylic acid)-blockpoly(glycerol monomethacrylate) (MPEG-b-PMAA-b-PGMA), 52 Methoxypoly(ethylene glycol)-b-poly(lglutamic acid-co-l-phenylalanine), 445 Methoxy poly(ethylene glycol)-b-poly[2(dibutylamino) ethylamine-lglutamate] (mPEG-SS-PNLG) copolymer, 8–9 Methoxy poly(ethylene glycol)N′-cystamine carbamatepoly[2-(diethylamino) ethylmethacrylate-co-N′-rhodamine 6G-ethylacrylamide] [PEG-CysP(DEAEMA-co-Rh6GEAm)], 10–11, 10s Methylcellulose (MC), 469 3-Methyl glutarylated polyglycidol (MGluPG), 310 3-Methyl-N-vinylcaprolactam (MVC), 285–286 Methyloxy-poly(ethylene glycol)b-poly[(benzyl-l-aspartate)co-(N-(3- aminopropyl) imidazole-l-aspartamide)] [mPEGSS-P(BLA-co-APILA)], 6–8, 7s Metoprolol, 558–559 Micelles, in cancer therapy magnetic-responsive, 454–455 multiresponsive, 455–457 pH-response in vitro trials, 446–449, 450f in vivo trials, 444–446, 447f redox-responsive, 451–454 surface ligand, 457–458 thermo-responsive, 449–451 Micellization theory, 270–272 Michael addition polymerization, 5, 8, 256–257 Microemulsion, 44, 44f Microflora-activated colon-specific drug delivery system (MCDDS), 552–555 Micro RNAs (miRNA), 278 Microvilli, 530–531 Mild hyperthermia enhanced chemotherapy, 143 MNP coated by large-pore mesoporous silica (MNP@LPMS), 52

MNP@PHP@DP, 52, 53f MNPs. See Magnetic nanoparticles (MNPs) Monomethoxy (polyethylene glycol)-bp(D,l-lactic-co-glycolic acid)-b-p(lglutamic acid) (mPEG-PLGA-PGlu), 257–258 Mononuclear phagocytic system (MPS), 276 Monophosphoryl lipid A (MPLA), 312 Moringa gum, 548–551t mPEG-Hy-PCL-SS-PCL-Hy-mPEG, 17 mPEG-OAL-DOX/Cy prodrug nanohydrogels., 29, 30s Mucopolysaccharides, 552–555 Multifunctional amphiphilic linearhyperbranched copolymer, 13, 14s Multifunctional liposomes, 307–309 Multiresponsive magnetoliposomes, 175–176, 176f for drug delivery, 175–176 in vivo applications, 177–178, 178f Multiresponsive micelles, 455–457 Multiresponsive polymeric carriers quadruple-stimuli responsive polymeric carriers, 146 with single stimulus, 149 tri-stimuli-responsive polymer-based composites and hybrids, 140–144 polymeric carriers, 134–140 supramolecular system, 144–146 Multistimuli-responsive magnetic assemblies, 169–173 Multistimuli-responsive nanogels, 139, 139s Multistimuli-responsive polymeric nanoparticles for drug delivery, 157–163 encapsulations and administration routes, 164–165t stimuli-responsive polymers, 156–157 Multiwalled carbon nanotubes (MWCNT), 323, 324t N N-acetyl glucosamine-poly(styrene-altmaleic anhydride)58-b-polystyrene130 [NAG-P(St-alt-MA)58-b-PSt130], 15 Nanobiomagnetism, 179 Nanocapsules, 23–25 Nanocarriers, 3–4

Index605

Nanohydrogels, 15–22 Nanomedicine, 443–444 oligonucleotide delivery, 277–278 passive and active targeting strategies, 274–277 physical penetration barriers, 277 Nanoparticles, 15–22 Nanotube-based antibody therapy, 331 National Environmental Policy Act (NEPA), 336–337 Natural polymers, 230–232 Near-infrared fluorescence (NIRF), 198–199, 227–228 Néel relaxation mode, 113 Negative temperature-sensitive hydrogels, 116–118 Negative thermosensitive polymer (NTSP), 466–467 NIPAM-β-cyclodextrin, 261, 262f NIR-photo-responsive polymersomes, 377–378 N-isopropylacrylamide (NIPAM), 66, 138–139 N-isopropylacryl-amide (NIPA) copolymers, 66 Nitric oxide (NO), 180–181 Nitrobenzyl chloroformate (NBCF), 293–294 Noncovalent functionalization, carbon nanotubes, 327 Non-Fickian mechanism, 404–405 Noninvasive imaging, 111 Nucleophilic substitution, 137 N-vinylpyrrolidone (VP), 285–286 O Ocular drug delivery (ODD) absorption mechanisms of conventional eye drops, 464–465, 465f ion-sensitive polymers, 470–471 gellan gum, 471–472 sodium alginate, 472–474 pH-responsive polymers, 474 carbomer, 475–477 chitosan, 477–479 in situ gelling, 464–465, 465f stimuli-responsive polymer, 466, 466t patented products, 480, 481t polymeric combinations, 479–480 thermo-responsive polymers

cellulose, 469–470 poloxamers, 467–468 poly (N-isopropylacrylamide), 470 xyloglucan, 470 Ocular drug targeting, 332 Oil-in-water (O/W) microemulsion, 44 Oleic acid (OA), 63–64, 64f Oligo(ethylene glycol) methacrylate (OEGMA), 286 Oligonucleotide delivery, 277–278 O-nitrobenzyl (ONB), 225 Optical imaging (OI), 198–199 Oral insulin delivery, 493, 494f barriers, 526–527, 528f glucose-responsive polymer, 539 gold nanoparticle-polypyrrolenanobiocomposite, 539–540 pH-sensitive polymers chitosan nanoparticles, 535–538, 535f PAA/S-chitosan hydrogel, 531–535, 532–533f poly(NIPAM), 539 ultrasound-responsive shell, 539 Organoboronic acids, 505 Oxidation-responsive polymersomes, 358–360, 361f P p(DMAEMA-SP), 258–259 P(NIPAM-co-AA), 101 P(NIPAM-co-DMAEMA), 101, 102f P(NIPAM-co-MAA), 101–102 Paclitaxel (PTX), 18, 25–26, 138, 253–254, 445, 451 Palmitoyl-homocysteine (PHC), 63–64 Palmitoyl oleoyl phosphatidyl ethanolamine (POPE), 63–64 PAMAM-magnetite nanoparticles, 171, 173f Paramagnetic manganese oxide (PMO), 42–44 Paramagnetic material, 37, 38f, 40f Paramagnetism, 46t Particle size dispersion, 160–163, 162f Passive targeting, 274–276 Patents, 480, 481t p(NIPAM)-b-p(His), 252, 254f P(St-g-PBDEMA)-b- P(MEO2MA-coOEGMA), 261

606Index

P(NIPAM)55-b-P(Histidine)125 micelles, 103, 104f PDMAEMA-b-PGA, 372–373 PDS-MPEG, 19–20, 19s Pectin, 547, 548–551t Pectin-derived matrices, 557–558 PEG. See Polyethylene glycol (PEG) PEG(PCL)2(PAA)2), 134–135 PEG-Azo-PEI-DOPE (PAPD), 292 PEG-b- PAEMA-PAMAM/Pt, 201 PEG-b-PLys-b-PCL triblock copolymer, 418 PEG-b-poly(lactic acid), 100 PEG-b-poly(propylene sulfide), 416 PEG-b-poly(acrylic acid)-b-poly(Nisopropylacrylamide) (PEG-b-PAA-bPNIPAM), 418–420 PEG-hexanethiol (PEG-C6), 293 PEG2k-pp-TAT-PEG1k-PE, 290–291 PEG1000-PE, 288–289 PEG2000-peptide-PTX, 288–289 PEG-POSS-(CD)7 polymer, 146, 147s PEG-pp-PEI-DOPE, 289, 289f PEG-pp-TAT-DOX, 290 PEG-SS-PBLG, 295 PEG-SS-PCL, 295–296 PEG-SS-PCL-SS-PCL-SS-PEG (tri-PESC), 149 PEG-SS-PLL/DNA, 296–297 PEG-SS-polyacrylate/cholesterol (PAChol), 357 PEGylated hyperbranched poly(amidoamine) (hPAMAM), 28 PEGylated hyperbranched poly(amidoamine)-doxorubicin (PPCD), 28 PE-PCL-b-PNIPAM-FA, 285 PE-PCL-b-PNVCL-FA, 285 Pepsomes, 423, 424f Perfluorocarbons (PFCs), 233 pH-dependent thermoresponsiveness, 101, 102f Phenylboronic acid (PBA), 365, 426 Phenylboronic acid-conjugated pluronic (Plu-SS-BA), 157–158 PHis-PLGA-PEG-PLGA-Phis, 287 pH-labile linkages, 227–229, 227f Phosphatidyl ethanolamine (PE), 63–64, 64f Photocage, 225 Photocleavable polymersomes, 427–428, 428f

Photodynamic triggered (PDT) system, 207–209 Photoirradiation-induced enhanced gene, 207–209, 209f Photoisomerization, 226 Photo-responsive polymers carbon nanomaterials, 223–224 conjugated polyelectrolyte polymers, 225 gold nanoparticles, 220–222 photocage, 225 photoisomerization, 226 PS-polymer complexes, 224–225 upconversion nanoparticles, 223 Photo-responsive polymersomes. See Lightresponsive polymersomes Photosensitizers (PSs), 207–209, 220, 221f Photosensitizers-polymer complexes, 224–225 Photo-, temperature-, and pH-responsive polymers, 135–136, 135s Photothermal therapy (PTT), 111, 207, 220–222 pH-responsive magnetic nanoparticles (MNPs) in drug delivery, 50–53, 51f, 53–54f in magnetic resonance imaging, 48–49, 50f pH-responsive micelles, 446–449 in vivo trials, 444–446, 447f in vitro trials, 446–449, 450f pH-responsive polymers, 90–92, 91t, 574–576 DOX release mechanism, 577f insulin delivery, 507–511 oral insulin delivery, 530–538 pH-induced charge-reversal and/or conformational changes, 227–228 pH-labile linkages, 228–229 pH-responsive polymersomes for cancer therapy, 420–423 drug delivery applications, 349–356 pH-sensitive curdlan, 313–314 pH-sensitive dextrans, 313 pH-sensitive immune-liposomes-CD33, 71–72 pH-sensitive liposomes cancer immunotherapy, 310–312 carboxylated polyglycidols, 310 curdlan, 313–314 dextrans, 313

Index607

inclusion of adjuvant functions, 312–313 poly(carboxylic acid)s, 309–310 pH-sensitive magneto-liposomes cage lipid derivatives, 64–65 as drug delivery systems, 70–72, 71f in magnetic resonance imaging, 72–73 with pH-sensitive polymers, 66–70, 67–69f polymorphic lipids, 63–64, 64f synthetic fusogenic peptides/proteins, 65–66 pH-sensitive polymeric micelles NC-6300 polymeric micelle, 282–283, 284f PAE-PEG-based micelles, 281–282 PEG-Hz-PE, 282, 283f pH-cleavable PEG-PE derivatives, 282 pH-labile linkers, 282 poly(β-amino ester), 281–282 poly(l-histidine), 279–281 poly(l-histidine) (PHIS), 281 poly(l-histidine)- b-PEG and poly(llactic acid)-b-PEG-b-polyHis-biotin, 280–281, 280f pH-sensitive polysaccharide, 558–561 Physical stimuli, 326, 529, 530f PLA-b-PEG-b-PHis micelles, 446 Plasmid DNA (pDNA), 335 Platinum (Pt)-prodrug-conjugated SCNs (SCNs/Pt), 201, 202f PLH-b-PLGA-b-TPGS copolymer, 450f Pluronics1. See Poly(ethylene oxide)poly(propylene oxide)-poly(ethylene oxide) triblock copolymers PMAA-based nanohydrogels, 15–17 PMAA/PNIPAM core/shell microspheres, 137–138, 138s PMAA/PNIPAM yolk/shell microspheres, 23, 24s, 137–138, 138s PMPC-b-PDPA, 373 P(NIPAM-ss-AA) nanogels, 19 Poloxamers, 122–124 in ocular drug delivery, 467–468 regulatory status, 467 thermo-gelling property, 467 Poly(2,4,6-trimethoxybenzylidine­ pentaerythritolcarbonate) (PTMBPEC), 422 Poly(2-ethyl acrylic acid), 309–310 Poly(2-propyl acrylic acid), 309–310

Poly(2-vinyl-4,4-dimethylazlatone) (PVDMA), 157, 157f Poly(aspartic acid) (PASP), 19 Poly(β-amino ester) (PAE), 281–282 Poly(diallyldimethylammonium chloride) (PDAC), 401–402, 402f Poly(dimethylaminoethyl methacrylate) (PDMAEMA), 92 Poly(ε-caprolactone) (PCL), 295–296 Poly(ethylene glycol) (PEG), 4 Poly(ethylenimine) (PEI), 92 Poly(γ-benzyl l-glutamate) (PBLG), 295 Poly(l-histidine), 279–281 Poly(l-histidine) (PHIS), 281 Poly(l-lactide) (PLLA), 286 Poly (lactic-co-glycolic acid) (PLGA), 52–53, 116, 166–167, 228, 558 Poly(methacrylic acid) (PMAA), 399 Poly(methacryloyloxy-3-thiahexanoyl-CPT), 27, 27s Poly(N- (2-hydroxypropyl) methacrylamide lactate-co-histidine), 100 Poly(N-isopropyl acrylamide) (PNIPAM), 90, 138–139, 285, 306, 329, 470, 539, 571–572 Poly(N-isopropylamide-b-butylmethacrylate) (PIPAA-b-PBMA), 449 Poly(N-vinylcaprolactam (PNVCL), 93, 285–286 Poly(N-vinylpyrrolidone) (PVPON), 399 Poly(sodium 4-styrenesulfonate), 401–402, 402f Polyacidic pH-responsive polymers, 90–92 Polyacids, 474 Polyacrylic acid derivative (PAAD), 507–511 Polyacrylic acid (PAA)-grafted dextran (Dex) nanohydrogels (NGs), 28 Polyamidoamine (PAMAM) dendrimers, 22–23 Polybases, 474 Poly(2-methacryloyloxyethyl phosphorylcholine)-block-poly(laspartic acid), 264 Poly(acrylic acid)-block-poly(vinyl alcohol) (PAA-b-PVOH), 260 Poly(ethylene glycol)-block-poly(4vinylbenzylphosphonate), 53 Poly(2-methacryloyloxyethyl phosphorylcholine)-block-poly(lhistidine) copolymers, 264

608Index

Poly(l-histidine)- b-PEG and poly(l-lactic acid)-b-PEG-b-polyHis-biotin, 280–281, 280f Poly(ε-caprolactone)-b-poly(2(diethylamino) ethyl methacrylate) (PCL-PDEA), 256–257 Poly(ε-caprolactone)-b-poly(triethylene glycol methacrylate-co-N(2-(methacrylamido)ethyl) folatic amide), 251–252 Poly(ε-caprolactone)-b-poly(triethylene glycol methacrylate-co-Nmethacryloyl caproic acid), 251–252 Poly(ethylene glycol)-b-poly(l-lysine), 251 Poly(ethylene oxide)-b-poly(furfuryl methacrylate) (PEO-b-PFMA), 11–12 Poly(ethylene oxide)-b-poly(Nisopropylamide), 449–451 Poly(l-histidine)-b-poly(ethylene glycol) (PHis-b-PEG), 444, 457 Poly(trimethylene carbonate)-b-poly(lglutamic acid) (PTMC-b-PGA), 402–403 Poly(vinyl alcohol)-b-poly(Nvinylcaprolactam), 141 Poly(ethylene glycol)-b-poly(ethanedithiolalt-nitrobenzyl)-b-poly(ethylene glycol) (PEG-b-PEDNB-b-PEG), 262–263 Poly(N-vinylcaprolactam)-bpolydimethylsiloxane-bpoly(N-vinylcaprolactam) (PVCL-b-PDMS-b-PVCL), 372, 372f Poly(ethylene glycol)- b-poly(acrylic acid-co-tert-butyl acrylate)-poly(εcaprolactone) (PEG43-b-P(AA30- cotBA18)-b-PCL53) triblock copolymer, 15, 16s Poly[2-(diisopropylamino)ethyl methacrylate] (PDP-b-ND), 287 Polyelectrolytes, 309–310, 396, 396–399t Poly[(2-ethoxy)ethoxyethyl vinylether] (pEOEOVE), 306–307, 307–308f Polyethylene glycol (PEG), 116, 118–119, 174–175, 276 Polyethylene glycol methacrylate (PEG-MA), 49 Polyglycidols, 310 Poly(BAC-AMPD)-g-PEG-g-CE, 5, 6s

Poly(β-amino ester)-grafted disulfide methylene oxide poly(ethylene glycol) (PAE-g-DSMPEG), 256–257 Poly(beta-amino ester)-grafted disulfide methylene oxide poly(ethylene glycol) (PAE-g-SWEG), 8, 8s Poly(l-glutamate)-g-tocopherol, 455 Polyhedraloligomeric silsesquioxane (POSS), 232–233 Polyion complexes, 355–356 Poly-l-arginine hydrochloride (PARG), 142–143 Polymeric carriers copolymer micelles, 134–137 copolymer microspheres/microgels, 137–140 Polymeric (CP) hydrogels, 138–139 Polymeric micelles, 270–274, 272f, 275t core-cross-linked micelles, 11–13 enzyme-sensitive, 288–291 hypoxia-sensitive, 291–294 pH-sensitive, 279–283 redox-sensitive, 294–297 self-assembled, 4–11 shell-cross-linked micelles, 14–15 thermosensitive, 283–288 Polymer nanoparticles core-shell nanoparticles, 22–23 nanocapsules, 23–25 nanohydrogels, 15–22 yolk-shell nanoparticles, 23 Polymer nanoprodrugs, 25–29 Polymer-protein biodynamer, 158–160 Polymer-PTX conjugate [P(L-PTX)], 25–26, 25s Polymersomes, 345. See also Cancer therapy biomedical applications, 347–348, 348f electrical stimuli, 382–383 enzyme-responsive system dextran vesicular approach, 362–363, 363f noncovalent host-guest interactions, 363–364 properties, 361–362 film rehydration, 347 future aspects, 383–384 gas-responsive, 366–369 glucose mediated insulin delivery, 364–366

Index609

vs. liposomes, 345–346 magnetic field-responsive systems, 378–380 photo-responsive system AZO-containing polyacrylate, 376 Ce6-loaded gold NPs, 378, 379f light, 373–374 NIR-triggered drug release, 377–378 photodegradable linker, 374–376, 375f spiropyran moieties, 377 pH-responsive system diblock copolymer, self-assembly, 355, 356f membrane permeability, 352 multivesicle assemblies, 352, 355f PEG-PLA hydrophobic block, 349, 350f PSMA-targeting, 349–351, 351f self-assembly, 351–352, 353f redox responsive system, 356 co-self-assembly, 357, 359f hypoxia/H2O2 dual-polymer, 360, 362f intracellular protein delivery, 357, 358f PAChol block, 357 preparation, 360, 361f sizes, 347 spherical forms, 346f temperature-responsive system, 369 PDMAEMA-b-PGA, 372–373 PEG-b-PAA-b-PNIPAM, 370–372 proteinosome preparation, 370, 371f PVCL-b-PDMS-b-PVCL, 372, 372f ultrasound-responsive, 381 Poly[methacrylic acid-co-poly(ethylene glycol) methyl ether methacrylate-coN,N-bis(acryloyl)cystamine] (PMPB) nanohydrogels, 17 Poly(ethylene-glycol)-N-distearolyphosphatidyl-ethanolamine (PEG-DSPE), 64–65 Poly[N-(2-hydroxypropyl)methacrylamideco-methacrylic acid] nanohydrogels, 15–17 Polyol process, 45 Poly-organophosphazene (PPZ), 121–122, 121f Poly(6-O-vinyladipoyl-d-galactose-ss-Nvinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), 17

Poly(di(ethylene glycol)ethyl ether acrylateco-poly(ethylene glycol) methyl ether acrylate) [P(DEGA-co-PEGA)], 158–160, 161f Poly(N-isopropylacrylamide-codimethylacrylamide) [P(NIPAAmcoDMAAm)], 287 Poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate-co-5-methyl-5-propargyl1,3-dioxan- 2-one) (PEG-P (TMBPEC-co-MPMC)), 12 Poly(oligo(ethylene glycol) methacrylate)polyaspartate (POEGMA-PAsp), 227–228 Poly(ε-caprolactone)-poly(ethylene glycol)poly(ε-caprolactone) (PCL-PEGPCL), 286–287 Poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers, 90 Poly(methacrylic acidco-N,N-bis(acryloyl) cystamine)/poly(N-isopropylacrylamideco glycidylmethacrylate-coN,N-bis(acryloyl)- cystamine) [P(MAA-co-BAC)/P(NIPAAm-co-G MA-co-BACy)], 137 Poly(β-amino ester)s (RPAE), 4 Poly(β-hydroxyl amine)s (RPHA), 9, 9s Poly(carboxylic acid)s, 309–310 Polysaccharide-based targeting system. See Colon-targeted drug delivery Polysaccharides, 547 Poly(ethylene glycol)-SS-poly(2-(diethyl amino)ethyl methacrylate) (PEG-SSPDEA), 257, 257f Poly(ethylene glycol)-SS-poly(2,4,6trimethoxybenzylidene-pentaerythritol carbonate) (PEG-SS-PTMBPEC) copolymer, 5, 5s, 256–257 Poly(epsilon-caprolactone)-SSpoly(N,N-diethylaminoethyl methacrylate)-r-poly(N-(3sulfopropyl)-N-methacrylateN,N-diethylammonium-betaine) (PCL-SS-PDEASB), 5–6, 7s Poly(e-caprolactone)SS-poly(ethylene glycol) with azobenzene (Azo) (AzoPCL-SS-PEG), 144–146, 145s

610Index

Polysuccinimide (PSI), 10, 251–252 Polyurethane/polyurea nanocapsules (NCs), 24–25 Poly-vinyl-alcohol (PVA), 116 Poly-vinyl-pyrrolidone (PVP), 116 Positive temperature-sensitive hydrogels, 116–118 Positive thermosensitive polymer (PTSP), 466–467 Positron emission tomography (PET), 199–200 PPEMA-co-PCPTM, 28 Protein-based nanospheres, 20–21 Proteinosomes, 370, 371f PS-β-CD/PEG-Fc-based polymersomes, 383 PTT. See Photothermal therapy (PTT) PTX. See Paclitaxel (PTX) PTX-HPC-PEG-Chol-biotin, 286 PTX-loaded micelles, 259–260 PUA/PSS/Au microcapsules, 142 Pullulan, 548–551t PVA/PAA/MWCNT nanofibers, 334 PVCL-b-polydimethylsiloxane-b-PVCL (PVCL-b-PDMS-b-PVCL), 372 Pyridyldisulfide ethyl methacrylate (PDSM), 21 Q Quadruple-stimuli responsive polymeric carriers, 146, 147–148s Quantum dots (Q-dots), 334–335 R Reactive oxygen species (ROS), 207–209 Redox-activated light-up micelles, 203, 204f Redox-responsive micelles, 451–454 Redox-responsive polymer, 577–579 Redox-responsive polymersomes, 356–360 Redox-sensitive polymeric micelles, 294–297 Redox stimulus, 512–513 Responsive polymers, 570–571 challenges and future aspects, 584–587 design strategies, 571, 572f drug delivery systems, 584, 585t electrically responsive carriers, 581 enzyme, 579–580 light, 581–583 magnetism, 580–581

pH, 574–576, 577f reduction-oxidation (Red-Ox) reactions, 577–579 temperature, 571–574 ultrasound, 583–584 Reversed-phase emulsion crosslinking, 501–503 Reversible addition-fragmentation chaintransfer (RAFT) polymerization, 26, 158–160, 254 RGD-PCSSD SCNPs, 254 Ring-opening polymerization (ROP), 15, 137 S Salmon calcitonin, 516 SBA-15, 52 Selenium/tellurium-containing polymers, 360 Self-assembled polymeric micelles, 270–272, 272f Self-assembling peptide, 402–403 Self-condensing vinyl copolymerization (SCVCP), 13 Self-condensing vinyl polymerization (SCVP), 27 Self-regulated devices, 394 Semiinterpenetrating network (SIPN) hydrogels, 138–139 Sensitive cluster nanobombs (SCNs), 201, 202f Sensitive liposomes (SL), 55–56, 57f Serum albumin protein, 231–232 Shell-cross-linked (SCL) micelles, 14–15 Shell-cross-linked nanoparticles (SCNPs), 254, 255f Silica-iron oxide (SiO2-Fe2O3), 170, 171f Single-photon emission computed tomography (SPECT), 199–200 Single-spot novel method, 171 Single-walled carbon nanotubes (SWCNT), 224, 323, 324t Small interfering RNA (siRNA), 277–278, 297 Smart bio-nanotubes, 332 Smart polymers, 464, 495 SN38, 420 Sodium alginate gelation mechanism, 472, 473f in ocular drug delivery, 472–474 structure, 472, 473f

Index611

Sol-gel method, 45 Solvothermal synthesis, 42–44 Sonication, 62–63 SPIONs. See Superparamagnetic iron oxide nanoparticles (SPIONs) SPIONs-F127-PLA-FA, 119–121, 120f Spiropyran (SP), 226, 373–374, 377 Spiropyran-based amphiphilic random copolymers [poly(NIPAM-co-SP and P(DMAEMA-SP)], 136, 136s SS-linked methoxy poly(ethylene glycol)b-poly(2-(dibutylamino)ethylaminel-glutamate) (mPEG-SS-PNLG), 260–261 SS-linked poly(ethyl glycol)-poly(εcaprolactone) (mPEG-SS-PCL), 256–257 Starch, 548–551t Star-PCLss-FA, 452–453, 453f Stimuli, 529, 530f Stimuli-responsive nanocarriers chemical and biochemical stimuli, 325 endogenous stimuli pH-responsive system, 201–203 redox-responsive system, 203 enzyme-responsive system, 205 exogenous stimuli light-triggered system, 205–209 magnetic field-triggered system, 210–211 photodynamic triggered system, 207–209 photothermal-triggered system, 207 US-triggered system, 211–212 in vitro, 103–104 in vivo, 103–104 physical stimuli, 326 sharp vs. gradual response to stimuli, 103 system’s complexity vs. cost-effectiveness, 104 Stimuli-responsive polymers (SRPs), 156– 157, 157f, 394–395, 394–395f, 525 classification, 464, 464f definition, 494 types, 495f Styrene malic acid (SMA) conjugated anticancer protein neocarzinostatin (SMANCS), 274–276 Subcutaneous Co112 human colon carcinoma tissue, 122–124, 123f

Succinylated polyglycidols (SucPG), 310 Sulfur hexafluoride (SF6), 233 Superparamagnetic Fe3O4 NPs, 143 Superparamagnetic iron oxide nanoparticles (SPIONs), 42–45, 43f, 156, 166, 230f applications, 169–170 BALB/c nude mice with subcutaneous tumors of U-87 MG, 124–125, 125f characteristics, 116, 117t doxorubicin release, 119–121 embedding in polymeric matrices, 170 encapsulation by dendrimeric macromolecules, 170–171 hematite, 114 hydrogel/SPIONs formulation, 124, 125f maghemite, 114 magnetic dipole-dipole interactions, 169–170 magnetic fluid hyperthermia, 121–122, 121f magnetite, 114 polyethyleneglycol, 118–119 poly-organophosphazene, 121–122, 121f SPION@APTES@FA-PEG, 170, 172f SPIONs-F127-PLA-FA, 119–121, 120f synthesis, 114, 115f Van-der Waals forces, 169–170 wet-chemical procedure, 116 Superparamagnetic materials, 39, 40f, 229–230 Supramolecular hydrogels, 146 SWCNT. See Single-walled carbon nanotubes (SWCNT) SWCNTPEG-GEM, 330–331 Swelling behavior, 157 Synthetic polymers, 232–233 T TAT pop-up pH-sensitive micelle, 444 TATp-PEG1000-phosphoethanolamine (PE), 288–289 Taxol in vitro drug-release patterns, 158, 160f loading on PC-SPMA micelles, 157–158, 159f Temperature-dependent pH responsiveness, 101–102 Temperature-responsive hydrogels, 116–118, 118f, 329

612Index

Temperature-responsive polymers, 88–90, 91t Temperature-sensitive liposomes multifunctional liposomes, 307–309, 309f pEOEOVE-based, 306–307, 307–308f poly(N-isopropyl acrylamide) based, 306 Tetra-aniline-conjugated PEG (TAPEG), 429–431 5,10,15,20-Tetrakis (4-carboxyphenyl) porphyrin (TCPP), 224–225 Theranostics, magnetic nanoparticles in, 167–169 Thermal-triggerable polymeric nanoparticles, 116 Thermo-responsive polymers, 571–574 insulin delivery, 511–512, 513f oral insulin delivery, 539 Thermo-responsive polymersomes, 369–373 Thermosensitive polymeric micelles, 283–288 Thiolated polymers, 535–538 Three-dimensional (3D) skin models, 314–315, 316f Toll-like receptor 4 (TLR4), 312 Traditional film method, 62–63 Transactivator of transcription (TAT) peptide (TATp), 280–281 Transdermal drug delivery systems (TDDSs), 334 Triple-stimuli-responsive nanocontainers (T-SRNs), 144 Tri-stimuli-responsive polymeric carriers PNiPAAm-S-S-PXCL, 137, 137s polymer-based composites and hybrids, 140–144 polymeric carriers copolymer micelles, 134–137 copolymer microspheres/microgels, 137–140 supramolecular system, 144–146 Tumor-responsive drug delivery vehicles, 139–140 Two-disulfide-functionalized 5-arm AB2C2 star terpolymers (PEG(PCL)2(PNIPAM)2, 134–135, 134s

Type I diabetes, 491, 526 Type II diabetes, 491 U Ultrasound contrast agents (UCAs), 233, 234f Ultrasound (US)-responsive polymers, 233–235, 583–584 Ultrasound responsive polymersomes biomedical applications, 381 for cancer therapy, 431 Unilamellar polyion complex vesicles (NanoPICsomes), 403, 403f Unimers, 270–272 Upconversion nanoparticles (UCNPs), 198–199, 223 Upper critical solution temperature (UCST), 89, 89f, 116–118, 511–512 US Environmental Protection Agency (EPA), 336–337 V Vaccine delivery, carbon nanotubes in, 335 Vancomycin, 426 Van-der Waals forces, 169–170 Vascular leakage, 274–276 Voltage responsive polymer, 581 Voltage responsive polymersomes biomedical applications, 382–383 for cancer therapy, 429–431 W Water-in-oil (W/O) microemulsion, 44 Water-soluble carboxylate-substituted pillar[5]arene (WP5), 144 Water-soluble pillar[6]arene (WP6), 144 X Xanthan gum matrix, 559 Xyloglucan, 470 Y Yolk-shell nanoparticles, 23 Y-shaped block copolymer mPEG-b-PLG-b(PLA)2, 14–15, 14s