Smart polymers and their applications [Second edition] 9780081024164, 9780081024171, 4394414504, 5435525535, 0081024169, 0081024177

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SMART POLYMERS AND THEIR APPLICATIONS

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Woodhead Publishing in Materials

SMART POLYMERS AND THEIR APPLICATIONS EDITED BY

Maria Rosa Aguilar Julio San Román

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 © 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: 978-0-08-102416-4 (print) ISBN: 978-0-08-102417-1 (online) For information on all Woodhead publications visit our website at https://www.elsevier.com/books-and-journals

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Contents Contributors xi 1.  Introduction to Smart Polymers and Their Applications MARÍA ROSA AGUILAR, JULIO SAN ROMÁN

1.1 Types of Smart Polymers 2 1.2 Applications of Smart Polymers 5 1.3 Conclusions 8 Acknowledgment 8 References 8

2.  Temperature-Responsive Polymers: Properties, Synthesis, and Applications RICHARD HOOGENBOOM

2.1 Introduction: The Role of Temperature-Responsive Polymers 13 2.2 Basic Principles of Temperature-Responsive Polymers in Aqueous Solution 16 2.3 Key Types of Temperature-Responsive Polymers in Aqueous Solution 20 2.4 Selected Applications of Thermoresponsive Polymers 31 2.5 Conclusions: Strengths and Limitations of Current Temperature-Responsive Polymers 36 2.6 Future Trends 36 References 36 Further Reading 44

3.  pH-Responsive Polymers: Properties, Synthesis, and Applications LUIS GARCÍA-FERNÁNDEZ, ANA MORA-BOZA, FELISA REYES-ORTEGA

3.1 Introduction 46 3.2 Basic Principles of pH-Responsive Polymers 47 3.3 Key Types and Properties of pH-Responsive Polymers 49 3.4 Synthesis of pH-Responsive Polymers 62 3.5 Application 67 3.6 Conclusions and Future Trends 76 References 78

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vi CONTENTS 4.  Photoresponsive Polymers X. XIONG, ARÁNZAZU DEL CAMPO, J. CUI

4.1 Introduction 87 4.2 Chromophores and Their Light-Induced Molecular Response 89 4.3 Key Types and Properties of Photoresponsive Polymers 91 4.4 Applications 114 4.5 Conclusions and Future Trends 140 References 144

5.  Enzyme-Responsive Polymers: Classifications, Properties, Synthesis Strategies, and Applications ANIKA B. ASHA, SHRUTI SRINIVAS, XIAOJUAN HAO, RAVIN NARAIN

5.1 Introduction 155 5.2 Historical Evolution of Enzyme-Responsive Polymer 157 5.3 Enzyme-Responsive Materials 159 5.4 Properties of Enzyme-Responsive Polymers 166 5.5 Fabrication Mechanisms of Enzyme-Responsive Polymers 168 5.6 Applications of Enzyme-Responsive Polymers 177 5.7 Conclusion 186 References 186 Further Reading 189

6.  Conductive Poly(3,4-Ethylenedioxythiophene) (PEDOT)-Based Polymers and Their Applications in Bioelectronics ANA SANCHEZ-SANCHEZ, ISABEL DEL AGUA, GEORGE G. MALLIARAS, DAVID MECERREYES

6.1 Introduction 191 6.2 Polymerization of Ethylenedioxythiophene (EDOT-ProDOT) Monomers 192 6.3 PEDOT-Based Aqueous Dispersion 195 6.4 Applications of Innovative PEDOT-Based Materials 202 6.5 Conclusions 210 Acknowledgments 210 References 211 Further Reading 218

7.  Inflammation-Responsive Polymers EVA ESPINOSA-CANO, MARÍA ROSA AGUILAR, BLANCA VÁZQUEZ, JULIO SAN ROMÁN

7.1 Introduction 219 7.2 Inflammatory Microenvironment 223 7.3 Key Types and Properties of Inflammation-Responsive Polymers 230 7.4 Current and Future Trends 245 7.5 Conclusions 246 References 246

CONTENTS vii

8.  Dual- and Multistimuli-Responsive Polymers for Biomedical Applications ELBAY MALIKMAMMADOV, NESRIN HASIRCI,

8.1 Introduction 256 8.2 Dual Responsive Polymers and Their Applications 258 8.3 Multiresponsive Polymers and Their Applications 268 8.4 Conclusions and Future Trends 275 References 275

9.  Smart Polymer Gels: Properties, Synthesis, and Applications ANDRÉS MONTERO, LETICIA VALENCIA, ROCÍO CORRALES, JOSÉ LUIS JORCANO, DIEGO VELASCO

9.1 Introduction 279 9.2 Key Types, Properties, and Applications of Smart Hydrogels 280 9.3 Conclusions and Future Trends 313 References 314 Further Reading 320

10.  Stimuli-Responsive Protein Fibers for Advanced Applications ISRAEL GONZALEZ DE TORRE, CARMEN GARCÍA-ARÉVALO, MATILDE ALONSO, JOSÉ CARLOS RODRÍGUEZ CABELLO

10.1 Peptide-Based Fibrous Systems 323 10.2 Silks-Based Fibers 339 10.3 Elastin-Based Smart Materials 353 10.4 Conclusions and Future Trends 361 References 362 Further Reading 372

11.  Self-Healing Polymeric Systems: Concepts and Applications MICHAEL DEN BRABANDER, HARTMUT R. FISCHER, SANTIAGO J. GARCIA

11.1 Introduction 379 11.2 Existing Healing Approaches 383 11.3 Functionality Restoration 390 11.4 Concluding Remarks 403 Acknowledgments 404 References 404 Further Reading 409

12.  Smart Instructive Polymer Substrates for Tissue Engineering CATARINA A. CUSTÓDIO, ARÁNZAZU DEL CAMPO, RUI L. REIS, JOÃO F. MANO

12.1 Introduction 12.2 Instructive Polymeric Surfaces 12.3 Instructive Hydrogels With a Physicochemical Response

411 412 415

viii CONTENTS 12.4 Materials With 3D-Defined Patterns 421 12.5 Applications in Tissue Engineering 423 12.6 Conclusion and Future Trends 428 References 429

13.  Smart Polymeric Nanocarriers for Drug Delivery A. DURO-CASTANO, M. TALELLI, G. RODRÍGUEZ-ESCALONA, M.J. VICENT

13.1 Introduction 439 13.2 Smart Polymeric Carriers for Drug Delivery: pH-Responsive Nanocarriers 441 13.3 Smart Polymeric Carriers for Drug Delivery: Enzyme-Responsive Nanocarriers 450 13.4 Smart Polymeric Carriers for Drug Delivery: Oxidation-Responsive Nanocarriers 459 13.5 Smart Polymeric Carriers for Drug Delivery: Temperature-Responsive Nanocarriers 461 13.6 Smart Polymeric Carriers for Drug Delivery: Nanocarriers Responsive to Other Stimuli 463 13.7 Conclusion and Future Trends 465 References 466 Further Reading 479

14.  The Use of Smart Polymers in Medical Devices for Minimally Invasive Surgery, Diagnosis, and Other Applications L.G. GÓMEZ-MASCARAQUE, R. PALAO-SUAY, BLANCA VÁZQUEZ

14.1 Introduction 481 14.2 Types and Preparation of Smart Polymers for Medical Devices: Polymers Classified by Type of Stimulus 482 14.3 Types and Preparation of Smart Polymers for Medical Devices: Polymers Classified by Structural Properties 487 14.4 Applications: Medical Devices Based on SMPs 502 14.5 Applications: SMPs in Minimally Invasive Surgery 504 14.6 Applications: Medical Devices for Cancer Diagnosis and Therapy 507 14.7 Applications: Biosensors for Diagnostic Medical Devices 509 14.8 Applications: Biosensors and Actuators for Enhanced Diagnostics and Therapy 512 14.9 Applications: Microfluidics-Based Biomedical Devices 514 14.10 Conclusion and Future Trends 517 References 519 Further Reading 531

15.  Smart Polymers for Bioseparation and Other Biotechnological Applications

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I.N. SAVINA, I.Y. GALAEV, S.V. MIKHALOVSKY

15.1 Introduction 533 15.2 Smart Polymers for Bioseparation: Use in Affinity Precipitation 534 15.3 Aqueous Two-Phase Polymer Systems Formed by Smart Polymers for Use in Bioseparation 541

CONTENTS ix

15.4 Chromatographic Carriers With Grafted SP and Adsorbents Produced From SP 543 15.5 Smart Cryogels 552 15.6 Membranes With SP-Grafted Pores 553 15.7 Use of Smart Polymers in Catalysis 558 15.8 Conclusion and Future Trends 561 References 562

16.  Smart Polymers for Optical Data Storage E. BLASCO, M. PIÑOL, C. BERGES, C. SÁNCHEZ-SOMOLINOS, L. ORIOL

16.1 Introduction 567 16.2 Photoinduced Molecular Motions of Azobenzene Chromophores 572 16.3 Macromolecular Architectures in Azopolymers 573 16.4 Synthetic Strategies to Azopolymers for Optical Data Storage 575 16.5 Photoinduced Response of Azobenzene Polymers 593 16.6 Conclusion 599 References 600

17.  Smart Polymers for Highly Sensitive Sensors and Devices: Micro- and Nanofabrication Alternatives ANA M. SANJUÁN, JOSÉ A. REGLERO RUIZ, FÉLIX C. GARCÍA, JOSÉ MIGUEL GARCÍA

17.1 Introduction 607 17.2 Smart Polymers in Sensor Devices 608 17.3 New Micro- and Nanosensor Polymeric Devices 622 17.4 Outlook and Perspectives 636 Acknowledgments 637 References 637

18.  Toward Smart Polymeric Binders for Battery Electrodes JAVIER CARRETERO-GONZÁLEZ, JORGE MONTERO, MIGUEL ANGEL LÓPEZ-MANCHADO

18.1 Introduction 651 18.2 Bio-Based Polymer Binders 656 18.3 Multifunctional Polymer Binders 658 18.4 Smart Polymer Binders 662 18.5 Conclusions and Outlook 667 References 667

Index 671

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Contributors María Rosa Aguilar  Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTPCSIC); Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain Matilde Alonso Bioforge, CIBER-BBN, Lucia Building; G.I.R Bioforge, ­University of Valladolid, Valladolid, Spain Anika B. Asha  Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, AB, Canada C. Berges  ICMA, CSIC-Universidad de Zaragoza, Zaragoza, Spain E. Blasco  ICMA, CSIC-Universidad de Zaragoza, Zaragoza, Spain José Carlos Rodríguez Cabello Bioforge, CIBER-BBN, Lucia Building; G.I.R Bioforge, University of Valladolid, Valladolid, Spain Javier Carretero-González  Institute of Polymer Science and Technology, ICTP-CSIC, Madrid, Spain Rocío Corrales  Department of Bioengineering and Aerospace Engineering, ­Universidad Carlos III de Madrid (UC3M), Getafe, Spain J. Cui  INM—Leibniz Institute for New Materials, Saarbrücken, Germany Catarina A. Custódio  CICECO, Department of Chemistry, University of Aveiro, Aveiro, Portugal Israel Gonzalez de Torre  Bioforge, CIBER-BBN, Lucia Building, University of Valladolid; Technical Proteins Nanobiotechnology (TPNBT S.L.), Valladolid, Spain Isabel del Agua  POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center, Donostia-San Sebastian, Spain Aránzazu del Campo  INM—Leibniz Institute for New Materials, Saarbrücken, Germany Michael den Brabander  Novel Aerospace Materials group, Department of Aerospace Structures and Materials, Faculty of Aerospace Engineering, Delft University of Technology, Delft, The Netherlands A. Duro-Castano  Polymer Therapeutics Lab., Prince Felipe Research Center, Valencia, Spain Eva Espinosa-Cano  Institute of Polymer Science and Technology (ICTP-CSIC), Spain and Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Málaga, Spain

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xii CONTRIBUTORS Hartmut R. Fischer  TNO Technical Sciences, Materials for Integrated Products, Eindhoven, The Netherlands I.Y. Galaev  DSM, Heerlen, The Netherlands Santiago J. Garcia  Novel Aerospace Materials group, Department of Aerospace Structures and Materials, Faculty of Aerospace Engineering, Delft University of Technology, Delft, The Netherlands Félix C. García  Polymer Research Group, Organic Chemistry Department, Faculty of Sciences, University of Burgos, Burgos, Spain José Miguel García  Polymer Research Group, Organic Chemistry Department, Faculty of Sciences, University of Burgos, Burgos, Spain Carmen García-Arévalo  Bioforge, CIBER-BBN, Lucia; G.I.R Bioforge, University of Valladolid, Valladolid, Spain Luis García-Fernández  Institute of Polymer Science and Technology (ICTPCSIC); Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain L.G. Gómez-Mascaraque  Institute of Polymer Science and Technology (ICTPCSIC), Spain and Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Málaga, Spain Xiaojuan Hao  CSIRO Manufacturing, Research Way, Clayton, VIC, Australia Nesrin Hasirci  BIOMATEN-Center of Excellence in Biomaterials and Tissue Engineering; Graduate Department of Micro and Nanotechnology; Graduate Department of Biomedical Engineering; Graduate Department of Polymer Science and Technology; Department of Chemistry, Middle East Technical University, Ankara, Turkey Richard Hoogenboom  Supramolecular Chemistry group, Centre of Macromolecular Chemistry (CMaC), Department of Organic Chemistry, Ghent University, Ghent, Belgium José Luis Jorcano  Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid (UC3M), Getafe; Division of Epithelial Biomedicine, CIEMAT-CIBERER, Madrid, Spain Miguel Angel López-Manchado  Institute of Polymer Science and Technology, ICTP-CSIC, Madrid, Spain Elbay Malikmammadov  BIOMATEN-Center of Excellence in Biomaterials and Tissue Engineering; Graduate Department of Micro and Nanotechnology, Middle East Technical University, Ankara, Turkey George G. Malliaras  Department of Engineering, Electrical Engineering Division, University of Cambridge, Cambridge, United Kingdom João F. Mano  CICECO, Department of Chemistry, University of Aveiro, Aveiro, Portugal David Mecerreyes  POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center, Donostia-San Sebastian; Ikerbasque, Basque Foundation for Science, Bilbao, Spain S.V. Mikhalovsky  ANAMAD Ltd, Brighton, United Kingdom

CONTRIBUTORS xiii

Andrés Montero  Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid (UC3M), Getafe, Spain Jorge Montero  Institute of Polymer Science and Technology, ICTP-CSIC, Madrid, Spain Ana Mora-Boza  Institute of Polymer Science and Technology (ICTP-CSIC); Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain Ravin Narain  Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, AB, Canada L. Oriol  ICMA, CSIC-Universidad de Zaragoza, Zaragoza, Spain R. Palao-Suay  Institute of Polymer Science and Technology (ICTP-CSIC), Spain and Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Málaga, Spain M. Piñol  ICMA, CSIC-Universidad de Zaragoza, Zaragoza, Spain José A. Reglero Ruiz  Polymer Research Group, Organic Chemistry Department, Faculty of Sciences, University of Burgos, Burgos, Spain Rui L. Reis  3B’s Research Group—Biomaterials, Biodegradables and Biomimetics, University of Minho, Guimarães; ICVS/3B’s, PT Government Associated Laboratory, Braga/Guimarães, Portugal Felisa Reyes-Ortega  Institute of Polymer Science and Technology (ICTP-CSIC); Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain G. Rodríguez-Escalona  Polymer Therapeutics Lab., Prince Felipe Research Center, Valencia, Spain Julio San Román  Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTPCSIC); Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain Ana Sanchez-Sanchez  Department of Engineering, Electrical Engineering Division, University of Cambridge, Cambridge, United Kingdom C. Sánchez-Somolinos  ICMA, CSIC-Universidad de Zaragoza, Zaragoza, Spain Ana M. Sanjuán  Polymer Research Group, Organic Chemistry Department, Faculty of Sciences, University of Burgos, Burgos, Spain I.N. Savina  University of Brighton, Brighton, United Kingdom Shruti Srinivas  Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, AB, Canada M. Talelli  Polymer Therapeutics Lab., Prince Felipe Research Center, Valencia, Spain

xiv CONTRIBUTORS Leticia Valencia  Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid (UC3M), Getafe, Spain Blanca Vázquez  Institute of Polymer Science and Technology (ICTP-CSIC), Spain and Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Málaga, Spain Diego Velasco  Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid (UC3M), Getafe; Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain M.J. Vicent  Polymer Therapeutics Lab., Prince Felipe Research Center, Valencia, Spain X. Xiong  INM—Leibniz Institute for New Materials, Saarbrücken, Germany

C H A P T E R

1

Introduction to Smart Polymers and Their Applications María Rosa Aguilar⁎,†, Julio San Román⁎,† ⁎

Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, (ICTP-CSIC), Madrid, Spain, †Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain Living systems respond to environmental conditions to accommodate their structure and functionality to variations in nature via the action of complex sensing mechanisms, actuating and regulating functions, and feedback control systems. Therefore, nature can be considered the best example a scientist can have in mind when developing new materials and applications; the overall challenge is to create materials with dynamic and tunable properties that mimic the active microenvironment that occurs in nature. Smart polymers or stimuli-responsive polymers undergo reversible, large, physical or chemical changes in their properties as a consequence of small environmental variations. They can respond to a single or multiple stimuli such as temperature, pH, electric or magnetic fields, light intensity, biological molecules, etc. that induce macroscopic responses in the material, such as swelling, collapse, or solution-to-gel transitions, depending on the physical state of the chains (Aguilar et al., 2007). Linear and solubilized smart macromolecules will pass from monophasic to biphasic near the transition conditions giving rise to reversible sol-gel states. Smart cross-linked networks undergo chain reorganization at transition conditions where the network passes from a collapsed to an expanded state. Smart surfaces change its hydrophilicity as a function of a stimulus providing responsive interfaces. All these changes can be used in the design of smart devices for multiple applications, for example, minimally invasive injectable systems (Nguyen and Lee, 2010), pulsatile drug delivery systems (Tran et al., 2013; Arora et al., 2011), or new substrates for cell cultures or tissue engineering (Duarte et al., 2011).

Smart Polymers and Their Applications https://doi.org/10.1016/B978-0-08-102416-4.00001-6

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© 2019 Elsevier Ltd. All rights reserved.

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1.  Introduction to Smart Polymers and Their Applications

Moreover, most polymers can be easily functionalized by prepolymerization (Guillerm et al., 2012) or postpolymerization (Arnold et al., 2012) methods incorporating functional molecules to the structure, such as biological receptors (Shakya et al., 2010). Therefore, polymer scientists have a wide range of possibilities in terms of polymer chemical structures, polymer architectures, and polymer modifications to develop an infinite number of applications with these smart materials (Stuart et al., 2010). The aim of this new edition of Smart Polymers and Their Applications is not only to guide the reader through the state-of-the-art in this area but also shed some light on future research directions in this research field. The first part of the book (Chapters 2 to 11) gives the reader a wide overview about different stimuli-responsive polymers. Temperature, pH, light intensity, conductive and electroactive-responsive polymers, metabolite and enzyme-responsive polymers, and inflammation-responsive polymers are described. Moreover, due to their actual and future applications, special attention was paid to smart protein fibers, smart hydrogels, and self-healing polymers.

1.1  TYPES OF SMART POLYMERS Temperature-sensitive polymers present low critical solution temperature (LCST) or upper critical solution temperature (UCST) depending on their transition behavior from monophasic to biphasic when temperature is raised or, on the contrary, from biphasic to monophasic when temperature is raised, respectively. LSCT polymers have been widely investigated, whereas UCST polymers are quite rare. Most common LCST polymers are the poly(N-substituted acrylamide), poly(vinyl amide), and poly(oligoethylene glycol (meth)acrylate) families. However, many other polymers can present LCST if the proper hydrophilic-hydrophobic balance is present in the macromolecules. Poly(vinyl ether)s (Aoshima and Kanaoka, 2008), poly(2-oxazoline)s (Guillerm et al., 2012), and poly(phosphoester)s (Wang et al., 2009) also present temperature-responsive behavior and are specifically described in Chapter  2. Moreover, the three main classes of T-responsive polymers are also reviewed, that is, shape-memory materials (Löwenberg et al., 2017), liquid-crystaline materials (Ober and Weiss, 1990), and responsive polymer solutions (Hoffman, 2013). Polymers that respond to temperature changes and, more specifically, those that undergo a phase transition in water solution are gaining special attention due to their potential applications in the biomaterials field (Bajpai et al., 2010), architecture (Yang et  al., 2013; Rotzetter et  al., 2012), or water-­recovery strategies (Yang et al., 2013), among others. pH-sensitive polymers bear weak polyacidic (poly(acrylic acids) or poly(methacrylic acids)) or polybasic (poly(N-dimethylaminoethyl ­



1.1  Types of Smart Polymers

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methacrylate), poly(N-diethylaminoethyl methacrylate), or poly(ethyl pyrrolidine methacrylate)) moieties in their structure that protonate or deprotonate as a function of the surrounding pH. Personal care, biomedical field (Yu et al., 2017), industrial processes (Kan et al., 2013), and water remediation (Wang et al., 2016) are some of the multiple areas of application described for this kind of smart polymer. Photosensitive polymers undergo a reversible or irreversible change in conformation, polarity, amphiphilicity, charge, optical chirality, or conjugation in response to a light stimulus. Reversible chromophores or reversible molecular switches (e.g., azobenzenes, spiropyran, diaryl ethane, or coumarin) undergo a reversible isomerization upon light irradiation (Wang and Wang, 2013) whereas irreversible chromophores are cleaved from the polymer chain upon light exposure (e.g., ο-nitrobenzyl photolabile protecting group) or induced reactivity resulting in the coupling of two species (e.g., 2-naphtoquinone-3-methides). Both molecular switches and irreversible chromophores have been applied in multiple applications such as drug delivery systems, functional micropatterns, responsive hydrogels, photodegradable materials, or photoswitchable liquid crystalline elastomers for remote actuation (Ohm et al., 2010). Intrinsically conductive polymers are organic polymers that conduct electricity. Chapter  7 focuses on conductive polymers for bioelectronics, that is, the interface between electronics and biology. Poly(3,4-ethylenedioxythiophene) (PEDOT) and its derivatives PEDOT:poly(styrene sulfate) (PEDOT:PSS), PEDOT:biopolymer, and poly(3,4-Propylenedioxythiophene) (ProDOT) and its derivatives are most successful in bioelectronics and have been used as electrodes for electrophysiology, organic chemical transistors (OECTs), organic electronic ionpump (OEIP), electronic textiles, and electronic skin (Simon et al., 2016). Peptides can be rationally designed by chemical or biotechnological procedures to assemble into different shapes (e.g., fibers, spheres, tubes) as a result of specific stimuli. Chapter 9 reviews stimuli-responsive protein fibers for their application as sensors (Liu et al., 1996). Moreover, their bioapplications as a drug and gene delivery system (Yucel et al., 2014), scaffolds for tissue engineering (Li et al., 2006), or wound dressing (Gil et al., 2013) of silk-based fibers are reviewed in depth. Polymer hydrogels play a key role in the development of new biomaterials due to their high levels of hydration and their 3D structure resembles natural tissue. However, despite the superior performance of hydrogels, they present several limitations mainly due to their poor controllability, actuation, and response polymers. Several advances have been made in this sense by the use of smart polymers in the preparation of hydrogels (Ravichandran et  al., 2012). For example, magnetically responsive polymer gels and elastomers are composites based on magnetic nanoparticles dispersed in a high elastic polymeric matrix. Magnetic field quickly deforms

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the polymer matrix without noise, heat evolution, or exhaustion, which make these materials ideal for the preparation of sensors, micromachines, energy transducing devices, controlled delivery systems, or even artificial muscles (Li et al., 2013). One of the limiting steps in the development of these materials has been the precise coupling of magnetic nanoparticles to the gel; however, this problem has been overcome when magnetic nanoparticles form the cross-linking nodes of the hydrogel (Ilg, 2013). Macroscopic transitions of the smart polymers can also be triggered by “biology-to-material” interactions in the so-called biointeractive polymers. These materials incorporate receptors for biomolecules that, when stimulated, cause localized or bulk modifications in the material properties. Those polymers that respond to selective enzyme catalysis are called enzyme responsive polymers. These materials represent an important advance in the integration of artificial materials with biological entities as they link together the polymer properties with specific biological processes naturally controlled by either regulating enzyme expression levels or availability of cofactors (Hu et al., 2012). Enzyme responsive polymers can also display reversible and dynamic responses to a stimulus in the formulation of new biomaterials such as cell supports, injectable scaffolds, or drug delivery systems (De La Rica et al., 2012). Among all the systems that interact with the biological environment, those that respond to a pathological microenvironment and, more specifically, to the inflammatory microenvironment have aroused great interest in the medical community. Inflammation is a fundamental natural defense process during the body’s response to pathogens and in the triggering of tissue repair. However, when uncontrolled, it can be associated with a large number of chronic diseases and also plays a key role in the formation and progression of cancer. One or more of the specific characteristics of inflammation microenvironment, that is, the increased permeability of the blood vessels, upregulation of specific cell surface receptors, reduced pH, high oxidative stress, and overexpression of inflammatory and matrix-remodeling enzymes, have been exploited in the development of inflammation-responsive polymeric systems for more effective treatment of these diseases. These macromolecular systems can be selectively accumulated in the inflammatory area via passive targeting (due to the socalled ELVIS effect) (D'Arcy and Tirelli, 2014); cell-mediated targeting of inflammation-recruited phagocytic cells (e.g., macrophages) (Dong et al., 2017); or direct targeting to specific cell surface receptors overexpressed in the inflammatory areas (Coco et al., 2013). Due to the complexity of the inflammatory microenvironment, dual and multistimuli-responsive polymers have also been described for this application (Daniel et al., 2016). Shape-memory polymers represent one of the most active areas in material science due to their easier processability and lower cost when compared with shape-memory metals or ceramics. These kind of smart polymers



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have the ability to recover their predefined shape (permanent) when stimulated by an external stimulus. A stable network and a reversible switching transition of the polymer are the two prerequisites for shape-memory effect. The stable network is responsible of the original shape and reversible switching transition fixes the temporary shape, which can be crystal­ lization/melting transition, liquid crystal anisotropic/isotropic transition, reversible molecule cross-linking (photodimerization, Deals-Alder reaction, and oxidation/redox reaction of mercapto groups), and supramolecular association/disassociation (hydrogen bonding, self-assembly metal-ligand coordination, and self-assembly of β-cyclodextrin). In addition to the mentioned reversible switches, other stimuli that change chain mobility can also trigger shape-memory effect, such as light, pH, moisture, electric field, magnetic field, pressure, etc. (Pretsch, 2010). Shape-memory polymers allow large recoverable strains; however, they normally present low mechanical properties and do not support great shape-recovery stresses. Therefore, great efforts are being made in the development of shape-memory composites with reinforced properties. Shape-memory polymers present numerous actual and potential applications in medicine, aerospace, textiles, engineering, microfluidics, lithography, and household products (Meng and Li, 2013). Self-healing or restoration of lost functionalities without external help is a dream come true when talking about self-healing polymers (Aïssa et  al., 2012). Extrinsic (the healing compound is isolated from the polymer matrix in capsules, fibers, or nanocarriers) or intrinsic (the polymer chains temporarily increase mobility and flow to the damaged area) healing mechanisms (Billiet et  al., 2013) are responsible for property restoration, such as structural integrity (White et al., 2001), surface aesthetics (Yao et al., 2011), electrical conductivity (Tee et al., 2012), hydrophobicity and hydrophilicity (Ionov and Synytska, 2012), and mechanical properties (Jones et al., 2013).

1.2  APPLICATIONS OF SMART POLYMERS The second part of the book (Chapters 12 to 18) compile relevant applications of smart polymers and their future trends according to the opinion of well-known researchers in the field. Most important developments were registered in the biomedical field by the use of smart polymers in the development of new therapies for the treatment of several diseases or sophisticated medical devices that react to the environment of the surrounding tissues (pH, temperature, enzymes, or analytes concentration) or external stimuli (light or magnetic radiation). Responsive polymeric substrates or instructive substrates regulate cell behavior in response to external factors and are of high importance in

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t­issue engineering applications (Pérez et  al., 2013). Cell behavior (adhesion, migration, and proliferation) is conditioned to substrate surface properties (Alves et al., 2010). Tunable surface properties such as stiffness and wettability, surface functionalization with bioactive molecules, or the design of 3D patterns at the micro- or nanoscale in hydrogels are interesting strategies actually being developed to obtain specific cell response to smart surfaces for tissue engineering applications, e.g., cell sheet engineering (Haraguchi et  al., 2012), smart biomineralization (Huang et  al., 2008), heart valve and vascular graft tissue engineering (Fioretta et  al., 2012), drug delivery (Moroni et al., 2008), cell recruitment (Custódio et al., 2012), or the development of new and more effective medical devices. Temperature-sensitive polymers and more specifically shape-memory polymers have been used in the preparation of minimally invasive surgery medical devices (Yakacki and Gall, 2010). The unique properties of these materials allow the introduction of the medical device in a compressed form that expands once located in the desired place by minimally invasive surgery procedures. One of the most relevant applications using this kind of polymer is the development of stents for either vascular or urologic procedures. Polymeric stents are considered a promising option compared to the conventional metallic stents not only due to their mechanical properties but also the possibility of incorporating a drug to be eluted in the functional place [e.g., to reduce restenosis and/or thrombosis after implantation in vascular stents or to minimize infections in urinary stents (Xue et al., 2012)]. Smart polymers have played a key role in the fabrication of new medical devices for cancer diagnosis and therapy. In this sense, magnetic nanoparticles have been used in the development of hyperthermia treatments, magnetic separation, immunoassay, cellular labeling, and magnetic resonance imaging diagnosis (Karimi et  al., 2013). Biosensors based on smart polymers have been used in clinical diagnosis and forensic analysis because alterations in the concentration of certain analytes [e.g., glucose in diabetes (Thammakhet et al., 2011)] or in physical variables such as temperature or pH [e.g., pH sensor for the quantification of partial pressure of CO2 in the stomach for the diagnosis of gastrointestinal ischemia (Herber et al., 2005)] occur in several diseases. Biosensors and actuators have been also combined in unique medical devices, for example, glucose-sensing and insulin-delivery medical devices (Brahim et al., 2002) or cochlear implants (Laursen, 2006). Microfluidics-based medical devices or “Lab on a Chip” also combine biosensors to detect systemic levels of certain analytes and actuators to release bioactive components in response to excessive or insufficient concentrations of these analytes (Do et al., 2008). Smart polymer nanocarriers for drug delivery applications play an important role in the development of highly active and selective treatments,



1.2  Applications of Smart Polymers

7

­ ermitting a controlled delivery of the drug in the right place at the right p moment (Fleige et  al., 2012). Better knowledge of the molecular biology and synthesis of new polymers with stimulus-sensitive moieties have given rise to more effective, specifically localized action and personalized therapies. This is the case for human neutrophil elastase degradable links that will be specifically degraded at inflammation sites where neutrophils act (Fleige et al., 2012; Aimetti et al., 2009) or cathepsin B-sensitive polyglutamates that will be better degraded in women than in men because the activity of lysosomal cysteine protease cathepsin B enzyme closely correlates with estrogen levels (Lammers et al., 2012). Smart polymers have also been used for bioseparation and other biotechnological applications such as purification techniques (Galaev et al., 2007). New smart polymers have benefited from progress in affinity precipitation (Gautam et al., 2012), aqueous polymer two-phase partitioning (Qu et  al., 2010), controlled permeation membranes (Wang and Chen, 2007), thermosensitive chromatography (Kanno et al., 2011), and modulation of catalytic processes (Zhang et al., 2010). Information and communication technologies, more specifically data storage devices, have improved amazingly in the last several years due to the fabrication of new smart materials. In this way, volume holographic storage will give rise to the next generation of data storage devices due to their much higher storage capacity and much higher transfer rate compared with actual 2D optical discs (Garan, 2013). In this sense, azobenzene chromophores stand by its capacity to induce optical anisotropy when incorporated in photoaddressable polymeric materials (Shishido, 2010). Smart polymers are also employed in the detection and quantification of specific ions and molecules by highly sensitive sensors for multiple applications, such as gas detection (Xue et al., 2013), heavy metal cations quantification (Tokuyama et al., 2016), and biological molecule detection (Shrivastava et  al., 2016). Conductive polymers, polymers with chiral motifs, molecularly imprinted polymers, and polymeric nanocomposites have been described with this purpose. Environmental purposes and more specifically climate change is moving the scientific community to develop more efficient rechargeable batteries for the electrification of the grid and automotive transportation. The polymeric binder is a key part of these batteries that provide mechanical stability to the electrode. Chapter 18 reviews the new strategies carried out to obtain advanced polymeric binders with hierarchical structures (Ling et  al., 2015), high elasticity (Wang et  al., 2017), and self-healing properties (Wang et al., 2013) to improve the cohesion between the active particles and buffer the dimensional changes occurring during the charge/ discharge process.

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1.3 CONCLUSIONS Multidisciplinary research involving scientists of very different disciplines will be required to make future advances in smart polymers and their application. Organic chemists, polymer chemists, material engineers, physicists, biologists, pharmacists, and medical doctors will have to work together in a very close and fluid manner to respond to the necessities of society in developing new materials that improve the quality of life not only from a medical point of view but also for the architectural, food industry, data storage, and energy storage fields.

Acknowledgment The authors greatly acknowledge the financial support from MAT2017-84277-R project.

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C H A P T E R

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Temperature-Responsive Polymers: Properties, Synthesis, and Applications Richard Hoogenboom Supramolecular Chemistry group, Centre of Macromolecular Chemistry (CMaC), Department of Organic Chemistry, Ghent University, Ghent, Belgium

2.1  INTRODUCTION: THE ROLE OF TEMPERATURE-RESPONSIVE POLYMERS Smart materials that respond with a property change to a change in the environmental conditions are an attractive class of materials for advanced applications. Responsive and adaptive materials are also omnipresent in natural systems. Examples include the focusing of the eye, the opening and closing of pores, as well as wound healing (Stryer, 1999). The majority of such natural responsive and adaptive processes are driven by conformational changes and/or aggregation of proteins, which can be regarded as nature's smart polymers. Similarly, responsive synthetic polymers are attractive building blocks for the development of artificial smart materials. A wide variety of responsive polymer materials have been reported that respond to various external parameters, such as temperature, pH, mechanical stress, and even certain molecules, including CO2 and sugars (see Roy et al., 2010; Wei et al., 2017 for recent reviews). The response of the polymer can also be manifold, such as a change in shape, color, or solubility. Temperature-responsive polymers are especially interesting because variations in temperature can be applied externally in a noninvasive manner. Furthermore, spontaneous temperature fluctuations also occur in nature, for example, during day and night cycles as well as the increased temperature of inflamed tissue.

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Different working mechanisms can be exploited for the development of temperature-responsive polymers as will be briefly outlined in this introductory paragraph. The three main classes of temperature-responsive polymers are: 1. Shape-memory materials 2. Liquid crystalline materials 3. Responsive polymer solutions Shape-memory materials are thermoplastic elastomers consisting of a hard phase with a high glass transition temperature (Tg; Tg,1 in Fig. 2.1) and a second switching phase with intermediate Tg,2 or melting temperature that enables the temperature-responsive behavior (Lendlein and Kelch, 2002; Liu et al., 2007; Wang et al., 2017). Such shape-memory materials can be deformed in any shape when heating above the highest Tg ­resulting in the permanent shape. When these materials are subsequently deformed between the two transition temperatures, a temporary shape can be induced, which can be frozen in by cooling the deformed state below the switching temperature. This shape-memory material will transform back to the permanent shape when heated above the switching temperature (Fig.  2.1). As such, these materials are thermoresponsive, but they have to be “reprogrammed” after each switching cycle. By introducing multiple intermediate temperature transitions, the number of programmable shape changes can be increased, and it has been demonstrated that four independent states can be programmed into a shape-memory material having one broad Tg (Xie, 2010). A very recent example reported a shape-memory photonic material based on a liquid crystalline polymer network that displays a broad range of stable colors between blue and orange (Moirangthem et al., 2017). Liquid crystalline polymers have a liquid crystalline phase in addition to the glassy state and the isotropic rubbery phase (Weiss and Ober, 1990;

FIG. 2.1  Schematic representation of the thermoresponsive behavior of a shape-memory polymer. Tg,1 represents the Tg of the hard phase, and Tg,2 represents the Tg of the switching phase.



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Donald et al., 2005). This liquid crystalline phase has a certain anisotropic order of the mesogens present in the polymer. It has been reported that polymers with main-chain nematic liquid crystalline blocks have an elongated main chain in the liquid crystalline phase that contracts to a random coil state when heated to the isotropic phase, which is a fully reversible polymer phase transition that has been utilized as a main switching mechanism for developing artificial muscles (Fig. 2.2; Li and Keller, 2006). Up to 40% contraction has been demonstrated for such materials upon heating. Polymeric networks with side-chain mesogens have also been developed having a chiral nematic liquid crystalline phase as is also used in LCD screens. Such side-chain liquid crystalline polymer networks have been utilized, for example, for the development of thermochromic materials (Sage, 2011). The third and most widely studied type of thermoresponsive polymers are polymers that undergo a solution liquid-liquid phase transition in response to variation of the temperature, that is, phase separation occurs from a homogeneous solution into a concentrated polymer phase and a diluted polymer phase. This phase transition is often accompanied by a transition from a clear solution to a cloudy solution—the corresponding phase transition temperature is also known as the cloud point temperature (TCP)—for low concentration polymer solutions due to the formation of (nano) droplets of the high concentration polymer solution in combination with the difference in refractive index between the two phases. When the phase separation occurs upon heating, this is referred to as a lower critical solution temperature (LCST) transition, whereas the

FIG.  2.2  (A) Change in conformations of main-chain LC polymers from the extended nematic phase to a collapsed isotropic phase upon heating. (B) Corresponding macroscopic shape change during this nematic-isotropic phase transition.

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reversed phase behavior is known as an upper critical solution temperature (UCST) transition. Early examples of LCST and UCST behavior of polymers has been reported in organic solvents, such as the UCST transition of poly(styrene) in cyclohexane (Schultz and Flory, 1952) and the LCST transition of poly(methyl methacrylate) PMMA in 2-propanone (Cowie and McEwen, 1976). Most interesting, however, are thermoresponsive polymer phase transitions in aqueous solutions because this provides high potential for biomedical applications, such as drug delivery and switchable synthetic cell culture surfaces (De las Heras Alercon et al., 2005; Schmaljohann, 2006; Ward and Theoni, 2011; Hoffman, 2013). The remainder of this chapter will focus on such temperature-responsive polymers in aqueous solution by discussing basic principles (Section  2.2), key types of temperature-responsive polymers (Section 2.3), as well as selected applications (Section 2.4).

2.2  BASIC PRINCIPLES OF TEMPERATURERESPONSIVE POLYMERS IN AQUEOUS SOLUTION The different types of polymer phase transitions that can occur in aqueous solutions of homopolymers are schematically depicted in Fig.  2.3, namely a LCST transition, an UCST transition or closed loop coexistence of LCST, and UCST transitions. These schematically drawn bimodal or coexistence curves represent the equilibrium concentration of the two phases in the phase separated state. The LCST is defined as the lowest temperature of this binodal curve (Fig. 2.3, left), whereas the UCST is defined as the highest temperature of this binodal curve (Fig.  2.3, middle). Closed loop coexistence has also been reported for a small number of polymers that have coinciding LCST and UCST phase behavior (Fig. 2.3, right). The most prominent example of a polymer with such closed loop coexistence is poly(ethylene glycol), albeit both LCST and UCST transitions only occur when heated far beyond the boiling point of water in closed vessels (Saeke et  al., 1976). Other polymers exhibiting closed loop coexistence phase

FIG.  2.3  Schematic representation of the polymer phase diagrams (bimodal or coexistence curves) for polymers exhibiting LCST behavior (left), UCST behavior (middle), and closed-loop coexistence (right).



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­ ehavior include partially acetylated poly(vinyl alcohol) (Nord et al., 1951) b and poly(hydroxyethyl methacrylate) (Longenecker et al., 2011). Besides these three types of polymer phase diagrams, there are also few examples of polymers that show a low temperature UCST transition and a high temperature LCST transition (not shown in Fig. 2.3), including poly(vinyl methyl ether) (Van Assche et al., 2011) and mixtures of poly(dimethylaminoethyl methacrylate) with a trivalent [Co(CN)6]3− anion (Plamper et al., 2007; Zhang et al., 2015a). The majority of recent reports on thermoresponsive polymers evaluate the phase transition temperature at a certain polymer concentration by turbidity measurements, that is, light scattering of a polymer solution at 500–700 nm as a function of temperature. It is important to note that the thus-obtained transition temperature is the TCP, whereby concentration should be specified, and not the LCST. Furthermore, one should be aware of potential kinetic effects during turbidimetry resulting in a kinetic phase diagram at a certain heating or cooling rate rather than an equilibrium phase diagram, as we recently reported for the LCST transition of a comb-shaped poly(oligo[2-ethyl-2-oxazoline]methacrylate) (Fig.  2.4; Weber et al., 2013). To enable comparison of TCP values reported by different laboratories and to minimize experimental errors, we recently recommended measuring TCP by turbidimetry using 10 mg mL−1 with heating and cooling rates of 0.5°C min−1 at a scattering wavelength of 600 nm that proved to be the most robust settings (Zhang et al., 2017). 95 CP curve

90 85 T [°C]

Coexistence curve 80 75 70 65

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30

40

50

60

c [wt%]

FIG. 2.4  Cloud point temperature (CP, squares; determined at 1 K min−1) and coexistence (dots; determined by refractive index of the low and high polymer concentration phases after 24 h equilibration) curves obtained for a binary mixture of a comb-shaped poly(oligo[2-ethyl-2-oxazoline] methacrylate) in water. The coexistence curve is fitted to guide the eye. Reproduced with permission from Weber, C., Rogers, S., Vollrath, A., Hoeppener, S., Rudolph, T., Fritz, N., Hoogenboom, R., Schubert, U.S., 2013. Aqueous solution behavior of comb-shaped poly(2-ethyl-2-oxazoline). J. Polym. Sci. Part A: Polym. Chem. 51, 139–148. https://doi.org/10.1002/pola.26332).

18

2.  TEMPERATURE-RESPONSIVE POLYMERS

The basic underlying mechanisms for LCST and UCST polymer phase transitions in aqueous solution will be discussed in the following paragraphs.

2.2.1  Polymers With LCST Behavior Polymers that undergo a LCST phase transition in water are soluble in water at low temperatures and phase separate upon increasing the temperature. From a thermodynamic point of view, this means that the Gibbs free energy (ΔG = ΔH − TΔS) of dissolving the polymer in water is negative at lower temperatures, and it becomes positive upon increasing the temperature. Such behavior is only possible if the enthalpy of dissolution (ΔH) is negative; favorable hydrogen bonding between water molecules and the polymer chains (hydration) and the entropy contribution (ΔS) is negative too, that is, water loses entropy when it is hydrated to the polymer chains. Upon increasing the temperature, the enthalpic hydrogen bonding interaction will become less, but more importantly the entropy term (−TΔS) will become dominant leading to a positive Gibbs free energy of mixing, thus, leading to phase separation. In other words, at elevated temperatures, the hydrated water molecules will go back to the bulk water leaving behind partially dehydrated polymer chains that will collapse and aggregate into a polymer-rich phase. It should be emphasized that there is never a complete dehydration of the polymer during the LCST phase transition, and the degree of dehydration of the polymer chains is strongly connected to the hydrophilicity of the polymer; the more hydrophilic the polymer, the more water is retained in the collapsed polymer globules. The LCST phase transition is a fully reversible cooperative (de)hydration process providing access to sharp reversible temperature-induced polymer phase transitions. In theory, all water-soluble polymers should undergo such an LCST phase transition in water, but in practice the phase transition cannot always be observed, especially not in water at ambient pressure, and superheating of the solution might be required as is the case for poly(ethylene glycol) (Saeke et al., 1976). In general, the LCST or TCP strongly depends on the polymer structure. As a general rule of thumb, it can be stated that better hydrated polymers have a higher TCP than less hydrated polymers. As such, increasing the molecular weight of a polymer, which decreases its hydration due to enhanced polymer-polymer interactions, will lead to a lower TCP. Furthermore, introducing hydrophilic end-groups or more hydrophilic (co)monomers will increase the TCP.

2.2.2  Polymers With UCST Behavior The thermodynamic effects of polymer hydration upon dissolution are the same for all polymers and, thus, both ΔH and ΔS for hydration are



2.2  BASIC PRINCIPLES OF TEMPERATURE-RESPONSIVE POLYMERS

19

negative, in principle leading to LCST behavior, vide supra (Section 2.2.1). However, to obtain and understand UCST behavior, another enthalpic term has to be introduced in the Gibbs free energy equation, namely ΔH for supramolecular association of the polymer chains. If the polymer chains have strong associative interactions that have to be broken upon polymer dissolution, this can render the polymer insoluble if this loss in energy is larger than the gain in energy upon dissolution. However, the supramolecular associative interaction strength decreases with increasing temperature, leading to the hydration term becoming dominant and, thus, leading to dissolution of the polymer. The polymer, however, should itself be very hydrophilic to avoid its potential LCST transition is lower than the UCST transition, which would lead to complete insolubility. An important difference between LCST and UCST transitions is that the LCST transition is a cooperative entropy-driven process whereas the UCST transition is an enthalpic process leading to a much shallower transition as has been demonstrated by the incorporation of pyrene as probe for the phase transition (Pietsch et al., 2010a,b). As the UCST phase transition in water is based on associative interactions, the dependency of the transition temperature will be directly correlated to the strength of the supramolecular interactions. This may lead to counterintuitive effects, such as increased transition temperatures upon incorporation of hydrophobic side chains. Even though hydrophobic side chains decrease the solubility of a polymer and would lower a LCST transition, they can also create a hydrophobic environment for associative hydrogen bonding interactions. This hydrophobic environment enhances hydrogen bonding strength leading to a higher UCST transition temperature (Seuring and Agarwal, 2012a). This basic description of UCST behavior in water based on polymer­polymer interactions does not explain the UCST transition of, for example, poly(ethylene oxide) at temperatures beyond the boiling point of water under pressurized conditions. Instead, this UCST transition of poly(ethylene oxide) in superheated water is not related to a major change in polymer properties or polymer association but rather to a change in solvent properties, that is, under superheated conditions, the polarity of water decreases making it a better solvent for poly(ethylene oxide), which leads to dissolution of the precipitated polymer chains. A similar change in solvent properties, that is, a decrease in polarity upon heating, occurs in a wide variety of alcohol-water mixtures based on the nonideal mixing behavior of such solvent combinations (Franks and Ives, 1966). Based on this phenomenon, a variety of polymers, including poly(methyl methacrylate) and poly(2-oxazoline)s, have been reported to undergo UCST phase transitions in alcohol-water mixtures in a temperature range from 0°C to 100°C (Piccarolo and Titomanlio, 1982; Lambermont-Thijs et al., 2010; Zhang and Hoogenboom, 2015b).

20

2.  TEMPERATURE-RESPONSIVE POLYMERS

2.3  KEY TYPES OF TEMPERATURE-RESPONSIVE POLYMERS IN AQUEOUS SOLUTION A wide variety of polymers are known to exhibit thermoresponsive behaviors in aqueous solution as covered in excellent recent reviews on LCST polymers (Liu et  al., 2009; Roy et  al., 2013) and UCST polymers (Seuring and Agarwal, 2012a; Zhang and Hoogenboom, 2015b; Niskanen and Tenhu, 2017). In general, all water-soluble polymers exhibit LCST behavior in water as the enthalpy of hydration becomes less and the loss of entropy for hydrating water molecules increases with increasing temperature. However, not all polymers exhibit LCST behavior in water at ambient pressure, that is, between 0°C and 100°C. Therefore, a subtle balance of hydrophilic and hydrophobic groups needs to be present in the polymer structure. Frequently observed hydrophilic moieties are amides and ethers, whereas short aliphatic groups constitute the majority of hydrophobic moieties. In this section, a noncomprehensive overview will be given of the most important types of LCST polymers (Sections 2.3.1–2.3.3) and UCST polymers (Section 2.3.4). In addition, the main synthetic procedures for the synthesis of these polymers will briefly be addressed.

2.3.1  Poly(Acrylamide)s and Poly(Vinyl Amide)s The most commonly studied and first reported thermoresponsive polymer in aqueous solution is poly(N-isopropylacrylamide) (PNIPAM; Fig. 2.5) (Scarpa et al., 1967; Schild, 1992; Aseyev et al., 2006; Aoshima and Kanaoka, 2008; Halperin et  al., 2015). The popularity of PNIPAM is not only based on the LCST that lays between body and room temperature (LCST ~32°C) making it very interesting for biomedical applications but also on the robust phase behavior. The position of the LCST of PNIPAM with regard to polymer concentration does not strongly shift with variations in chain length. Furthermore, small variations in polymer concentration and solution pH do not induce strong changes in TCP. Shortly after this first report on the LCST behavior of PNIPAM, the LCST behavior of poly(N-vinyl caprolactam) (PVCL, Fig. 2.5) was reported to be ~31°C

O

NH

PNIPAM

N

O

PVCL

FIG. 2.5  Structures of poly(N-isopropylacrylamide) (PNIPAM) and poly(N-vinyl caprolactam) (PVCL).

2.3  Key Types of Temperature-Responsive Polymers in Aqueous Solution

21

(Solomon et al., 1968; Kirsh, 1993; Aseyev et al., 2006). Furthermore, both PNIPAM and PVCL have been reported to be similarly biocompatible making them ideal candidates for biomedical applications (Vihola et al., 2005). With regard to the very similar properties of both polymers, it is quite surprising that PNIPAM is considered to be the gold standard of thermoresponsive polymers, especially for biomedical applications, and that PVCL has never reached or even come close to such status. Both PNIPAM and PVCL also share a common drawback for use in biomedical applications and that is their very high glass transition temperatures (Tg ~ 140–150°C), which has been reported to lead to vitrification of the high concentrated polymer phase during phase separation, potentially inducing hysteresis between the heating and cooling transitions (Meeussen et al., 2000; Van Durme et al., 2004). The polymerization of both the N-isopropylacrylamide (NIPAM) and N-vinylcaprolactam (VCL) monomers can be achieved by free radical polymerization of the vinyl group using a common radical initiator, such as azobisisobutyronitrile. Also in recent years, the controlled radical polymerization (CRP) of both monomers has been developed, resulting in polymers with controlled chain length, narrow molecular weight distribution, and defined end-groups. Such defined polymers are a prerequisite for biomedical applications, whereas the control over end-groups enables straightforward modification and conjugation toward biological species. In this regard, it is important to note that the vinyl group of NIPAM is activated by the amide group whereas the vinyl group in VCL is much less activated due to reversal of the amide moiety. As a result, the choice and optimization of CRP method will be quite different for both monomers as exemplified on the basis of reversible-addition fragmentation chain-­ transfer (RAFT) polymerization. The RAFT polymerization of NIPAM can be best performed with RAFT agents comprising dithiobenzoate or trithiocarbonate groups, whereas the RAFT polymerization of vinyl amides, including VCL, does not go well with these RAFT agents but works best with xanthates as a RAFT agent (Lowe and McCormick, 2007; Nakabayashi and More, 2013). Finally, anionic polymerization methods can be used for the direct polymerization of VCL as well as for the polymerization of protected NIPAM derivatives (Ishizone and Ito, 2002). The versatility of the radical polymerization mechanism of NIPAM and VCL provides straightforward access to a wide range of copolymers based on the large variety of commercially available vinyl monomers. As such, the TCP of PNIPAM and VCL can easily be controlled and tuned by the preparation of statistical copolymers with inert comonomers having higher or lower hydrophilicity to increase or decrease the TCP, respectively (Schild, 1992; Dimitrov et al., 2007). Furthermore, switchable comonomers can be introduced resulting in the formation of multistimuli-responsive copolymers. Examples of such multiresponsive polymers include pH-­responsive

22

2.  TEMPERATURE-RESPONSIVE POLYMERS

materials based on the incorporation of pH-switchable side chains, such as tertiary amines or carboxylic acids, and UV-responsive materials based on the incorporation of UV-switchable side groups, such as azobenzene or spiropyran moieties (Dimitrov et al., 2007; Roy et al., 2010, 2013). Of course, the temperature-responsive behavior of poly(acrylamide)s and poly(vinyl amide)s is not limited to the exact structures of PNIPAM and PVCL, and also analogue polymer structures have been reported to undergo temperature-induced phase separation upon heating in aqueous solution, such as poly(N-cyclopropylacrylamide) (Kuramoto and Shishido, 1998), poly(N,N-diethylacrylamide) (Lessard et  al., 2001), poly(N-vinyl piperidone) (Ieong et al., 2011), and various substituted poly(N-vinyl pyrrolidone)s (Yan et al., 2010).

2.3.2  Poly(Oligo Ethylene Glycol [Meth]acrylate)s Despite the beneficial properties of PNIPAM, there has been an ongoing search for alternative LCST polymers with further improved properties, especially with regard to (1) lowering the Tg to avoid formation of a glassy polymer phase and suppressing the occurrence of hysteresis, and (2) easier synthesis by CRP because, in practice, CRP of NIPAM can be cumbersome. The most studied class of alternatives to PNIPAM in recent years are the poly(oligo ethylene glycol [meth]acrylate)s (POEGMA) consisting of a poly(meth)acrylate backbone decorated with oligo ethylene glycol side chains (Lutz, 2008; Weber et al., 2012; Vancoillie et al., 2014). The thermoresponsive behavior of such POEGMAs, prepared by living anionic polymerization, was first reported in 2003 demonstrating the tunability of the TCP by variation of the number of ethylene glycol repeat units and, more recently, also by systematical variation of the oligo ethylene glycol chain end functionality (Fig. 2.6; Han et al., 2003; Ishizone et al., 2008). In 2006, Lutz and coworkers reported the versatility of the CRP of OEGMAs using atom transfer radical polymerization (ATRP) not only for their homopolymerization but especially for their copolymerization (Lutz and Hoth, 2006a). The copolymerization of OEGMA monomers with short and long oligo ethylene glycol side chains, that is, corresponding to POEGMA homopolymers with low and high TCP, respectively, allows accurate fine-tuning of the TCP of the copolymers between the two extremes. A detailed comparison of such POEGMAs and PNIPAM revealed that both polymers have very similar thermoresponsive behavior with regard to salt, molecular weight, and concentration dependence of the TCP (Lutz et al., 2006b). However, the POEGMA does not show significant hysteresis between the heating and cooling cycles, whereas PNIPAM does show such hysteresis, ascribed to the high Tg (Fig. 2.7), vide supra. This groundbreaking work, in combination with the commercial availability of the

2.3  Key Types of Temperature-Responsive Polymers in Aqueous Solution

100

23

CH3 CH2 C

n COO

Tc (°C)

80

O

R

m

68°C

R = CH3

60

52°C 37°C

40

42°C

26°C

27°C

20

0

15°C R = CH2CH3 4°C 1

2

4

3

5

Number of oligo(ethylene glycol) unit (m)

FIG. 2.6  Variation of cloud point temperature (Tc) of poly(oligo ethylene glycol methac­

Transmittance (%)

rylate)s as a function of the number of oligo(ethylene oxide) unit (m) and end-group functionality. Reproduced with permission from ACS. Ishizone, T., Seki, A., Hagiwara, M., Han, S., 2008. Anionic polymerizations of oligo(ethylene glycol) alkyl ether methacrylates: effect of side chain length and ω-alkyl group of side chain on cloud point in water. Macromolecules 41, 2963–2967. https:// doi.org/10.1021/ma702828n.

100

100

80

80

60

60

40

40

20

20

0

0

(A)

25

30

35

40

(B)

25

30

35

40

Temperature (°C)

FIG. 2.7  Transmittance plotted versus temperature during heating (solid lines) and cooling (dotted lines) of aqueous solutions of POEGMA (A) and PNIPAM (B). Reproduced with permission from the ACS. Lutz, J.-F., Akdemir, O., Hoth, A., 2006b. Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: is the age of poly(NIPAM) over? J. Am. Chem. Soc., 128, 13046–13047. https://doi.org/10.1021/ja065324n.

24

2.  TEMPERATURE-RESPONSIVE POLYMERS

PMA monomers and straightforward CRP, made these POEGMAs very popular thermoresponsive polymers, which nowadays strongly compete with PNIPAM (Lutz, 2008, 2011; Weber et al., 2012). Similar to the poly(acrylamide)s and poly(vinyl amide)s, POEGMA can be prepared by free radical polymerization, CRP, and anionic polymerization, whereby the latter two methods result in well-defined polymer structures with defined end-groups. Even though CRP of OEGMA can be performed by ATRP and RAFT polymerization (Lutz and Hoth, 2006a; Becer et al., 2008), the methacrylate obstructs OEGMA homopolymerization by nitroxide-mediated polymerization. This can, however, be overcome by copolymerization with a minor amount of styrenic comonomer that enables good control over the polymerization (Charleux et al., 2005; Lessard et al., 2012). A related class of thermoresponsive LCST polymers are the POEGAs in which the polymethacrylate polymer backbone is replaced by a polyacrylate backbone. The latter is more flexible and less hydrophobic resulting in a TCP that is ~20°C higher when keeping the oligo ethylene glycol side chain length and chain end functionality the same, for example, the TCP of poly(diethylene glycol methyl ether methacrylate) (PmDEGMA) is ~25°C whereas the TCP of poly(diethylene glycol methyl ether acrylate) (PmDEGA) is ~45°C. In recent years, POEGAs are gaining significant interest due to their polymerizability with anionic polymerization, ATRP, RAFT, and NMP (Skrabania et al., 2007; Lessard and Maric, 2008). However, the “early” reports on thermoresponsive POEGAs are based on the copolymerization of a defined OEGA monomer with a larger OEGA comonomer having a side chain length distribution. Only recently, the full potential of OEGA monomers for the preparation of defined thermoresponsive polymers was unveiled by the copolymerization of very similar defined monomers, such as 2-methoxyethyl acrylate (MEA) or 2-­hydropropyl acrylate (HPA) with 2-hydroxyethyl acrylate (HEA). Based on the very low TCP of PMEA (longer PMEA is even water-insoluble) and PHPA and the high water solubility of PHEA, these monomer combinations provide access to defined copolymers with a TCP tunable between 0°C and 100°C using NMP, ATRP, or RAFT polymerization (Fig.  2.8; Hoogenboom et al., 2009a, 2012; Steinhauer et al., 2010; Lavigueur et al., 2011; Vancoillie et al., 2014). The thermoresponsive behavior of POEG(M)As can be further tuned by the copolymerization with other (meth)acrylate comonomers to tune the hydrophilicity/hydrophobicity of the polymer, leading to higher/lower TCP (Dimitrov et al., 2007; Roy et al., 2010, 2013). Similar to PNIPAM and PVCL, multiresponsive POEG(M)As can be obtained by the incorporation of comonomers that respond to other stimuli, such as pH or UV radiation (Dimitrov et al., 2007; Roy et al., 2010, 2013).

2.3  Key Types of Temperature-Responsive Polymers in Aqueous Solution

25

FIG. 2.8  Cloud point temperature of HEA-MEA and HEA-HPA copolymers prepared by NMP or RAFT polymerization as function of HEA fraction (FHEA). Reproduced with permission from the RSC. Hoogenboom, R., Zorn, A.-M., Keul, H., Barner-Kowollik, C., Moeller, M., 2012. Copolymers of 2-hydroxyethylacrylate and 2-methoxyethyl acrylate by nitroxide mediated polymerization: kinetics, SEC-ESI-MS analysis and thermoresponsive properties, Polym. Chem. 3, 335–342. https://doi.org/10.1039/c1py00344e.

2.3.3  Other Polymers Besides the main classes of thermoresponsive polymers covered in the previous two sections, a wide variety of other polymers have been reported to exhibit LCST behavior in water, ranging from relatively simple poly(propylene oxide)-co-poly(ethylene oxide) copolymers (Alred et  al., 1994), via poly(oligo[ethylene glycol] vinyl acetate)s (Hedir et al., 2017), to rather complex polypeptides with a repeating Val-Pro-Gly-Val-Gly (VPGVG) motif inspired by elastin (Urry, 1984). Similarly, all other (co) polymers with the correct balance between hydrophilicity and hydrophobicity will undergo an LCST phase transition upon heating. In this section, we will highlight three other classes of thermoresponsive polymers, namely poly(vinyl ether)s, poly(2-oxazoline)s, and poly(phosphoester)s. The LCST behavior of poly(methyl vinyl ether) (PMVE) was already reported in 1971 with a TCP of 34°C (Horne et al., 1971; Aseyev et al., 2006; Aoshima and Kanaoka, 2008), which is shortly after the first reports on the LCST behavior of PNIPAM. The phase behavior of PMVE is rather unusual with two minima in the phase diagram, one dependent on the polymer molar mass similar to PVCL, and one at a higher polymer concentration of which the position is independent of polymer molar mass, as is the case for PNIPAM (Fig. 2.9; Schäfer-Soenen et al., 1997). In addition to PMVE, the thermoresponsive behavior of various ethylene glycol modified poly(vinyl ether)s has been reported, whereby the TCP can be altered

26

2.  TEMPERATURE-RESPONSIVE POLYMERS

35

Temperature (°C)

O

30

O O

O

Tcp = 70°C PMOVE

Tcp = 20°C PEOVE

O

PMVE

O O

25 0.0

0.2

0.4

0.6 f2

0.8

1.0

Tcp = 40°C PEOEOVE

O

FIG. 2.9  Left: Demixing temperature from DSC measurements (0.1 K min−1) for aqueous solutions of PMVE (squares: PMVE with Mn = 11 kDa, Ð = 2.5; triangles: PMVE with Mn = 19, Ð = 7.8) as a function of polymer weight fraction. Right: Structures and cloud point temperatures (TCP) of various poly(vinylether)s (Aoshima et al., 1992). Left: Reproduced with permission from ACS (Schäfer-Soenen, R., Moerkerke, R., Berghmans, H., Koningsveld, R., Dusek, K., Solc, K., 1997. Zero and off-zero critical concentrations in systems containing polydisperse polymers with very high molar masses. 2. The system water-poly(vinyl methyl ether). Macromolecules 30, 410–416. https://doi.org/10.1021/ma960114o).

by variation of the ethylene glycol length and end-group as illustrated in Fig. 2.9 (Aoshima et al., 1992). Although vinyl ethers can be polymerized by free radical polymerization, this commonly results in slow polymerization and low polymerization degrees due to insufficient activation of the vinyl group by the ether moiety. Therefore, the preparation of (defined) poly(vinyl ether)s is commonly performed by (living) cationic vinyl polymerization, which is enabled by stabilization of the cationic propagating species by the ether group. As such, fast uncontrolled polymerization can be obtained with strong cationic initiators, such as stannyl tetrachloride or boron trifluoride (Schröder, 2000). Modification of the cationic polymerization procedure to obtain equilibrium between cationic propagating species and dormant covalent species enables living cationic polymerization of vinyl ethers leading to well-defined polymers with defined end-groups (Miyamoto et al., 1984; Kojima et al., 1989). A recently emerging class of thermoresponsive polymers are poly(2-­ oxazoline)s, which are synthetic poly(amide)s comprising a tertiary amide group in the repeat unit and a variable side chain as shown in Fig.  2.10 (Hoogenboom, 2009b; Hoogenboom and Schlaad, 2011, 2017). Poly(2oxazoline)s with methyl side chains are very hydrophilic and do not show

2.3  Key Types of Temperature-Responsive Polymers in Aqueous Solution 100 O

pEtOx150

O N

O

Tcp = 25°C PnPropOx

O N

LCST = 35°C PiPropOx

Transmittance (%)

LCST = 60°C PEtOx

N

Heating Cooling pEtOx120-stat-nPropOx30

80

Heating Cooling pEtOx75-stat-nPropOx75

60 40

Heating Cooling pnPropOx150

20 N

Tcp = 30°C PcPropOx

27

Heating Cooling

0 10 20 30 40 50 60 70 80 90 100 Temperature (°C)

FIG. 2.10  Left: Structures and cloud point temperatures (TCP) of various poly(2-oxazoline)

s. Right: Transmittance versus temperature plots for various poly(2-oxazoline)s consisting of 2-ethyl-2-oxazoline (EtOx) and 2-n-propyl-2-oxazoline (PropOx). Reproduced with permission from the RSC. Hoogenboom, R., Thijs, M.H.L., Jochems, M.J.H.C., Van Lankvelt, B.M., Fijten, M.W.M., Schubert, U.S., 2008. Tuning the LCST of poly(2-oxazoline)s by varying composition and molecular weight: alternatives to poly(N-isopropylacrylamide)? Chem. Commun. 5758–5760. https://doi.org/10.1039/b813140f.

an LCST phase transition in water but extends the hydrophobic side chain length to ethyl or propyl induces thermoresponsive LCST behavior. The LCST of poly(2-ethyl-2-oxazoline) has been reported to be ~60°C (Lin et al., 1988) but has also been demonstrated to be strongly molecular weight and concentration dependent (Christova et al., 2003; Hoogenboom et al., 2008). Further extending the side-chain length to n-propyl leads to polymers with a TCP of ~25°C (Park and Kataoka, 2007; Hoogenboom et al., 2008), yet the variation of the propyl side chain provides further control over the TCP as demonstrated by the TCP of ~35°C and ~30°C for poly(2-oxazoline) s with isopropyl and cyclopropyl side chains, respectively (Uyama and Kobayashi, 1992; Bloksma et al., 2011). Copolymerization of the different 2-oxazoline monomers allows facile tuning of the TCP and copolymers of 2-ethyl-2-oxazoline (EtOx) and 2-n-propyl-2-oxazoline (nPropOx) with a TCP close to body temperature were demonstrated to be a promising alternative to PNIPAM showing similar concentration dependence of the TCP yet no significant hysteresis was present, ascribed to the lower Tg and the absence of intramolecular hydrogen bonding in the collapsed state when compared to PNIPAM (Hoogenboom et al., 2008). A wide variety of copoly(2-oxazoline)s with different side chains resulting from copolymerization and/or postpolymerization modification have been reported for accurate tuning of the TCP (see recent review: Hoogenboom and Schlaad, 2017). Poly(2-oxazoline)s can be prepared by living cationic ring-opening polymerization of the 2-oxazoline monomers utilizing an electrophilic initiator, such as methyl tosylate or methyl triflate (Verbraeken et  al., 2017). Attack of the monomer onto this initiator leads to the formation

28

2.  TEMPERATURE-RESPONSIVE POLYMERS

of a cationic oxazolinium species, and subsequent monomer attack leads to ring-opening whereas the newly added monomer ends up as cationic oxazolinium chain end. As such, well-defined polymers can be obtained, and the chain-end functionalities can be controlled during initiation and termination (Aoi and Okada, 1996). A final class of thermoresponsive LCST polymers highlighted in this chapter are poly(phosphoester)s (Iwasaki, 2011). Poly(phosphoester)s comprise hydrolysable phosphoester groups in the main chain and represent a relatively new class of biocompatible and biodegradable polymers (Zhao et al., 2003). When the hydrophilicity of the phosphoester moieties is counterbalanced by hydrophobic alkoxy side chains, such as ethyloxy or isopropyloxy, thermoresponsive poly(phosphoester)s are obtained with a TCP of 38°C or 5°C, respectively, as depicted in Fig. 2.11 (Iwasaki et al., 2007; Iwasaki, 2011). Furthermore, the TCP linearly depends on the monomer feed ratio in copolymers of these two monomers. In addition, it was recently reported that poly(phosphoester)s with tri(ethylene glycol) thiol ether side chains (PTEGP) also exhibit LCST behavior and that the TCP depends on the polymer chain architecture, that is, the TCP of a cyclic polymer was found to be higher compared to the linear analogue (Fig. 2.11; Yuan et al., 2012). Finally, the accurate tuning of TCP has been demonstrated by postpolymerization modification of a furfuryl containing poly(phosphoester) by Diels-Alder reactions (Becker et al., 2017). Poly(phosphoester)s are commonly prepared by ring-opening polymerization of cyclic 2-alkoxy-2-oxo-1,3,2-dioxaphopholanes (cyclic phosphoesters) in the presence of stannous octoate (Sn(Oct)2) as a catalyst and an alcohol as an initiator. In recent years, significant progress

O P O O

O O P O O

TCP = 38°C PEP O P O O

TCP = 5°C PiPP

O

TCP = 46.7°C

S O

PTEGP

O

TCP = 48.5°C

3

FIG. 2.11  Left: Structures and reported cloud point temperatures (TCP) of thermorespon-

sive poly(phosphoester)s. Right: Effect of polymer architecture of PTEGP on the TCP (Yuan et al., 2012).

2.3  Key Types of Temperature-Responsive Polymers in Aqueous Solution

29

has been made in replacing this Sn(Oct)2 catalyst by organic bases, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD), yielding well-defined, metal-free poly(phosphoester)s (Iwasaki and Yamaguchi, 2010; Clement et al., 2012).

2.3.4  UCST Polymers Thermoresponsive polymers with UCST behavior in water are quite rare, especially in comparison to the rather generally observed LCST behavior. As explained in Section  2.2.2, UCST behavior in water under ambient pressure conditions results from strong supramolecular ­polymerpolymer interactions, such as electrostatic interactions or hydrogen bonding. Furthermore, UCST behavior can result from a change in solvent quality upon heating, mostly observed in nonideal alcohol-water solvent mixtures. In this section, the most import classes and types of UCST polymers will be discussed. The most famous type of polymers with UCST behavior in water are the so-called poly(betaine)s, which are zwitterionic polymers that comprise both positive and negative charges in every repeat unit (Kudaibergenov et  al., 2006). As such, strong polymer-polymer interactions are present based on electrostatic interactions leading to collapsed structures that are more hydrophobic than the solubilized polymer chains at elevated temperatures due to charge compensation and the release of counterions into solution. The most common poly(betaine)s with UCST behavior are poly(2-dimethyl[methacryloxyethyl] ammonium propane sulfonate) (PDMAPS-MA) and poly(3-[N-(3-methacrylamidopropyl)-N,N-dimethyl] ammonium propane sulfonate) (PDMAPS-MAM) as depicted in Fig. 2.12 (Schulz et  al., 1986; Huglin and Radwan, 1991; Mary et  al., 2007). The phase behavior of PDMAPS-MA was reported to be highly dependent on the polymer chain length, whereby the UCST transition increases with increasing chain length as would be expected from the enhanced number of electrostatic interactions that increase the polymer-polymer interactions (Fig. 2.12; Mary et al., 2007). Alternatively, UCST behavior in water can be achieved based on the interactions between a polyelectrolyte with multivalent counterions as described for solutions containing poly(dimethylamino ethyl methacrylate) with the trivalent anion [Co(CN)6]3− (Plamper et  al., 2007; Zhang et  al., 2015a). Despite the common knowledge of the hydrogelation of polyelectrolytes in the presence of multivalent ions, such as the gelation of alginate in the presence of calcium(II), there are only few studies focusing on the UCST-type phase transitions of such hydrogels or polymer solutions. The synthesis of such UCST polymers based on (meth)acrylate monomers can be performed by radical polymerization as discussed in Section 2.3.1.

30

2.  TEMPERATURE-RESPONSIVE POLYMERS 80

O

O

O

NH

N+

N+

O S O O–

O S O O–

PDMAPS-MA

Critical temperature Tc (°C)

70

PDMAPS-MAM

NSPE 6442

60 50 40 30

2147

895 429

20

1f

177

10 2f 0 0.0001

0.001

0.01

0.1

1

Polyzwitterion volume fraction fp

FIG.  2.12  Left: Structure and cloud point temperatures (TC) of common poly(betaine)s. Right: Phase diagram for the UCST behavior of poly(2-dimethyl[methacryloxyethyl] ammonium propane sulfonate) (PDMAPS-MA) in water as a function of the degree of polymerization (NSPE). Reproduced with permission from the ACS. Mary, P., Bendejacq, D.D., Labeau, M.-P., Dupuis, P., 2007. Reconciling low- and high-salt solution behavior of sulfobetaine polyzwitterions. J. Phys. Chem. B 111, 7767–7777. https://doi.org/10.1021/jp071995b.

O

NH2

PMAm

O

O

NH

NH O

O NH2 PNAGA

H2N

O

NH2

PNAAGA

FIG. 2.13  Structure of polymers that exhibit hydrogen bonding-based UCST behavior in water.

Polymers with UCST behavior in water based on attractive hydrogen bonding interactions have recently gained significant interest, mostly based on the discovery that primary amide groups present in the polymer side chains can induce UCST behavior on the condition that no ionic impurities are present in the polymer due to partial hydrolysis of the side chains (Seuring and Agarwal, 2012a). Fig. 2.13 depicts some recently reported homopolymers that exhibit such hydrogen bonding-based UCST behavior including poly(methacrylamide) (PMAm; Seuring and Agarwal, 2012b), poly(N-acryloylglycinamide) (PNAGA; Glatzel et  al., 2010; Seuring and Agarwal, 2010), and poly(N-acryloylasparaginamide) (PNAAGA; Glatzel et al., 2011). Furthermore, copolymers of poly(acrylamide) with hydrophobic comonomers also reveal UCST behavior in



2.4  Selected Applications of Thermoresponsive Polymers

31

water (Seuring and Agarwal, 2012b), and replacing the primary amide group with a primary ureido-functionality also yields UCST thermoresponsive polymers in water (Shimada et al., 2011). The final class of thermoresponsive polymers with UCST behavior in alcohol-water mixtures consists of hydrophobic polymers that comprise good hydrogen bond-accepting moieties, such as ester groups, ether groups, or tertiary amides to interact with the solvent (Zhang and Hoogenboom, 2015b). Reported examples include poly(methyl (meth)acrylate)s (Piccarolo and Titomanlio, 1982; Hoogenboom et al., 2009c; Can et al., 2010), poly(2-oxazoline)s (Lambermont-Thijs et al., 2010), as well as POEGMAs (Roth et al., 2011). Multiresponsive UCST polymers have also been reported in ethanol-water systems by incorporating photoswitchable (Zhang et al., 2015c) or redox-switchable units into the polymer (Bertrand et al., 2016).

2.4  SELECTED APPLICATIONS OF THERMORESPONSIVE POLYMERS Thermoresponsive polymers provide a promising basis for the development of smart materials. In this section, selected recent examples will be discussed to highlight this potential, focusing on the more common LCST polymers. For more comprehensive overviews of the use of thermoresponsive polymers for biomedical applications, the reader is referred to a number of recent review articles (De las Heras Alercon et  al., 2005; Schmaljohann, 2006; Ward and Theoni, 2011; Hoffman, 2013). The LCST transition of a polymer is accompanied by (partial) dehydration of the polymer chains, which has been applied for the development of polymeric temperature sensors. The incorporation of a solvatochromic dye molecule in the polymer side chain provides a direct readout of the temperature transition of the polymer by a change in color or fluorescence resulting from the change in the polarity of the microenvironment of the dye as illustrated in Fig. 2.14 (Pietsch et al., 2011). Such polymeric thermometers were recently developed for accurate local temperature determination inside living cells, for which the readout was changed to fluorescence lifetime rather than emission wavelength or intensity to have a more robust sensor (Okabe et al., 2012). Furthermore, dual sensors have been developed by combing a LCST polymer with a pH-responsive solvatochromic dye, which led to a sensor that allows determination of both the solution temperature and pH by a single UV measurement (Pietsch et  al., 2009). More recently, the effect of comonomers on sensor behavior was demonstrated for solvatochromic dye-functionalized OEGA copolymers (Zhang et al., 2015d). It was found that a hydroxyl-containing comonomer (2-hydroxyethylacrylate) led to significant broadening of the

32

2.  TEMPERATURE-RESPONSIVE POLYMERS

FIG. 2.14  Schematic representation of the concept of polymeric sensors based on a polymer phase transition as thermoresponsive structure and solvatochromic dyes to provide a visual or fluorescence readout signal of the change in the polarity of the microenvironment. Reproduced with permission from the RSC. Pietsch, C., Schubert, U.S., Hoogenboom, R., 2011. Aqueous polymeric sensors based on temperature-induced polymer phase transitions and solvatochromic dyes. Chem. Commun. 47, 8750–8765. https://doi.org/10.1039/C1CC11940K).

t­ emperature-sensing regime due to more gradual dehydration of the polymer globules around the LCST phase transition. The change in polymer conformation during the LCST transition can also be applied to control the proximity of side-chain functionalities. In a recent report, this characteristic of the polymer phase transition has been exploited to control the binding kinetics of mannose functionalized PNIPAM hydrogel nanoparticles to sugar-binding proteins, so-called lectins (Hoshino et al., 2012). As may be expected, the binding of the PNIPAM nanoparticles was stronger in the hydrated state below the TCP compared to the collapsed state, which can be ascribed to the higher mobility and availability of the mannose units. However, the binding was found to be even stronger in the phase transition regime where partial dehydration leads to contraction of the nanoparticles and, thus, close proximity of the mannose groups, while apparently they are still mobile enough to fit to the lectin. As such, variation of temperature might lead to on-and-off switching of the nanoparticle-lectin binding. In addition to applications based on the change in the polymer chain conformation, the change in effective polymer concentration upon LCST dehydration and aggregation of the polymer chains has been applied to control osmotic strength of a polymer solution and to induce a reversible movement of water through a membrane (Fig. 2.15; Noh et al., 2012). Acylated branched poly(ethylene imine)s were utilized as thermoresponsive polymers exhibiting tunable TCP between 20°C and 54°C (Fig. 2.15). The osmotic flux experiment was optimized and developed with the n-butyl acetylated polymer having a TCP of ~30°C. A solution of this polymer was placed in contact with a lower concentration NaCl solution via a



2.4  Selected Applications of Thermoresponsive Polymers

33

FIG.  2.15  Schematic representation to the reversible temperature-induced control over osmotic flux (top) and the structure of the utilized thermoresponsive butylated branched poly(ethylene imine) (Noh et al., 2012).

semipermeable cellulose trifluoroacetate membrane that only allows water to pass leading to osmotic water flux from the NaCl solution to the polymer solution at 21°C (Fig. 2.15). Upon heating the system to 55°C, the polymer undergoes the LCST transition leading to aggregation and, thus, a lower effective polymer concentration resulting in reversed osmotic flux. This process was demonstrated to be fully reversible in three repetitive cycles, and it has been suggested that such a system might find potential use for the desalination of seawater. In a related study, the application of thermoresponsive polymers for the collection of water from fog was reported (Yang et al., 2013). Cotton fibers were modified with a thermoresponsive PNIPAM coating resulting in a thermoresponsive cotton with a TCP ~ 32°C. The water-uptake of these PNIPAM-modified cotton fibers was highly temperature responsive revealing high water uptake at 24°C (~350 wt%) and almost no water uptake at 33°C (~50 wt%) and higher temperatures. Furthermore, it was demonstrated that the water-uptake can be reversibly switched, thereby enabling

34

2.  TEMPERATURE-RESPONSIVE POLYMERS

T/ºC

50 No gel

40

30

PNIPAM 0

360

180 t/min

FIG. 2.16  Temperature variation inside a miniaturized building during alternating rain and sun exposure cycles with and without a PNIPAM hydrogel on the roof. Reproduced with permission from Wiley. Rotzetter, A.C.C., Schumacher, C.M., Bubenhofer, S.B., Grass, R.N., Gerber, L.C., Zeltner, M., Stark, W.J., 2012. Thermoresponsive polymer induced sweating surfaces as an efficient way to passively cool buildings. Adv. Mater. 24, 5352–5356. https://doi.org/10.1002/ adma.201202574.

water absorption from the atmosphere at lower temperatures, for example, during the night, and release, that is, collection, upon heating, for example, during daytime. Similar control over water absorption and release by a cross-linked PNIPAM hydrogel has been proposed for passive cooling of buildings (Rotzetter et al., 2012). During rain, the hydrogel is below the TCP of the PNIPAM hydrogel leading to water absorption, whereas in the sun the temperature rises beyond the TCP and the water is expelled from the hydrogel. Evaporation of the released water leads to passive cooling as has been clearly demonstrated by measuring the temperature of a miniaturized building with and without such a PNIPAM hydrogel on the roof during artificial sun and rain cycles (Fig. 2.16). Thermoresponsive polymers also provide opportunities for the preparation of thermoresponsive hydrogels (Klouda and Mikos, 2008; Ward and Theoni, 2011; Van Vlierberghe et al., 2011). High concentrated thermoresponsive polymer solutions (commonly >10 wt%) undergo LCSTbased temperature-induced gelation upon heating due to the partial dehydration of the polymer chains leading to the formation of a physically cross-linked polymer network that solidifies the solution. More recently, however, a thermoresponsive poly(isocyanide) bearing ethylene glycol functionalized peptidic side chains was reported to undergo



2.4  Selected Applications of Thermoresponsive Polymers

35

LCST-driven temperature-induced hydrogelation at concentration as low as 0.006 wt% (Kouwer et  al., 2013). This highly efficient hydrogelation was ascribed to the high stiffness of the helical polymer chains in combination with the formation of physical cross-links by bundling of individual helical polymer chains in larger fibers upon partial dehydration of the side chains. Surprisingly, these hydrogels revealed shear-thickening behavior, and their properties closely resembled the properties of naturally occurring gels based in intermediate actin filaments. A final recent trend is the design of multiresponsive polymers that undergo an “isothermal” LCST phase transition (Phillips and Gibson, 2015). In other words, the solution temperature of the polymer solution is kept constant while a secondary response of the polymer induces a shift of the LCST binodal curve, thereby inducing the “isothermal” LCST phase transition as depicted in Fig. 2.17. A wide variety of secondary responses have been utilized to alter the hydrophilicity/hydrophobicity of the polymer end-groups (Jochum et al., 2009), polymer molar mass (Phillips and Gibson, 2012), or side chains (Fournier et al., 2007) by, for example, chemical modification, (de)protonation, or photoisomerization as recently reviewed (Phillips and Gibson, 2015). Especially interesting are isothermally responsive polymers that are insoluble at body temperature but become water-soluble due to partial (side-chain) hydrolysis under mild acidic conditions as found in the vicinity of tumors as well as in the endosomes after cellular uptake. These polymers are also referred to as transiently thermoresponsive polymers that have high potential for biomedical applications, especially therapeutics and drug delivery (Vanparijs et al., 2017). The comonomers in such transiently responsive LCST polymers were found to strongly influence the hydrolysis rate, which was significantly enhanced in the presence of 2-hydroxyethylacrylate compared to 2-methoxy(diethylene glycol) acrylate ascribed to the more pronounced hydration of the collapsed polymer globules due to the presence of the alcohol groups (Zhang et al., 2015e).

FIG. 2.17  Schematic representation of the “isothermal” LCST phase transition whereby the phase transition of the polymer from collapsed and phase segregated to soluble is induced by a secondary response that moves the binodal curve upward.

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2.  TEMPERATURE-RESPONSIVE POLYMERS

2.5  CONCLUSIONS: STRENGTHS AND LIMITATIONS OF CURRENT TEMPERATURE-RESPONSIVE POLYMERS Thermoresponsive polymers have gained significant interest in the past decade, especially those that undergo a temperature-induced phase transition in aqueous solutions. Water-soluble polymers generally undergo an LCST phase transition in water and, thus, the majority of reports focus on such LCST polymers. In recent years, the gold standard of LCST polymers, namely PNIPAM, has lost terrain to other alternative thermoresponsive polymers, of which the TCP can be more easily tuned, and that shows less hysteresis between heating and cooling cycles, including POEG(M) As and poly(2-oxazoline)s. In contrast to LCST polymers, there is only a relatively small number of polymers reported that undergo a UCST transition in aqueous solution. Recent progress includes the development of UCST polymers with primary amide side chains that strongly interact by hydrogen bonding, but the UCST transition is strongly affected by minor ionic impurities as well as the ionic strength of the solution. Therefore, the major challenge in this field is the development of polymers with a robust UCST transition in aqueous solution. The large application potential of LCST polymers is currently being explored for a wide variety of smart materials, ranging from biomedical applications, to sensors, water collection, and energy efficient buildings. However, further in-depth studies are required before such materials will be able to enter the market.

2.6  FUTURE TRENDS Future trends are expected to further focus on the development of multiresponsive polymers that combine an LCST phase transition with another response, such as redox, pH, or the presence of certain analytes. As such, the phase transition can be induced isothermally by the second response parameter to further broaden the application potential for sensors and biomedical applications. Furthermore, the development of novel polymers with UCST behavior will be an important research topic for the coming years as well as the development of applications of UCST polymers. Finally, I am convinced that the application potential of both LCST and UCST polymers for smart materials will be significantly broadened in the near future.

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Lessard, D.G., Ousalem, M., Zhu, X.X., 2001. Effect of the molecular weight on the lower critical solution temperature of poly(N,N-diethylacrylamide) in aqueous solutions. Can. J. Chem. 79, 1870–1874. https://doi.org/10.1139/v01-180. Lessard, B.H., Ling, E.J.Y., Maric, M., 2012. Fluorescent, thermoresponsive oligo(ethylene glycol) methacrylate/9-(4-vinylbenzyl)-9H-carbazole copolymers designed with multiple LCSTs via nitroxide mediated controlled radical polymerization. Macromolecules 45, 1879–1891. https://doi.org/10.1021/ma202648k. Li, M.-H., Keller, P., 2006. Artificial muscles based on liquid crystal elastomers. Phil. Trans. R. Soc. A 364, 2763–2777. https://doi.org/10.1098/rsta.2006.1853. Lin, P., Clash, C., Pearce, E.M., Kwei, T.K., 1988. Solubility and miscibility of poly(ethyl oxazoline). J. Polym. Sci. B Polym. Phys. 26, 603–619. https://doi.org/10.1002/ polb.1988.090260312. Liu, C., Qin, H., Mather, P.T., 2007. Review of progress in shape-memory polymers. J. Mater. Chem. 17, 1543–1558. https://doi.org/10.1039/b615954k. Liu, R., Fraylich, M., Saunders, B.R., 2009. Thermoresponsive copolymers: from fundamental studies to applications. Colloid Polym. Sci. 287, 627–643. https://doi.org/10.1007/ s00396-009-2028-x. Longenecker, R., Mu, T., Hanna, M., Burke, N.A.D., Stöer, H.D.H., 2011. Thermally responsive 2-hydroxyethyl methacrylate polymers: soluble-insoluble and solubleinsoluble-­soluble transitions. Macromolecules 44, 8962–8971. https://doi.org/10.1021/ ma201528r. Lowe, A.B., McCormick, C.L., 2007. Reversible addition–fragmentation chain transfer (RAFT) radical polymerization and the synthesis of water-soluble (co)polymers under homogeneous conditions in organic and aqueous media. Prog. Polym. Sci. 32, 283–351. https://doi.org/10.1016/j.progpolymsci.2006.11.003. Lutz, J.-F., 2008. Polymerization of oligo(ethylene glycol) (meth)acrylates: toward new generations of smart biocompatible materials. J. Polym. Sci. Part A: Polym. Chem. 46, 3459– 3470. https://doi.org/10.1002/pola.22706. Lutz, J.F., 2011. Thermo-switchable materials prepared using the OEGMA-platform. Adv. Mater. 23, 2237–2243. https://doi.org/10.1002/adma.201100597. Lutz, J.-F., Hoth, A., 2006a. Preparation of ideal PEG analogues with a tunable thermosensitivity by controlled radical copolymerization of 2-(2-methoxyethoxy)ethyl methacrylate and oligo(ethylene glycol) methacrylate. Macromolecules 39, 893–896. https://doi. org/10.1021/ma0517042. Lutz, J.-F., Akdemir, O., Hoth, A., 2006b. Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: is the age of poly(NIPAM) over? J. Am. Chem. Soc. 128, 13046–13047. https://doi.org/10.1021/ja065324n. Mary, P., Bendejacq, D.D., Labeau, M.-P., Dupuis, P., 2007. Reconciling low- and high-salt solution behavior of sulfobetaine polyzwitterions. J. Phys. Chem. B 111, 7767–7777. https://doi.org/10.1021/jp071995b. Meeussen, F., Nies, E., Berghmans, H., Verbrugghe, S., Goethals, E., Du Prez, F., 2000. Phase behaviour of poly(N-vinyl caprolactam) in water. Polymer 41, 8597–8602. https://doi. org/10.1016/S0032-3861(00)00255-X. Miyamoto, M., Sawamoto, M., Higashimura, T., 1984. Living polymerization of isobutyl vinyl ether with hydrogen iodide/iodine initiating system. Macromolecules 17, 265–268. https://doi.org/10.1021/ma00133a001. Moirangthem, M., Engels, T.A.P., Murphy, J., Bastiaansen, C.W.M., Schenning, A.P.H.J., 2017. Photonic shape memory polymer with stable multiple colors. ACS Appl. Mater. Interfaces 9, 32161–32167. https://doi.org/10.1021/acsami.7b10198. Nakabayashi, K., More, H., 2013. Recent progress in controlled radical polymerization of N-vinyl monomers. Eur. Polym. J. 49, 2808–2838. https://doi.org/10.1016/j.eurpolymj.2013.07.006. Niskanen, J., Tenhu, H., 2017. How to manipulate the upper critical solution temperature (UCST)? Polym. Chem. 8, 220–232. https://doi.org/10.1039/c6py01612j.

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Further Reading Lin, C., Qin, H., Mather, P.T., 2007. Review of progress in shape-memory polymers. J. Mater. Chem. 17, 1543–1558. https://doi.org/10.1039/b615954k.

C H A P T E R

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pH-Responsive Polymers: Properties, Synthesis, and Applications Luis García-Fernández⁎,†, Ana Mora-Boza⁎,†, Felisa Reyes-Ortega⁎,† ⁎

Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain, † Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain

Abbreviations 4-VBA CD AMP API ATRP DDS DMAEMA DOX EGDMA FA GGS-SA GTP HA IPN Ka LMWH LSPR MAA miRNA MTS OEI-PBA PA PAA PAMAM

poly(4-vinylphenylboronic acid) cyclodextrin antimicrobial peptide 1-(3-aminopropyl) imidazole atom transfer radical polymerization drug delivery system N,N-dimethylaminoethylmethacrylate doxorubicin ethylene glycol dimethylacrylate folic acid succinate-modified guar gum crosslinked with sodium alginate group transfer polymerization hyaluronic acid interpenetrating polymer network dissociation constant low molecular weight heparin localized surface plasmon resonance methacrylic acid micro-RNA 1-methoxy-1-(trimethylsiloxy)-2-methylpro-1-ene oligoethylenimine functionalized with phenylboronic acid peptide amphiphilic poly(acrylic acid) poly(amidoamine)

Smart Polymers and Their Applications https://doi.org/10.1016/B978-0-08-102416-4.00003-X

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© 2019 Elsevier Ltd. All rights reserved.

46 PAMPS PBA PDEAEM PDEAEMA PDMAEMA pDNA PEG PEI PLL PMA PMMA PNIPAA PPI PS pSi PTX PVA PVP QDs RAFT ROP ROS SRPB THF

3.  pH-RESPONSIVE POLYMERS

poly(2-acrylamido-2-methylpropane sulfonic acid) phenylboronic acid poly(2-diethylaminoethyl methacrylate) poly(N,N′-diethyl aminoethyl methacrylate) poly(N,N-dimethylaminoethylmethacrylate) plasmid DNA poly(ethylene glycol) poly(ethylenimine) poly(l-lysine) poly(methacrylic acid) poly(methyl methacrylate) poly(N-isopropylacrylamide) polypropylene imine polystyrene porous silicon paclitaxel poly(vynil alcohol) poly(vinylpyrrolidone) quantum dots reversible addition-fragmentation chain transfer polymerization ring-opening polymerization reactive oxygen species stimulus-responsive polymer brushes tetrahydrofuran

3.1 INTRODUCTION pH-responsive polymers are just one of the stimuli-responsive polymers that undergo structural and properties changes (surface activity, solubility, chain conformation and configuration) in response to a change in the environmental pH. pH-responsive polymers are commonly used to define polyelectrolytes that include weak acidic or basic groups in their structures that either accept or release protons depending on the variation of the pH (Hafeli, 1998). The research and use of pH-responsive polymers has increased in the last several years; this system provides the possibility of designing smart functional materials on demand. Consequently, there are many potential applications in different fields, such as personal care (Yu et al., 2017), industrial processes (Kan et al., 2013), water remediation (Wang et al., 2016), and the biomedical field (Ju et al., 2009). The biomedical field is one of the most important points in the research of pH-­responsive polymers, because the design and preparation of new drug delivery systems (DDS) (Kumar et al., 2017; Liu et al., 2017), gene carriers (Li et al., 2017; Mathew et al., 2017), and biosensors (Sousa et al., 2017) are continually developing. As an example, pH-responsive polymers play an important role in the design of new DDS for tumor treatment. The extracellular pH of most tumors is acidic (5.8–7.2), and smart polymeric nanodevices can be designed to maximize activity and reduce side effects of anticancer drugs (Colby et al., 2017).



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A variety of synthetic methodologies with some of their salient features are described in this chapter, as well as several polymeric structures and the important characteristics that govern their behavior in solutions.

3.2  BASIC PRINCIPLES OF pH-RESPONSIVE POLYMERS Polymers having acidic or basic groups in their structures (i.e., carboxylic acids [COOH], sulfonic acids [SO3H], tertiary amines, etc.) are typically described as pH-responsive polymers because the ionization of the groups with a pH change results in a change in their structure. The acidic or basic groups of these polyelectrolytes can be ionized just like acidic or basic groups of monoacids or monobasic; however, complete ionization of these systems is more difficult due to the electrostatic effects exerted by other adjacent ionized groups. This makes the apparent dissociation constant (Ka) different from that of the corresponding monoacid or monobasic. The physical properties, such as chain conformation, configuration, solubility, and volume of pH-responsive polymers, can be tailored by manipulating the charges along the polymer backbone or electrolyte concentrations, resulting in electrostatic repulsion forces that create an increase in the hydrodynamic volume of the polymer. This transition between a tightly coiled and expanded state is influenced by any condition that modifies electrostatic repulsion, such as pH, ionic strength, and type of counterions. The transition from collapsed state to expanded state is explained by changes in the osmotic pressure exerted by mobile counterions neutralizing the network charges (Dai et al., 2008). Polyacid polymers will be collapsed at low pH, because the acidic groups will be protonated and unionized. When increasing the pH, a negatively charged polymer will swell. The opposite behavior is found in polybasic polymers, as the ionization of the basic groups will increase when pH decreases. The pH range where the reversible phase transition happens can generally be modulated in two ways: selecting the ionizable moiety with a pKa matching the desired pH range (selecting between polyacid or polybase) and incorporating hydrophobic moieties into the polymer backbone (selectively control their nature, amount, and distribution) (Na et al., 2004). The introduction of a more hydrophobic moiety can offer a more compact conformation in the uncharged state and a more accused phase transition (Kocak et  al., 2017). pH-responsive polymers can be synthesized through conventional or controlled radical polymerization techniques (Gregory and Stenzel, 2012; Mu et  al., 2011). Emulsion polymerization is among the most popular synthetic routes for preparing vinyl-based, pH-responsive particulate systems, especially microgel systems (Gao et al., 2009; Chuang et al., 2009). Typical examples of pH-sensitive polymers with anionic groups are the poly(carboxylic acids), such as poly(acrylic acid) (PAA) or

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3.  pH-RESPONSIVE POLYMERS

poly(­methacrylic acid) (PMAA), and the polysulfonamides, which are derivatives of p-­aminobenzene sulfonamide (Arya et al., 2017; Kang and Bae, 2002). These weak polyacids present a pKa that narrowly varies from 3 to 11, depending on the electron-removing nature of the substituent on the nitrogen. At low pH, carboxyl groups are protonated and hydrophobic interactions dominate, leading to volume withdrawal of the polymer that contains the carboxyl groups. At high pH, carboxyl groups dissociate into carboxylate ions, resulting in a high charge density in the polymer, causing it to swell. The chain configuration of weak polyacid is a function of the pKa of the polymer (Fig. 3.1A). An opposite behavior is shown by cationic polyelectrolytes (Fig. 3.1B), for example, poly(N,N-dialkyl aminoethyl methacrylates), poly(l-lysine) (PLL), poly(ethylenimine) (PEI), and chitosan. These polyelectrolytes are acid-swellable groups, in contrast to the alkali-swellable carboxyl group. Under acidic environments, the polybasic groups are protonated, increasing the internal charge repulsions between neighboring protonated polybasic groups. Charge repulsion leads to an expansion in the overall dimensions of the polymer containing the groups. At higher pH values, the groups become less ionized, the charge repulsion is reduced, and the polymer-polymer interactions increase, leading to a decrease of the overall hydrodynamic diameter of the polymer. These characteristics are used, for example, to obtain pH-responsive hydrogels that are widely used as carriers in drug delivery systems (Liu et  al., 2017; Arya et  al., 2017). Swelling of a hydrogel increases as the external pH increases in the case of weakly acidic (anionic) groups but

FIG. 3.1  Structures and states depending on the ionization of the ionic chain groups of pH-responsive polyelectrolytes (A) poly(acrylic acid) and (B) poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA).



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

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­ ecreases if the polymer contains weakly basic (cationic) groups. When d the ionic strength of the solution is increased, the hydrogel can exchange ions with the solution. In that way, the hydrogel keeps charge neutrality, and the concentration of free counter ions inside the hydrogel increases. An osmotic pressure difference between the hydrogel and the solution appears and causes the gel to swell. If ionic strength is equal to or higher than 1–10 M, the hydrogel will shrink. This is due to the decreasing osmotic pressure difference between the gel and the solution. The solution now has an osmotic pressure in the range of the osmotic pressure inside the gel (Guvendiren et al., 2009). The interaction between pH-sensitive polymers and the biological environment ultimately governs how biological processes proceed on these materials, for example, biomolecule adsorption/desorption and cellular interaction. By controlling the surface physical and chemical properties of materials, the interfacial characteristics can be altered to dictate these interactions. The versatility with which the surface characteristics can be manipulated and switched using external stimuli means pH-sensitive polymers have received much interest for the potential to alter biological interactions/functions. Many biological mechanisms are strongly affected by the levels of charge in ionic strength required to switch such materials. The adjustment in pH alters the ionic interaction, hydrogen bonding, and hydrophobic interaction, resulting in a reversible microphase separation or self-organization phenomenon. For example, because the extracellular pH of most tumors is acidic (pH 5.8–7.2), smart polymeric nanodevices can be designed for anticancer drug delivery, where the release of drugs can be triggered by manipulating pH. The pH triggering can be done by incorporating a pH-responsive moiety into the polymer structure, destabilizing a self-assembled polymeric aggregate, or by chemical conjugation of pH-liable linkage between polymers and drugs. These strategies are particularly useful in targeted drug delivery (Arya et al., 2017; Colby et al., 2017).

3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS From the viewpoint of chemical structure, many pH-responsive polymers can be designed.

3.3.1  Classification of pH-Responsive Polymers There are two principal kinds of pH-responsive polymers: polymers with acidic groups and polymers with basic groups, and they can be obtained from natural sources or by synthetic procedures.

50

3.  pH-RESPONSIVE POLYMERS

Natural ­pH-responsive polymers and multiresponsive polymers have gained great attention in the last decade. 3.3.1.1  pH-Responsive Acidic Polymers Also called polyacids or polyanions, acidic polymers contain acidic functional groups in their structures. Changes in the external pH determine the total number of negatively charged groups on the polymer chain allowing hydrophilicity tuning in the aqueous media. We can classify them depending on their functional groups. Carboxylic acid. The most commonly studied member of this group is PAA (Fig. 3.1A). This group of polymers present carboxylic acids (COOH) attached to the polymer chain. The COOH groups start to deprotonate at high pH values (low concentration of H+ ions) and release their H+ ions producing an increase of negatively charged groups in the polymer chain. The opposite effect is observed at low pH. The value of the dissociation constant (Ka) of the acid determines the pH at which the acid becomes ionized, and this value in the polymer is different from the monoacid and depends on their polymeric composition and molecular weight (Bazban-Shotorbani et al., 2017). For example, the pKa of PAA is reported to be 4.28 (Kurkuri and Aminabhavi, 2004); at pH values below 4.28, the polymer becomes predominately uncharged, and from a pH value of 4.28, it is anionically charged. The effect of the polymeric composition can be observed in Table 3.1. An increase in the length of the alkyl side groups causes stronger hydrophobic interactions, and this interaction originates a more compact structure resulting in an increase in the pKa (Kurkuri and Aminabhavi, 2004; Hoffman et al., 2001; Kharlampieva and Sukhishvili, 2003; Grainger and El-Sayed, 2010). Sulfonic acid. These pH-responsive polymers represent a class of strong polyelectrolyte hydrogels that possess a high degree of ionization. They have pendant sulfonate groups (SO3H) in their structure and present pKa values between 2 and 3. The most widely used polymers containing sulfonic groups are poly(2-acrylamido-2-methylpropane sulfonic acid) (PAMPS) and poly(4-styrene sulfonic acid) (Kim et al., 2004). Due to the high degree of ionization, these polymers present a gradual transition over a broad pH interval. This limitation restricts the use of these polymers as pH-responsive systems (Gao et al., 2015). TABLE 3.1  pKa of Different pH-Responsive Carboxylic-Containing Polyanions R

pKa

H

CH3

CH2CH3

CH2CH2CH3

CH2CH2CH2CH3

4.28

6

6.3

6.7

7.4



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

51

FIG. 3.2  (A) Chemical structure and pH-sensitivity of sulfonamides. (B) Usual substituent groups (R) for sulfonamides and their pKa values (Huh et al., 2012; Kang and Bae, 2002, 2003; Kang et al., 2001).

Sulfonamide groups. A new class of pH-responsive polymers was developed to overcome the challenges of sulfonic acid polymers (Park and Bae, 1999). These polymers are derivatives of p-amino benzenesulfonamide, which consists of the sulfonamide functional group attached to aniline (Fig.  3.2A). The sulfonyl group can act as an electron-withdrawing element from the amine nitrogen atom, resulting in ionization of the hydrogen atom attached to it (Fig.  3.2A) (Huh et  al., 2012). The pKa of these polymers depends on the chemical structure of the R group (Fig. 3.2B) and present a narrow transition pH range (0.2–0.3 units) (Kang and Bae, 2002). 3.3.1.2  pH-Responsive Basic Polymers Also called polybases or polycations, basic polymers contain basic functional groups in the polymer chain that can change the amount of positively charged groups in response to the external pH variation (Fig.  3.1B) by accepting protons at pH below their pKa, generally the ionization-­deionization transition undergo from pH 7–11 (Kocak et  al., 2017). The principal polycations present primary, secondary, or tertiary amine groups in the polymer chain and, in particular, vinyl, acrylamide, methacrylamide, acrylates, and methacrylates containing tertiary amine groups are some of the typical monomers that can be used to synthesize pH-responsive polymers (Huh et  al., 2012). For example, poly(N,N′-­ diethyl aminoethyl methacrylate) (PDEAEMA) (pKa ≈ 7.3) is in protonated and stable form in acidic or neutral environments but presents an abrupt precipitation over pH 7.4 (Schmalz et al., 2010). Another class of cationic polymers are polymers with nitrogen-­ containing groups, that is, pyridine, imidazole, pyrrolidine, or ­morpholino

52

3.  pH-RESPONSIVE POLYMERS

FIG. 3.3  Polycations with nitrogen-containing groups. (A) pH-sensitivity of poly(2-vinyl pyridine) and (B) pH-sensitivity of poly(4-vinyl imidazole).

(Wang et  al., 2014; Velasco et  al., 2011; González et  al., 2005; Gan et  al., 2001). The most common pH-responsive polycations are pyridine and imidazole derivatives. These polycations present a lone pair of electrons available for proton bonding (Fig. 3.3). An example of polypyridines are poly(2-vinyl pyridine) and poly(4-­ vinyl pyridine), which have pKa values of 5.9 and 5.39, respectively (Pinkrah et  al., 2003), and polymers containing imidazole are poly(N-­ vinyl imidazole) and poly(4-vinyl imidazole) with pKa values around 6 (Asayama et al., 2007). 3.3.1.3  pH-Responsive Natural Polymers Although a number of synthetic biodegradable polymers have been developed for biomedical applications, the use of natural biodegradable polymers remains attractive because of their abundance in nature, good biocompatibility, and ability to be readily modified by simple chemistry (Alvarez-Lorenzo et  al., 2013; Basu et  al., 2015; Hoffman, 2012). Natural polymers are promising materials in the delivery of protein drugs due to their compatibility, degradation behavior, and nontoxic nature on administration. On suitable chemical modification, these polymers can provide better materials for drug delivery systems. The salient feature of functional biopolymers is their all-or-none linear response to external stimuli. Small changes happen in response to varying parameters until the critical point is reached when the transition occurs in the narrow range of the parameter variation and, after the transition is completed, there is no significant further response of the system (Hoffman, 2012). Despite the weakness of each interaction taking place in a separate monomer unit, these interactions, when summed through hundreds and thousands of monomer units, can provide significant driving forces for the processes occurring in such systems. The use of biopolymers such as dextran, chitosan, alginate, and hyaluronic acid is very common in drug delivery systems. Chitosan. Chitosan is the only cationic polysaccharide of natural origin. It is obtained by partial deacetylation of chitin. The degree of deacetylation determines the percentage of primary amine groups in the polymer chain responsible for its pH sensitivity. The pKa value of chitosan is 6.5,



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

53

which means that chitosan is dissolved at pH values below 6.5 due to the protonation of amine groups, yet it precipitates at pH values over 6.5 due to the hydrogen bonding between uncharged amine groups and hydroxyl groups (Fig. 3.4) (Bazban-Shotorbani et al., 2017). Chitosan is the most extensively studied natural polymer for biomedical and pharmaceutical application. The pKa value close to the physiological pH make chitosan-based systems good candidates for drug delivery systems. It has been shown that extracellular pH in solid tumors (median, 5.5–6.5) is more acidic than normal tissue pH (median, 7.4–7.5) (Neri and Supuran, 2011). This difference provides available opportunities for the development of targeted drug delivery systems of anticancer and/or antiangiogenesis drugs (Dai et al., 2017; Majedi et al., 2014). Also, chitosan has been reported to enhance drug permeation across the intestinal, nasal, and buccal mucosa. Chitosan microspheres have arisen as a promising candidate in nasal or other mucosal administration for improving the transport of biomacromolecules such as peptides, proteins, oligonucleotides, and plasmids across biological surfaces (Chonkar et al., 2015). Alginate. Alginate is a nonbranched, high-molecular weight binary copolymer of (1–4) glycosidically linked β-d-mannuronic acid and α-l-­ glucuronic acid monomers (Fig. 3.4). The high acid content allows alginic acid to undergo spontaneous and mild gelling in the presence of divalent cations, such as calcium ions. These mild gelling properties are pH-­ dependent and allow the encapsulation of various molecules or even cells within alginate gels with minimal negative impact. Further, the carboxylic acid groups of alginic acid are highly reactive and can be appropriately modified for various applications. Alginate has been extensively investigated as a drug delivery device wherein the rate of drug release can be altered by variations in the drug polymer interactions as well as by chemical immobilization of the drug to the polymer backbone using the reactive carboxylate groups. Hydrophobically modified alginates are also used for drug delivery applications. The encapsulation of proteins and bioactive factors within ionically cross-linked alginate gels is known to greatly enhance their efficiency and targetability and, as a result, extensive investigation has been undertaken to develop protein delivery systems based on alginate gels (Mohy Eldin et al., 2016). A disadvantage of using alginate-based gels, apart from their poor degradability, is poor cell adhesion. Several natural polymers such as chitosan have been combined with sodium to increase the encapsulation efficiency and hence the protein (Treenate and Monvisade, 2017). Hyaluronic acid (HA). Hyaluronic acid has attracted particular attention due to its abundant existence in living organisms and the human body. HA is a linear anionic polysaccharide made of a repeated disaccharide of (1–3) and (1–4)-linked β-d-glucuronic acid and N-acetyl β-d-glucosamine monomer (Fig.  3.4). Hyaluronic acid has been combined with alginates,

54 3.  pH-RESPONSIVE POLYMERS

FIG. 3.4  Structure of (A) chitosan, (B) alginate, and (C) hyaluronic acid, which are pH-responsive biopolymers used in drug delivery systems.



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

55

chitosan, and other molecules to develop pH-responsive particles for drug delivery applications (Cai et al., 2017; Ekici et al., 2011). Additionally, pectin and carboxymethyl cellulose are other anionic polysaccharides with carboxylic functional groups; finally agar, carrageenan, and chondroitin sulfate also show pH-responsive behavior due to the presence of sulfonate groups in their structure (Bazban-Shotorbani et al., 2017)

3.3.2  Different Architectures of pH-Responsive Polymers The most common pH-sensitive polymer structures described in the literature are: linear homopolymers or copolymers; amphiphilic block copolymers, which form micelles; grafted copolymers; polymer brushes; star and dendritic polymers; nanoparticles; vesicles; or hydrogels (Fig.  3.5). Some of these examples are explained in this section.

FIG. 3.5  Different architectures and size of pH-responsive polymers.

56

3.  pH-RESPONSIVE POLYMERS

3.3.2.1  Amphiphilic Block Copolymers Block copolymers are promising candidates for preparing responsive soft materials due to their self-assembling properties. In solution, amphiphilic block copolymers can self-assemble into micellar structures, such as spheres, which can be used as nanoreactors and stimuli-responsive materials. pH-responsive amphiphilic block copolymers contain a number of ionizable groups in their main chains and pendants; therefore, their domains can be tuned to respond to aqueous environments. When the pH value is changed, these groups can accept or donate protons in aqueous solution to yield polyelectrolytes, weak polyacid, or weak polybase, depending on their structures and pH values. pH-sensitive triblock copolymers derived from poly(ethylene glycol) (PEG), poly(acrylamide), and poly(lactide) were synthesized by atom transfer radical polymerization (ATRP) (Pal and Pal, 2017). Encapsulation of fluorescence probe guest molecule (pyrene) into a copolymer micelle and its release behavior reveals that it is pH-stimulated and shows sustained release behavior at pH 7.4. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of hydrophobic drugs. Various groups have reported the microencapsulation of drugs in polymeric micelles, which have a core-shell architecture that self-assemble in aqueous media due to their amphiphilic block copolymers. PEG is a popular choice for a shell due to its biocompatibility and water solubility. Wang et al. (2017) described a multifunctional and programmable pH-­responsive nanoparticle composed of natural materials for doxorubicin (DOX) delivery. The nanoparticle was constructed from a cross-linked, pH-­sensitive polyamine core and tethered PEG chains. Under high or neutral pH, the PEG gel showed a collapsed structure; however, as the pH decreased, it demonstrated an increased volume transition and subsequent release of drugs. Reyes Ortega et al. (2013) prepared low molecular weight heparin (LMWH) NPs by W/O emulsion and inversion phase emulsion (O/W) using well-defined PMMA-b-PMAETMA block copolymers synthesized by reversible addition-fragmentation chain transfer polymerization. PMMA-b-PMAETMA sequences resulted in a self-assembled core-shell NP in water with a positively charged surface that interacts with negatively sulfated and carboxylate groups of LMWH. Stupp and coworkers (Shah et al., 2010) prepared supramolecular structures using peptide amphiphilic (PA), bioactive materials that self-assemble from aqueous media into supramolecular nanofibers of high aspect ratio. These molecules, targeted to serve as the components of artificial extracellular matrices, consisted of a peptide segment covalently bonded to a more hydrophobic segment such as an alkyl tail. They carried out an in vitro study showing that self-assembling PA scaffolds can support human mesenchymal stem



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

57

cell viability and chondrogenic differentiation, leading to upregulated gene expression of cartilage. They demonstrated in vivo that PA synthesized with a peptide-binding sequence to TGF β-1 significantly enhanced the regenerative potential of microfracture-treated chondral defects. Recently, Martín-Saldaña and coworkers develop a pH-sensitive nanoparticle with antioxidant and antiinflammatory properties (MartínSaldaña et al., 2018). The nanoparticles were based on a mixture of two pseudoblock polymer drugs, one composed of 1-vinylimidazol and a methacrylic derivative of ibuprofen and the other one composed of vinylpyrrolidone and α-tocopherol or α-tocopheryl succinate, which were used for the encapsulation of dexamethasone. The author studied in vivo the effect against cisplatin-induced hearing loss in rats. Cisplatin treatment produced a slight decrease of the pH environment of the tissue and induced the release of the dexamethasone in the inner ear. The combination of the copolymeric drug-based nanoparticle and the release of dexamethasone ameliorate cisplatin-induced ototoxicity in a murine model. 3.3.2.2  Hydrogels and Microgels Hydrogels are polymeric tridimensional networks that swell but do not dissolve in aqueous media. Polymer microgels are cross-linked particles that form a network structure like hydrogels. Both systems may absorb from 10%–20% up to thousands of times their dry weight in water. They are called reversible or physical gels when the networks are held together by molecular entanglements and/or secondary forces including ionic, H-bonding, or hydrophobic forces. In the opposite case, they are called permanent or chemical gels when they are covalently cross-linked networks (Hoffman, 2012). A mixture of physical and chemical crosslinked networks forms a semi-interpenetrated network (semi-IPN). Gels exhibiting a phase transition in response to change in external conditions such as pH, ionic strength, temperature, and electric currents are known as “stimuli-responsive” or “smart” gels. Anionic hydrogels have pendant groups such as carboxylic groups or sulfonic acid groups, and can be used to develop formulations that release drugs in a neutral or basic pH environment (Fig. 3.6). They can show sudden or gradual changes in their dynamic or equilibrium swelling behavior as a result of changing the external pH. The degree of ionization of these gels depends on the number of pendant acidic groups in the gel, resulting in increased electrostatic repulsions between negatively charged carboxyl groups on different chains. This, in turn, results in increased hydrophilicity of the network and greater swelling ratio at high pH. The kinetics of the swelling of the hydrogels can be controlled by changing the polymer composition and varying the ionic concentrations, which can be changed as the pH of the environment changes. Kim and Peppas (2003) studied

58

3.  pH-RESPONSIVE POLYMERS

FIG.  3.6  Hydrogel swelling behavior: In a cationic hydrogel at low pH, the drug is released due to the swelling of the polymer network. In an anionic hydrogel at high pH, the drug is released due to the swelling of the polymer network.

the mesh sizes of the HGs at different pH values, and they observed ­methacrylic acid (MAA) HGs with a very small mesh at pH 2.2 (18–35 Å) in the collapsed state, which became very large meshes (70–111 Å) in the swollen state at pH 7.0. In addition, as the MAA content of the feed monomers was increased, the mesh size decreased at pH 2.2 but increased at pH 7.0. When the cross-linking ratio of the copolymer increased, the swelling ratio decreased at both pH 2.2 and pH 7.0. Reyes Ortega et al. (2013) described a hydrogel formed by gelatin and sodium hyaluronate loaded with LMWH nanoparticles. Gelatin was chemically cross-linked with genipin, and sodium hyaluronate entanglements were distributed along the tridimensional network creating a semiIPN. The swelling degree of these hydrogels depends on the pH of the medium, allowing the highest swelling and LMWH release at physiological pH (pH 7.4). Conversely, cationic hydrogels contain basic pendant groups, such as amines, and swell at low pH (Fig. 3.6). Patil et al. (2012) described different hydrogel formulations based on the combination of an aliphatic triisocyanate with pH-insensitive amine functional polyether and pH-sensitive poly(ethyleneimine) segments in a minimally toxic solvent suitable for the sol-gel reaction. These hydrogels showed the capability to deliver glucose and regulate the pH of a DMEM culture medium when the pH of the medium became acidic due to the evolution of cell culture. The ability of the



3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

59

hydrogel to perform these functions “automatically” represents a highly promising and convenient approach to the long-term support of living cells in laboratory-scale cultures. Yu et al. (2014) developed a stable supramolecular hydrogel based on a combination of 4β-aminopodophyllotoxin, a derivative of podophyllotoxin (POD), low-molecular-weight methoxy-poly(ethylene glycol), and α-cyclodextrin (α-CD). The hydrogel demonstrated unique gel-sol transition properties and pH-dependent drug release behavior in acidic environments, such as a tumor environment. 3.3.2.3  Polymer Brushes Stimulus-responsive polymer brushes (SRPB) are a category of polymer brushes that exhibit a change in their conformation, surface energy, or change state triggered by an external stimulus such as a change in solvent, temperature, pH, ionic strength, light, or mechanical stress. The control and reversible polymer chain conformation and surface energy discovery in SRPB has offered exciting and novel possibilities for the fabrication of adaptive or responsive surfaces and interfaces. pH-responsive polymer brushes contain ionizable pendant groups that can accept or donate protons in response to an environmental change in pH. These brushes often contain weakly acidic or basic groups with pKa values around which the degree of ionization is dramatically altered. A rapid change in the net charge of pendant groups causes a dramatic change in the hydrodynamic volume of the polymer chains, which ensues from changes in the osmotic pressure exerted by mobile counterions neutralizing the polymer charges. Moreover, pH-responsive polymer brushes are typically also responsive to changes in ionic strength, where screening of repulsive electrostatic interactions increase with increasing ionic strength resulting in brush collapse (Chen et al., 2010). Another innovative application was developed by Yan et al. (2016). A layer of PMMA was covalently immobilized over a layer of antimicrobial peptides (AMP). Under physiological conditions, the PMMA chains remain expanded and render the hierarchical surface biocompatible to mammalian cells. When bacteria colonization occurred on the surface, the physiological medium becomes acidic, and the PMA chains collapse exposing the underlying AMP, and therefore, the hierarchical surface became bactericidal. This work broadens the clinical applications of cationic AMP and provides the basis for the development of smart materials with multifunctionalities to practical biomedical applications. 3.3.2.4  Nano- and Microparticles Polymers containing ionizable groups, such as amines and carboxylic acids, are the best candidates for fabricating pH-sensitive nanocarriers. Particulate carriers offer some unique advantages such as delivery,

60

3.  pH-RESPONSIVE POLYMERS

s­ ensing, and image enhancement agents (Felber et al., 2012). These nano-/ microcarriers are generally considered for use in the target-specific drug or gene delivery systems to various sites in the body, to improve therapeutic efficacy, while minimizing undesirable side effects. One advantage of these pH-responsive carriers is their capacity to respond specifically to a certain pathological trigger. Some particles are based on a core and a shell, with different compositions and properties in each layer. Zou et al. (2015) prepared pH-responsive microspheres based on chitosan. In their study, a novel inverse emulsion-ionic cross-linking approach was adopted to prepare pH-responsive chitosan microspheres. The results showed that drug release occurred faster in acidic media, and microspheres have potential as carriers for intelligent drug delivery systems. Yu et  al. (2009) developed drug-loaded microparticles based on chitosan, alginates, and pectin. An alginate with carboxyl groups shrank at low pH but dissolved at high pH. Therefore, the solubility of chitosan was reduced by the alginate network under low pH conditions. The dissolution of alginate was reduced by chitosan at high pH. Results showed that drug release at pH 1.2 and 5.0 was slow. The release at pH 7.4 was much faster. These microparticles had a high pH sensitivity and can be potentially used for site-specific protein drug delivery through oral administration. 3.3.2.5  Dendritic Polymers Dendritic architectures (Fig. 3.7A) show very beneficial properties for the development of drug delivery systems and thus many different systems based on dendrimers, dendroms, or hyperbranched polymers have been developed (Oliveira et  al., 2010). In general, one can distinguish between two different release mechanisms from dendritic molecules depending on the way the guest was incorporated (Wong et  al., 2012) (Fig. 3.7B). Either the guest molecule is incorporated and retained by noncovalent interactions or it is covalently bound via a pH-degradable linker to the dendrimer. In the case of noncovalent encapsulation, the guest is released due to the protonation of internal functional groups or due to the cleavage of the shell. Some dendritic molecules already show pH-responsive behavior without requiring further modification (York et al., 2008). The first dendrimer used for the encapsulation of a guest molecule was a poly(propylene imine) (PPI) dendrimer. Malik and coworkers modified the PPI dendrimer surface with protected amino acids and encapsulated different guests in the so-called “dendritic box” (Malik et al., 2000). Over the last decade, pH-responsive dendrimers have attracted growing attention in smart delivery of pharmaceutical agents. PPI and poly(amidoamine) (PAMAN) are the most used dendritic carriers due to the presence of primary amines on the periphery and tertiary amines at



61

3.3  KEY TYPES AND PROPERTIES OF pH-RESPONSIVE POLYMERS

Dendroms linking

Dendrom

(A)

Dendrimer

Y Y Y

Y

Y Y

Y Y

X

X Y

Y

Initiator core

Y YY YY Y Y Y

Y Y

X

Y

Y Y Y Y

X

Y

Y

Y

Y

Y

Y

Y

Y Y

Y

X

Y Y

Y

Y

Divergent synthesis method Y

Y

Z Y

Y

+

Z Z

Y

Z

Z Z

(B)

Y

Y

Y

Y Y

Z

Y

Y

+

Y

Y Y

+ Y

YY

Y

Y

Y

Y

Y

Y

Y

Y

Convergent synthesis method

Y YY YY

Y Y Y Y Y Y Y Y Y Y YY

Y YY Y

Y YY

Y

Y Y

Y

Y Y Y Y Y Y Y Y Y Y YY

Y Y YY Focal point Z

Y Y

YY Y Y

Y

Y Y

FIG. 3.7  Scheme of (A) dendrom structure and dendrimer architecture and (B) different dendrimer methods of synthesis.

branching points (Bazban-Shotorbani et al., 2017). Hydrophobic drugs can be encapsulated into the hydrophobic core of the dendrimer and release in acidic condition. The protonation of the amine groups decreases the dendrimer hydrophobicity and changes the conformational structure, which can cause faster release of the drug (Liu et al., 2009). The direct conjugation of drugs to the end of the dendritic backbone via pH-degradable linkers is also a powerful tool in designing responsive drug delivery systems (Lee and Nan, 2012). The conjugation of DOX to polyester dendrimers via acid-labile hydrazone bonds reduced their cytotoxicity in physiological conditions, but at pH = 6 a rapid release of the drugs was observed. This behavior makes these systems an ideal candidate for cancer-targeted drug delivery (Padilla De Jesus et al., 2002; Calderon et al., 2011).

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3.  pH-RESPONSIVE POLYMERS

3.4  SYNTHESIS OF pH-RESPONSIVE POLYMERS In the next section, the most innovative and frequently used methods for the preparation of pH-responsive polymers are described.

3.4.1  Emulsion Polymerization Emulsion polymerization is among the most popular synthetic routes to prepare vinyl-based pH-responsive polymers, especially microgel systems (Rao and Geckeler, 2011; Chandra Sekhar et  al., 2014; Chen et  al., 2015a; Kuznetsov et al., 2016; Ramos et al., 2014). This technique employs a radical chain polymerization methodology to form latexes of narrow particle size distributions. The emulsion polymerization systems are commonly composed of monomer(s), water, water-soluble initiator, and surfactant (emulsifier). Colloidal stabilizers may be electrostatic, steric, or electrosteric (combining both stabilizing mechanisms). When phase separation occurs, the formation of solid particles takes place before or after the termination of the polymerization reaction. One of the disadvantages of this technique is the use of surfactants, which may need to be removed at the end of the polymerization reaction, but it is not always easy to carry out. The removal of surfactant, either by dialysis or desorption, may lead to coagulation or flocculation of the latex. An alternative process is the surfactant-free emulsion polymerization characterized by the absence of added emulsifier (Rao and Geckeler, 2011). This kind of emulsion polymerization can be used to prepare well-­ defined core-shell NPs (Hu et al., 2014b; Zhang et al., 2014). Hu et al., for example, developed silica/poly(styrene-N,N-dimethylaminoethyl methacrylate) cationic pH-responsive core-shell. These particles exhibited a diameter of  7 (Zhou and Huck, 2005).

3.6  CONCLUSIONS AND FUTURE TRENDS This chapter has attempted to compile the most recent advances performed in the field of pH-sensitive polymers and their applications as drug and gene delivery carriers, and biosensors. pH-sensitive hydrogels are basically polyelectrolytes of either charge and operate by widening



3.6  Conclusions and Future Trends

77

of the mesh sizes of their network, resulting from repulsive forces developed due to ionization or protonation of the constituent polymer chains. Whereas cationic polyelectrolytes such as chitosan work well in the low pH environment of the stomach, anionic hydrogels such as PAA, PMA, etc., work efficiently in the alkaline environment of the colon. Depending on the end application and desired functioning, various geometrical and chemical architectures such as polymer brushes, amphiphilic block copolymers, hydrogels, and nanoparticles have been designed to achieve high performance. Polymer brushes find application in stimuli responsive surfaces, chemical gates, cell-growth confinement, etc. Block copolymers and, in particular, amphiphilic block copolymers, di- and triblock copolymers, biodegradable aliphatic polyesters, etc., have been prepared by specific well-controlled methodologies such as GTP, ATRP, and RAFT polymerization, and they have been evaluated for many biomedical applications. pH-responsive polymers of different chemical architecture with novel physicochemical properties have shown potential for applications as promising drug-carrying vehicles in various drug delivery technologies. Although their synthesis and in vitro study seems to be simple, from the viewpoint of in vivo applications, the polymer systems need to be judged with extreme care before they can be accepted ultimately for commercial applications. The use of pH-sensitive polymers in drug delivery technologies not only has to focus on the possible medical benefits but must also consider the economic aspects of the developed materials and/or technology. Huge efforts in synthetic polymer chemistry must be undertaken to design tailor-made macromolecular systems that will offer novelty in their operation and performance. Above all, the systems developed must be acceptable to the patient community who are the end-users of any successful research and technology. Because pH-responsive polymers can be obtained under economical experimental conditions, there is large scope for synthetic polymer chemistry to commercialize DDS with these kinds of polymers and incorporate them into multiresponsive systems. The next generation of biomaterials looks toward the development and clinical use of smart materials, which will allow better control over processes occurring postimplantation. The host site may itself control the material through local changes in pH, ionic strength, or other specific molecular interactions. The use of supramolecular assemblies of responsive polymers (e.g., shell or core cross-linking structures) can be utilized to achieve long-term structural stability of sensors. The detection motifs exhibiting more sensitive and selective responses should be further developed and incorporated into responsive polymer matrices, aimed at sensing and discriminating subtle changes in the gradients and concentrations of pH, temperature, glucose, bioactive small molecules, and other biorelevant ­macromolecular

78

3.  pH-RESPONSIVE POLYMERS

species. The development of pH-responsive polymers is centered on systems capable of selectively detecting multiple analytes simultaneously. The challenge remains to optimize material responses and to incorporate these into medical devices to ensure that these novel smart materials reach their application potential, both in vitro and in vivo. In vivo uses are becoming more thoroughly investigated, with promising work toward disease therapies and targeted drug delivery. Dual stimuli-responsive materials will give rise to technologies that combine different properties, augmenting both the specificity and efficacy of cell targeting, cell responsiveness, and drug delivery. By appropriate copolymerization, cross-linking, and ligand attachment, the properties of smart materials can be tailored to meet the needs of specific applications. These novel strategies for producing smart materials are so far providing exciting new tools for drug delivery, neuronal and other cell manipulation, and tissue engineering for regenerative medicine. However, much of the work done to date is purely experimental and of little immediate clinical benefit.

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C H A P T E R

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Photoresponsive Polymers X. Xiong, Aránzazu del Campo, J. Cui INM—Leibniz Institute for New Materials, Saarbrücken, Germany

4.1 INTRODUCTION Photoresponsive polymers undergo a change in their properties in r­esponse to a light stimulus (Irie and Ikeda, 1997; Shibaev et  al., 2003; Zhao, 2007; Krauss et  al., 2010). Different molecular properties can be light-­regulated, including conformation (Shinkai et  al., 1982; Nor et  al., 2007; Lai and Hong, 2010; Gupta et  al., 2008; Ruchmann et  al., 2011; Everlof and Jaycox, 2000; Irie, 1993), polarity (Zakhidov and Yoshino, 1995; Wu et al., 1999; Hidayat et al., 2002; Sajti et al., 2002; Pandey et al., 2012; Wang et al., 2012), amphiphilicity (Chen et al., 2011; He and Zhao, 2011; Chen et al., 2012a; Han et al., 2012), charge (De et al., 2010; Fries et al., 2010; Byrne et al., 2011), optical chirality (Mayer and Zentel, 1998; Zhang et al., 2011a), conjugation (Kim et al., 2005; Uchida et al., 2005), etc. The light-­induced molecular change is reflected in a macroscopic change of material ­properties such as shape (i.e., contraction or bending), wettability, solubility, optical properties, conductivity, adhesion, etc. Light-control possesses intrinsic advantages compared to temperature, pH, electric, and magnetic stimuli: (i) noncontact and remote control, (ii) can be easily dosed to tune the strength of the response, and (iii) allows accurate temporal and positional resolution of the response. The functionality and, ultimately, the application potential of such a polymer are mainly determined by three parameters: (i) the magnitude of the property change after light triggering, (ii) the rate at which this change occurs, and (iii) the reversibility of the process. In general, an ideal responsive polymer is one that exhibits instantaneous and drastic property variation upon light exposure. Depending on the application, a modulation of the response with the light intensity or a reversible property change may also be advantageous. To obtain photoresponsive polymers, a photoresponsive functional group (chromophore) needs to be incorporated into the polymer chain.

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Depending on the type of chromophore used, the response can be reversible or irreversible. Reversible systems can alternate material properties in two photostationary states and are used as switches. Reversibility is important in many applications such as information store (Feringa et al., 2000) or artificial muscles (Ikeda et  al., 2007) and actuators. Irreversible chromophores are mainly photocleavable, which could be applied to photoinduced micropatterns, photodegradable materials, and controlled drug delivery. The advantage of irreversible chromophores is the possibility of 100% photoconversion because no equilibrium between two states is involved. This leads to the effective release of drugs (Zhao, 2009) or to a drastic decrease of the molecular weight in degradation application (Pasparakis et al., 2012). Different aspects of photoresponsive polymers have been recently reviewed: Fustin and Gohy summarized reported work on photoresponsive block copolymers (Schumers et al., 2010a); Zhao and coworkers reported their light-induced self-assembly, copolymer micelles, and light-cleavable main-chain photoresponsive polymers (Zhao, 2009; Zhao, 2012; Gohy and Zhao, 2013; Yan et al., 2013); Yan et al. summed the photoresponsive polymeric micelles (Huang et al., 2014); Theato et al. reviewed the photosensitive polymers containing photoremovable groups (Zhao et al., 2012); Das and coworkers reported pseudorotaxane-based photoresponsive assemblies (Mandal et al., 2015); Tian et al. reviewed the functional host-guest photoresponsive system (Qu et  al., 2015); and Wang et  al. reviewed the amphiphilic azo polymers and their photoresponsive properties (Wang and Wang, 2013). In addition, several reviews about azobenzene-based polymer systems (Goulet-Hanssens and Barrett, 2013; Bushuyev et  al., 2017; Wei et  al., 2015; Yu and Ikeda, 2011; Ikeda et  al., 2007; Iqbal and Samiullah, 2013; Yu, 2014; Mukhopadhyay et al., 2014), light-triggered actuation (Priimagi et al., 2014; Bisoyi and Li, 2014; Bisoyi and Li, 2016), supramolecular systems (Lee and Flood, 2013; Jones et al., 2016; Draper and Adams, 2016), drug delivery (Cho et al., 2015; Rwei et al., 2015; Bansal and Zhang, 2014; Swaminathan et al., 2014; Linsley and Wu, 2017), and so on (Wondraczek et al., 2011; Zheng et al., 2013; Al-Malaika et al., 2010; Barrett et al., 2007; Ercole et al., 2010) have been recently reported. We also highlighted the functionality and application of photolabile polymer at surfaces (Cui et al., 2013a). In this review, we focus on representative examples of recently developed polymer systems incorporating p ­ hotosensitive groups excluding blends (Suzuki and Tanaka, 1990) and self-­assembled (Wang et  al., 2007; Willerich and Gröhn, 2010) photosensitive polymers, which have been recently reviewed elsewhere (Yu and Ikeda, 2011; Yagai and Kitamura, 2008). We introduce the main types of chromophores and photoresponsive polymers and their properties in Sections 4.2 and 4.3. Special attention is paid to supramolecular polymers as one of most relevant developments in the last several years. The main applications for these



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systems are described in Section 4.4, including controlled drug delivery, patterned thin films of hydrogels and polymer brushes, photodegradable materials, and liquid crystal actuators. Finaly, we give our critical view of the field and its future development.

4.2  CHROMOPHORES AND THEIR LIGHT-INDUCED MOLECULAR RESPONSE Chromophores can be classified into two categories: reversible and irreversible. Reversible chromophores, often named molecular switches, undergo a reversible isomerization upon light excitation at a specific wavelength. The photochromic interconversion between isomeric forms allows switching the properties of the polymer material by irradiation at two different wavelengths. Fig. 4.1 presents some examples. Azobenzene

FIG. 4.1  Typical examples of reversible and irreversible photoresponsive groups.

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alternates between planar trans form and bent cis form via light-induced isomerization of the NN bond (Barrett et al., 2007). When coupled to a polymer chain, azobenzene has enabled switching of hydrophilicity (Zhao, 2012), chirality (Maxein and Zentel, 1995), optical properties (KozaneckaSzmigiel et al., 2011; Kravchenko et al., 2011; Alicante et al., 2012; SchabBalcerzak et  al., 2012), and coordinative interaction (Barille et  al., 2009; Royes et al., 2012) in polymer materials. Spiropyran changes from an unconjugated spiroheterocycle to a charged planar merocyanine (MC) form with extended conjugation (Paramonov et  al., 2011). The light-induced change of a neutral to a charged system has been applied to control wettability (Anastasiadis et al., 2008), vesicle dissociation (Lee et al., 2007), molecular recognition (Andersson et al., 2008), solubility of polymer chains (Szilagyi et al., 2007), and ion penetration (Nayak et al., 2006). Ultraviolet (UV) irradiation of a spirooxazine initiates an electrocyclic ring-opening reaction of a closed spiro form, which results in the formation of an open MC form with an extended conjugated system able to strongly absorb in the visible region (Nori and Chu, 1983). Diarylethene exists as either antiparallel or parallel rotamer. Under light exposure, the antiparallel rotamer undergoes closing of the six-membered ring within its core (Walko and Feringa, 2007). When attached to a polymer chain, cyclization can induce an extension of conjugation structure and rigidification. This leads to a change in the photoelectric properties of the polymer, i.e., oxidation properties of polythiophene, conductivity of polyfluorene, or fluorescence quantum efficiency of a photochromic system (Luo et  al., 2011). In the case of fulgides, UV irradiation results in the closing of the six-­membered ring within its core, which results in the formation of thermally irreversible colored isomers (Yokoyama, 2000). These three examples involve light-­induced intramolecular transitions. Coumarin derivatives undergo reversible intermolecular dimerization to form thermally stable and colorless isomers in response to light (Cardenas-Daw et al., 2012). Dimerization has been applied to adjust the lower critical solution temperature (LCST) of polymers or to stabilize polymersomes by intramolecular or intermolecular cross-linking. Typical examples of irreversible chromophores include photolabile protecting groups (o-nitrobenzyl, coumarin-4-ylmethyl derivatives, and phenacyl esters (Inomata et al., 2000)), pyrenylmethyl, cinnamate derivatives (Ding and Liu, 1998), and 2-naphthoquinone-3-methides (Zhao, 2009; Arumugam and Popik, 2009, 2011a, b; Arumugam et  al., 2012). Photolabile groups are cleaved from the polymer chain upon light exposure. Depending on the position in the chain where the chromophore has been inserted, different light-induced molecular processes can be induced: charge generation in the side groups (Brown et  al., 2009a, b; Cui et  al., 2011), depolymerization and chain shortening (Zhao et al., 2012; Theato, 2011), activation of catalyst and “click” reactant, the formation of active



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groups, etc. (Mayer and Heckel, 2006) o-nitrobenzyl ­derivatives undergo light-­induced intramolecular oxidation resulting in the released (uncaged) functionality and a nitrosocarbonyl byproduct, while (­ coumarin-4-yl) methyl leaves a solvent-trapped coumarin byproduct (Goeldner and Givens, 2005). Upon irradiation, phenacyl esters undergo a cleavage by homolytic CO bond scission to give an acryloxy radical and a phenacyl derivative radical. The rapid H atom transfer to the acryloxy radical to yield the carboxylic acid and p-methoxyacetophenone as the photoproduct (Bertrand et al., 2011; Bertrand et al., 2012). 2-naphthoquinone-3-methides generate a highly ­reactive radical that can selectively react with vinyl compounds incorporating an electron-donating group (i.e., oxygen) via very rapid Diels-Alder, adding 2-naphthoquinone-3-methides into the reaction, resulting in the coupling of two species (Arumugam and Popik, 2009, 2011a,b; Arumugam et  al., 2012). Incorporating this group into polymer side chains enables light-induced reactivity, which is useful in photolithography.

4.3  KEY TYPES AND PROPERTIES OF PHOTORESPONSIVE POLYMERS From the viewpoint of chemical structure, several key types of photoresponsive polymers were collected.

4.3.1  Main-Chain Photochromic Conjugated Polymers Photosensitive groups able to switch between a conjugated and a nonconjugated structure (i.e., diarylethenes and spiropyrans) can be introduced into the backbone of a conjugated polymer chain and applied to switch the optoelectronic properties of the material (Luo et al., 2011). The first example of a diarylethene-based backbone photochromic polymer (1, Fig.  4.2) was reported in 1999 (Stellacci et  al., 1999). In the diarylethene open form, it exhibited an absorbance maximum, λmax, at 320 nm. Upon irradiation with a UV light at 313 nm, the open-form polymer was converted to the closed form, which shifted the λmax to >600 nm. The most interesting property of this system was the high quantum yield experimentally obtained for the photoconversion (86%), which was much higher than the 50% value predicted by theory, taking into account the coexistence of the two conformations in equilibrium. The authors attributed the experimental high quantum yield to the stabilization of the active conformation in the polymer structure as a consequence of collective conrotatory motions along the main chain. The switch between closed and open forms also enabled light regulation of the polymer electrochemical response: the closed form of 1 can undergo a reversible redox process whereas the open form

92 4.  Photoresponsive Polymers

FIG. 4.2  Polymers including reversible photosensitive groups in the main chain.



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decomposes during the redox process. This allowed a photogated electroswitch. This property has been demonstrated in the d ­ iarylethene-based oligothiophene 2 (Areephong et al., 2008). Terthiophene 2 was polymerized via electrochemical oxidation method. In the presence of light, only the open form was obtained, although both open and closed forms can undergo a reversible redox reaction (Areephong et al., 2008). The possibility of a photoregulated polymerization allowed the authors to deposit a pattern of the conjugated polymer on indium tin oxide (ITO). These results represent an important development for the manufacture of organic electronic devices, although no data on the photoswitching ability of the polymeric film were reported. Following this pioneering work, other two dithienylethene (DE)-based polymers (3, 4) were synthesized via Horner or Wittig reaction (Bertarelli et al., 2004). The inclusion of long alkyl chains in the polymer architecture made these systems soluble in tetrahydrofuran (THF) and facilitated the synthesis of polymers with higher molecular weights (Mn 11600 for 3 and Mn 2702 for 5). In 1999, a different diarylethene-based backbone photochromic polymer (6) was obtained via the Suzuki coupling of dioctylfluorene and diarylethene (Kawai et al., 1999). The resulting polymer had a photocontrollable electrical conductivity: 5.3 × 10−13 S cm−1 in open form and 1.2 × 10−12 S cm−1 in a closed-ring one. The higher conductivity of the closed-ring form was attributed to the extended conjugation pathway throughout the polymer backbone. Substitution of the dioctylfluorene by trimethylsilyl-­substituted phenylene vinylene increased the conductivity of the resulting polymer to 3 × 10−9 (open) and 2.5 × 10−8 (closed) S cm−1 in polymer 7 (Kim and Lee, 2006). Polymers 8 and 9 were also reported to have photoswitchable electrical conductivity (Choi et al., 2005; Kawai et al., 2005). In principle, any photochromic switching unit can be conjugated to a π-electron polymer to allow light-induced changes in the conductivity and optoelectronic properties. Dimethyldihydropyrene, for instance, was introduced into polymer 10 via Suzuki cross-coupling (Marsella et al., 2000). The closed form of polymer 10 allows conjugation through the switching core, whereas the open form has a localized electronic structure. A conductive polymer film was prepared from polymer 10, but solid-state switching could not be observed, presumably due to a slow switching speed. In polymer 11, containing the photochromic switch spirobenzopyran, an absorption band at >500 nm appeared upon irradiation at 365 nm due to the formation of highly conjugated MC (Yang and Ng, 2006). Azobenzenebased main-chain conjugated polymers (12, 13) were accomplished by polycondensation involving Sonogashira-Hagihara cross-coupling and Glaser coupling, respectively. Polymer 12 can undergo photoinduced E→Z isomerization, whereas polymer 13 does not due to the strongly enhanced π, π-stacking interactions of its electron-withdrawing acetylene units (Yu and Hecht, 2015). Polymer 14 could act as “molecular zippers” in the

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state of thin film in which light-induced E→Z isomerization of 20% azobenzene chromophores triggers a complete disorder of the alkyl chains, which induces the amorphization of the rigid main-chain polymer film (Weber et al., 2015). Main-chain azobenzene conjugated polymers could also show helically folded phenomenon with photoresponsive properties (Sogawa et al., 2013).

4.3.2  Polymers With Photoresponsive Terminal Groups Single photochromic groups attached to the ω-end of a polymer chain have also been used to control the properties of the polymer chains (Roth et al., 2010). Fig. 4.3 presents some examples. The first reported example was polymer 15 containing 2-diazo-1,2-naphthoquinone; a chromophoric unit can undergo Wolff rearrangement to form changed hydrophilic 3-­indenecarboxylates (Goodwin et al., 2005). Amphiphilic 15 can form micelles embedding dye molecules in aqueous solution. Upon irradiation at 350 nm, the change in the hydrophilicity of the terminal group causes dissociation of the aggregates’ release of the encapsulated dye. In a similar approach, polymer 16 was prepared by atom transfer radical polymerization (ATRP) of N-isopropylacrylamide (NIPAM) using an azobenzene derivative substituted with a 2-chloropropionyl group as an initiator (Akiyama and Tamaoki, 2007). Due to the differences in hydrophilicity between the cis (more hydrophilic) and the trans isomers, a cloud-point shift from 32°C to 34°C was induced by switching from trans to the cis isomer upon exposure at 365 nm. A similar effect was observed in poly(oligo[ethylene glycol] methyl ether methacrylate) with a single azobenzene end group (17 in Fig. 4.3) (Roth et al., 2010; Jochum et al., 2009). Similar polymers modified at both ends with azobenzene showed a LCST difference up to 4.3°C between irradiated and nonirradiated solutions (Jochum et al., 2009). It is worth mentioning that this strategy is only effective with low molecular weight polymer chains, and the end-group effects vanish with increasing molecular weight. Recently, several novel examples have been developed. For instance, the tadpole-shaped azobenzene polymer 18 can self-assemble into a large vesicle in aqueous solution, but undergo reversible smooth-curling transformation upon UV irradiation due to the quick trans-cis isomerization of the azobenzene moieties. It can be used for controlled release of drugs (Wang et al., 2015a). Polymers 19 and 20 show interesting photoswitchable fluorescence resonance energy transfer (FRET) properties. 4,4-Difluoro-4bora-3a,4a-diaza-sindacene (Bodipy, donor) and spiropyran (acceptor) are anchored on the terminals of polymers, respectively. The emission of Bodipy is only slightly quenched due to the weak conversion to the open form of spiropyran upon excitation at 360 nm. However, efficient energy transfer from Bodipy to the ring-opened MC form occurs owing to their good spectral overlap of polymers 20 (Kong et al., 2014).

4.3  Key Types and Properties of Photoresponsive Polymers

FIG. 4.3  Polymers containing photosensitive groups on the terminal.

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4.  Photoresponsive Polymers

Helical-shaped bulky alkenes are chiroptical switches and motors that can switch their helical sense in response to light (Feringa et  al., 2000). When attached as end-groups of a helical polymer chain (i.e., poly[nhexyl isocyanate] [PHIC] as represented in 21), they can alternate molecular chirality by light-driven rotation (Pijper et al., 2008). PHIC without a chiral unit adopts an equal ratio of right- and left-handed helical conformation. Addition of chiral end-groups induces the polymer chain to adopt a preferred helical sense (Green et al., 1999). Switching of the helical sense of the terminal group enables reversible control of the preferred helical sense even in the liquid crystalline state. Recently, DE is conjugated to ­oligo(para-phenylene) (polymer 22) for controlling the helicity of its ­assembled state. It was found that the photoisomerization of the chiral DE* terminal moieties prior to assembly leads to a change in the structure helicity (San Jose et al., 2014). In addition to the reversible system, the irreversible nitrobenzyl-based terminal group can also be used to mediate the self-assembly of polymers (de Gracia Lux et al., 2012). Amphiphilic polymers 23 and 24 could self-­ assemble into vesicles to encapsulate the drug doxorubicin (Dox) in aqueous. Upon UV irradiation, the cleavage of the nitrobenzyl group altered the hydrophobicity of the polymers and then triggered a disassembly to release Dox (Cheng et al., 2016; Liu et al., 2017). On the other hand, nitrobenzyl moiety could also be coupled with chain transfer agents (CTA) to prepare end-functionalized homopolymers (Coumes et al., 2016a,b)

4.3.3  Side-Chain Photochromic Polymers Fig.  4.4 presents recent examples of polymers with reversible ­ hotochromic groups incorporated in the side chains. In copolymer 25, p a dimethylaminoethyl methacrylate chain was copolymerized with a ­coumarin-based methacrylic monomer (Zhao et al., 2011a). The LCST of a diluted solution of the copolymer polymer could be modulated between 35°C and 65°C by photocontrolled intramolecular dimerization of the coumarin units upon exposure at 310 nm. The light-triggered formation of chain loops reduced interchain entanglement and caused an increase in the cloud point. Azobenzene- and spiropyran-containing copolymers with light-regulated LCST have also been reported (Zhao et al., 2010). The LCST of spiropyran-containing copolymers increased when the ­chromophore was switched from hydrophobic neutral form to the hydrophilic charged state. The mechanism of azobenzene regulation is less straightforward. In general, bent cis-azobenzene (with a dipole moment of ~4.4 D according to a density functional theory calculation) is more hydrophilic than the trans-azobenzene (0 D) and, therefore, the cloud point of the polymer increases when switching to the cis isomer. However, the contrary effect was observed in a copolymer of N,N´-dimethylacrylamide and

4.3  Key Types and Properties of Photoresponsive Polymers

97

FIG. 4.4  Polymeric systems with reversible photosensitive groups in the side chains.

98

4.  Photoresponsive Polymers

­azobenzene methacrylate. The cis form seems to interact with the neighboring N,N´-dimethylacrylamide unit, and this interaction decreases the LCST. The copolymer mixture 26 exploits the host-guest interaction of azobenzene and cyclodextrins (CD) as responsive engines to induce light-control assembly (Tomatsu et al., 2006). trans-Azobenzene can be selectively encapsulated by CD and, therefore, extend polymer molecular weight via intermolecular cross-linking. Upon UV exposure, the azobenzene unit undergoes trans-cis isomerization and is released from the α-CD site. This leads to an effective decrease in the molecular weight and, consequently, to a decrease of the viscosity of the solution. A similar strategy was used to control sol-gel transition (Tomatsu et al., 2005; Liao et al., 2010). Polymer 27 bears three distinct functional groups including ­azoaromatic, carbazole, and chiral spacer on the side chain, showing high optical activity, additional chiroptical and photoresponsive properties, which gives the possibility of application as a chiroptical switch (Angiolini et al., 2014). Liquid crystal polymers containing azobenzene groups in the side chains have also been reported. Polymers 28-35 (Fig. 4.4) (Fu and Zhao, 2015; Bobrovsky et al., 2014; Bobrovsky et al., 2017; Ryabchun et al., 2017; Kim et  al., 2014a; Cozan et  al., 2016) are interesting examples in which light-triggered conformational changes of the azobenzene units led to nematic/smectic-isotropic phase transitions (Yu and Ikeda, 2011; Li et al., 2003). These systems will be discussed in detail in Section 4.3. Isomerisation of spiropyran moieties (36 in Fig. 4.4) introduced in the side chain have also been used to modulate polymer solubility in an aqueous environment (Byrne et al., 2011). To avoid the incompatibility of the spiropyran derivative’s feature and ATRP technique, copper-catalyzed cycloaddition (click chemistry) was employed to obtain well-defined spiropyran functionalized polymer 37, which showed similar behavior with comparable ring-closure kinetics and photostability comparing with the star-like spiropyran polymers (Ventura et  al., 2014). Comb-shaped graft copolymer 38 at two side-chain lengths featuring polyacrylonitrile backbones and photoreactive side chains could be coated on the porous film to achieve self-cleaning properties. Before any photo treatment, the as-coated membrane surface comprises mostly hydrophobic spiropyran groups that allow the adsorption of organic solutes such as proteins on the membrane surface. Upon UV irradiation, the spiropyran groups are converted into hydrophilic MC groups, which leads to the release of adsorbed molecules and the full recovery of the initial water flux (Kaner et al., 2017). In addition to hydrophobicity, the sypropyran-based polymers could also be exploited as the photochromic acceptor of fluorescent moieties (Keyvan Rad et al., 2016), fluorescence photomodulation, or cell imaging (Chamberlayne et al., 2014; Lee et al., 2014). Recently, ­sypropyran-based copolymers were



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modified on upconversion nanoparticles via self-assembly and used for photocontrolled release by near-infrared (NIR) light (Xing et al., 2015). Photoresponsive polymers have great potential in photoswitchable molecular devices and optical memory storage systems. Polymer 39 contains 2, 5-demethyl (thienyl) ring with a photochromic ligand on the side chain (Price and Ragogna, 2013). It shows a very high recyclability with almost no decomposition after five cycles. In addition to this example, a series of photoresponsive and full-colored fluorescent-conjugated copolymers have been prepared by combining phenylene- and thienylene-based main chains with photochromic DE side chains. They show photoswitchable fluorescence in both solution and film states through light-controlled photoisomerization (Watanabe et  al., 2015). Copolymer 40 has both DE and fluorene moieties on side chains. Its fluorescence intensity significantly decreased with increasing photocyclizaiton conversion of the DE due to the quenched fluorescence of many fluorescence moieties by one closedring DE moiety (Nakahama et al., 2017). Fig.  4.5 shows some examples of reported polymer systems carrying irreversible photochromic groups in side chains. Polymer 41 bears a dimethylphenylsulfonium triflatecan unit as a photoacid generator, which undergoes homolytic cleavage followed by hydrogen abstraction and rearrangement to generate triflic acid after expose with UV light of 254 nm (Brown et  al., 2009b). The resulting strong acid catalyzes the hydrolysis of neighboring t-butyl esters and leads to the formation of poly(methacrylic acid) (PMAA). Thin films of this polymer show a light-induced wettability change. Simaliar photoacid generator can be incorporated into a polymer (42) for killing cell (Sumaru et  al., 2013) and photolithography (Liu et al., 2014a). In a different approach, photocleavable units attached to ionizable carboxylic or amine groups were exploited to change the solubility and wettability of polymer brushes (43, 44, 45) (Cui et  al., 2011, 2012a; Dinu et  al., 2016). Polymer 43 presents one example where the 4,5-­ dimethoxy-2-nitrobenzyl (NVOC) photocleavable protecting group is attached to the side chain carboxylic groups of a PMAA chain (Brown et al., 2009a). Light irradiation removed the NVOC group and released free carboxylic groups. When a surface covered with these polymer brushes was irradiated through a mask, a surface pattern with zones with different wettabilities was generated. Regulation of the exposure dose allowed the development of different wetting states as a consequence of different photoconversion degrees (Cui et al., 2012a). Based on this idea, a series of photolabile polymers with pendent nitrobenzyl groups (polymer 46, 47) have been developed and applied in micelles/nanoparticles preparation and drug/dye encapsulation (Olejniczak et  al., 2015; Zhao et  al., 2016; Shen et al., 2017). Polymer 45 also bears the NVOC-protected cationic moiety, but it was used to generate an intramolecular ionic pair for phototriggered cell uptake and slow releasing (Dinu et al., 2016). Both polymers 44 and 48

100 4.  Photoresponsive Polymers

FIG. 4.5  Polymers with photolabile groups on the side chains.



4.3  Key Types and Properties of Photoresponsive Polymers

101

have protected amine group. Polymer 44 was applied to light-control the selectively of ionic permeation when incorporated into the pores of membranes (Cui et al., 2011; Brunsen et al., 2012) whereas polymer 48 was used to make stable patterns by light-activating amine moieties to react with featuring pentafuorophenyl ester (Zhao and Theato, 2013). Polymer 49 represents a strategy to photoregulate the formation of supramolecular polymers by attaching a caged 2-ureido-4-pyrimidone (UPy) in the side chain (Foster et  al., 2009). UPy can dimerize via self-­ complementary quadruple H-bonding with high affinity (De Greef et al., 2009; Sijbesma et al., 1997). In polymer 49, UPy units were modified by reaction with the photolabile o-nitrobenzenyl. This modification ­inactivated the H-bonding acceptor. Irradiation of a diluted solution of polymer 49 removed the cage and induced intramolecular cross-linking by H-bonding, resulting in the formation of single molecular nanoparticles. In contrast, the o-nitrobenzyl chromophore in polymer 50 was designed as photodegradable cross-linker, which allowed UV-mediated depolymerization. This system underwent softening by 20%-30% upon irradiation at a dose tolerated by living cells (Frey and Wang, 2009). Similar photodegradable nanoparticle 51 was designed for controlling protein delivery. It was prepared by an emulsion copolymerization of 2-(dimethylamino) ethyl methacrylate and a photoliable o-nitrobenzyl diacrylate cross-linker. In a demonstration with bovine serum albumin and green fluorescent protein as model proteins, the nanoparticles show a photo-triggered release in presence of cells (Jiang et al., 2015).

4.3.4  Side-Chain Photochromic Block Copolymers Photosensitive block copolymers have been intensively studied due to their self-assembling properties and drug delivery applications. Several recent reviews (Zhao, 2009; Schumers et al., 2010a; Zhao et al., 2012) have been recently published and, therefore, this section only reviews recent developments. Fig. 4.6 presents diblock copolymers with reversible photoresponse. Most of these systems have been developed to photocontrol micelle formation by changing the hydrophilic-hydrophobic balance in the chain. Pioneering work was carried out in Zhao’s research group. They used ATRP to synthesize polymer 52, a block copolymer containing one random poly(t-butyl acrylate-co-acrylic acid) sequence and a poly-(methacrylate) block with azobenzene chromophores in the side chains (Tong et al., 2005). The polymer self-assembled into core-shell micelles or vesicles when the azobenzene adopted the trans form, an almost symmetrical structure with a near-zero dipole moment (no charge separation). Illumination of the micellar solution with UV light (360 nm) switched the trans azobenzene to its cis-isomer with a dipole moment of ~4.4 D, which resulted in a large increase in the polarity of the hydrophobic block. As a

102 4.  Photoresponsive Polymers

FIG. 4.6  Block copolymers with reversible photosensitive groups on the side chains.



4.3  Key Types and Properties of Photoresponsive Polymers

103

result, the azobenzene modified block was no longer hydrophobic enough to preserve the micellar association, and micelles dissociation occurred. By exposing the system to visible light (440 nm), the trans isomer was favored and micelles reformed. The transition can also be used to trigger a reversible sol-gel transition in triblock polymers system like 53 (Ueki et  al., 2015). This approach can be applied to any photochromic molecule with isomers with different polarities, like in the case of polymer 54 consisting of hydrophilic PEO block and methacrylate ester block with photosensitive spiropyrane on side chain (Lee et al., 2007). With its amphiphilic structure, 54, 55 (Wang et al., 2015b) self-assembled into micelles. Under UV irradiation, conversion of the hydrophobic spiropyran moieties into their hydrophilic zwitterionic MC counterparts occurred and, consequently, the micelles disassembled. Recovery of the micells was triggered by exposure to visible light (620 nm). Polymer 56 could act as the soft interface to control wettability and cell adhesion by alternating irradiation using UV and visible light (He et al., 2017). Polymer 57 formed micelles with reversible cross-links (Jiang et al., 2007; Babin et al., 2008), and polymer 58 formed liquid crystalline phases with photoswitchable orientation in the solid state (Yu et al., 2006). Fig. 4.7 exhibits the examples of diblock copolymers with irreversible photoresponse. Polymer 59 contains photolabile-protecting groups attached to carboxylic groups in the side chains (Jiang et  al., 2005). Upon UV irradiation, photosolvolysis of the pyrenylmethyl ester occurs, 1-­ pyrenemethanol is cleaved from the polymer chain, and carboxylic acid groups are released. As a consequence, the hydrophobic block turns into a hydrophilic PMAA block. Core-shell micelles formed by 59 disappeared after irradiation with UV light of 365 nm. This design was further validated with other chromophores (polymers 60-63) (Babin et al., 2009; Jiang et  al., 2006; Schumers et  al., 2012). Polymer 64 was prepared by a ring-opening polymerization of 3-methyl-3-nitrobenzyl-trimethylene carbonate bearing numerous nitrobenzene photolabile groups. It can self-­ assemble into spherical micelles upon heating in an aqueous solution. Upon light irradiation, a burst occurs on the particles, which could be used to release the encapsulated drug (Fang et al., 2015). Polymer 65 has a side chain containing disulfide spacer and pendant o-nitrobenzyl t­hioether group. This side chain can respond to both Glutathione and light, which allows for synergistic control release (Sun et al., 2015). Both polymer 66 and 67 also show light-activated release. In polymer 66, a photocleavable linkage is used to connect a cationic group that could effectively complex pDNA into salt-stable polyplexes with appropriate sizes (Green et  al., 2014). Irradiation-induced cleavage in 66 leads to facilitative pDNA release and efficient nucleic acid delivery. Compared to the cationic group, the functional retinoic acid group could be covalently attached to polymer 67 through a photosensitive nitrobenzene linker (Gupta et al., 2017). As a

104 4.  Photoresponsive Polymers

FIG. 4.7  Block copolymers with photolabile groups on the side chains.



4.3  Key Types and Properties of Photoresponsive Polymers

105

result of the amphiphilic structure, it could self-assemble into micelles. When exposed to a light of 365 nm, the nitrobenzene linker was efficiently cleaved and consequently, the retinoic acid released. In addition, nitrobenzyl group was recently integrated into polypeptide block polymers for the fabrication of photoresponsive nanomedicine (Liu and Dong, 2012), preparing thin films with nanostructures (Schumers et al., 2012), and prodrug releasing system (Hu et al., 2013). In polymer 68, the polystyrene (PS) and poly(ethylene oxide) blocks were connected by a photolabile o-nitrobenzyl linker (Theato, 2011). Light exposure cleaved the polymer backbone and separated the hydrophobic and hydrophilic blocks. This process was successfully carried out in both liquid and solid states. Thin films of polymer 68 can be annealed to generate a vertically aligned cylindrical morphology. After UV irradiation followed by methanol/water washing, the film leads to a nanoporous PS structure (Kang and Moon, 2009). This kind of diblock copolymer can be obtained either by ATRP polymerization or by copper(I)-catalyzed azidealkyne cycloaddition of the two presynthesized blocks. The latter method is preferred if the composition of the copolymer needs to be tailored (Han et al., 2012; Schumers et al., 2010b).

4.3.5  Photosensitive Dendritic Polymers Aida et al. reported the first azobenzene-core dendrimer in 1997 (Jiang and Aida, 1997). The phenyl ring on the periphery of the dendrimer can harvest the light at long wavelengths and transfer the energy into the core via a multiphoton absorption process, leading to the trans-cis transition of azobenzene. Reported work on light-harvesting dendrimers has been recently reviewed (Bradshaw and Andrews, 2011) and, therefore, we do not include them in this chapter. Azobenzene-based dendrimers or dendrons constitute a big family (Chen et al., 2012a; Deloncle and Caminade, 2010). The chromophore can be integrated into the molecular periphery, at internal positions, or in the core depending on the expected properties (Zhang et al., 2011b). Reported examples have been reviewed in 2010 (Deloncle and Caminade, 2010), and we collect here only relevant systems reported since then (Fig. 4.8). Dendrimer 69 contains azobenzenyl-linked polyphenylenes (Nguyen et al., 2011). Upon irradiation at 365 nm, the extended six dendrons curled toward the core as a consequence of the trans-cis transition of azobenzenyl spacers, resulting in high density closed structure. Because of its rigidity, the dendrimer can retain guest molecules in the closed form and release them in response to light. Such photoinduced size change is also found in carbosilane dendrimers bearing 4-phenylazobenzonitrile units (Koyama et al., 2009). Dendrimer 70 is the first water-soluble dendrimer that responds to light stimulus (Hayakawa et al., 2003). UV irradiation in

106 4.  Photoresponsive Polymers

FIG. 4.8  Photosensitive dendrimer and dendritic polymers.



4.3  Key Types and Properties of Photoresponsive Polymers

107

aqueous solution induces unusual irreversible trans-cis isomerization and leads to 100% of cis isomer. Interestingly, the fluorescence maximum of the stilbene core in this dendrimer shifted from 424 nm to 411 nm and then to 389 nm by increasing generation from G1 to G3. This shift was attributed to the isolation of the stilbene core by the hydrophobic dendron, which decreases the interaction between the stilbene and water and consequently, reduces the stabilization of the excited state of the stilbene core by water. Stilbene was also integrated into the branch, but the p ­ hoto-responsive behavior was not demonstrated (Cano-Marín et al., 2005). Hyperbranched polymer 71 obtained by modification of hyperbranched poly(ether amine) with 4-phenylazophenyl glycidyl ether self-assembled in aqueous solution at 80°C into nanoparticles with 10-18 nm diameter (Yu et al., 2010). Light exposure switched trans-azobenzene to the cis form, which caused an increase in the LCST of the system of 5.3°C. Linear-dendritic polymer 72 has an amphiphilic structure with azobenzene in the periphery and thus could encapsulate of both hydrophobic and hydrophilic molecules through forming polymeric vesicles in water. Light-induced trans-to-cis isomerization of the azobenzene moieties with a low dose can lead to the release of the loaded molecules (Blasco et  al., 2013a). In the case of amphiphilic linear-dendritic polymers 73 in which the azobenzenene moieties were diluted by alkyl chains, the trans-to-cis photoisomerization rate is faster (Blasco et al., 2013b). Polymer 74 has a hydrophilic core and an ­azobenzene-containing hydrophobic shell. With light stimulus, the ­polymer is able to encapsulate anionic guests from an aqueous solution to an organic layer (Cao et al., 2015). These polymers may be good candidates to develop drug delivery systems because they can be easily synthesized and possess intrinsic “core-shell” structures. In addition to delivery systems, photochromic azobenzene moiety could also be applied to prepare liquid crystalline and nonlinear optical materials (Kim et al., 2014b; Yang et al., 2016). Spiropyran is the other chromophore frequently incorporated into hyperbranched polymers. Polymer 75 is one of the recent examples (Chen et al., 2012b). It could self-assemble to biocompatible micelles with an average diameter of 186.3 nm. After 5 min of UV irradiation, the diameter of the micelles decreased gradually to about 100 nm, which is ascribed to the transformation of hydrophobic spiropyran to hydrophilic MC. This study provides a convenient way to construct smart nanocarriers for controlled release and re-encapsulation of hydrophobic drugs. Irreversible photoresponsive dendritic polymers have mainly been developed for photodegradation properties (Pasparakis et  al., 2012; Kevwitch and McGrath, 2007; Kevwitch and McGrath, 2001; Kevwitch and McGrath, 2002). Fig. 4.9 displays three examples containing photolabile groups at the core, the branch, or the periphery of the dendritic structures. Compound 76 is the first reported caged dendritic structure with a LeuLeuOMe unit on the periphery connected by a photolabile spacer to

108 4.  Photoresponsive Polymers

FIG. 4.9  Dendritic polymers with irreversible photosensitive groups.



4.3  Key Types and Properties of Photoresponsive Polymers

109

the core (Watanabe et al., 2000). Upon irradiation, about 50% LeuLeuOMe was released. Polymer 77 contains a photolabile core that converts the original polymer into smaller dendrons by photodegradation under UV exposure (Smet et al., 2000). Dendrimer 78 contains photolabile o-nitrobenzyl groups at the periphery, which formed a hydrophobic rigid shell that can prevent the diffusion of encapsulated salicylic acid (Li et al., 2010). UV exposure cleaved the chromophore and left an amine-terminated dendrimer, which breaks the shell. As a consequence, the release of encapsulated molecules in the dendrimer could be significantly improved. Polymer 79 has a linear-dendritic structure with a photolabile spacer. It was designed for light-triggered synergistic effect for releasing dyes (Kalva et  al., 2015). Diazonaphthoquinone was modified on linear-dendritic amphiphiles 80, the structure of which could undergo Wolff rearrangement and change from hydrophobic to hydrophilic triggered by both UV and NIR light. This transformation could increase the release rate of drug molecules stored in the self-assembled micelles of 80 and then kill the cells in an NIR-triggered manner (Sun et al., 2014).

4.3.6  Photosensitive Supramolecular Polymers In 1998, supramolecular polymers with photocontrol molecular weights were reported for the first time (Fig.  4.10) (Folmer et  al., 1998). These are formed by the self-assembly of telechelic polymers terminated into 2-­ureido-4-pyrimidone (UPy) units. UPy can dimerize by quadruple H-bonding with high affinity (Km of 2.2 × 106 M−1 in chloroform), building up long chains (Sijbesma et  al., 1997). A chloroform solution of this polymer (81) behaves like a solution of a conventional covalently linked polymer. The degree of polymerization and, therefore, the viscosity, shearing effects, and viscoelastic properties are controlled by the ratio of monofunctional UPy added to the solution, which end-caps the growing chains (Sijbesma et  al., 1997). By protecting the UPy end-groups or the monofunctional UPy with the photolabile group o-nitrobenzyl, the ability of UPy to dimerize is prevented. As a consequence, the polymerization and depolymerization processses can be tuned by irradiation with UV light. This phototriggering H-bonding strategy was applied to synthesize single molecule nanoparticles (polymer 49) and prepare light-responsive hydrogels with self-healing ability (Berda et al., 2010). Recently, we synthesized a novel silanizing agent containing o-nitrobenzyl protected UPy (82) for studying UPy dimerization underwater (Cui and del Campo, 2012). H-bonding cross-linking interaction is widely used to build higher structures in biological systems such as protein and nucleic acid but was rare in the synthetic systems underwater because of the disturbance of water molecules. To fully study the flexibility of the dimerization of UPy underwater, 82 was modified on a substrate to generate a photo-activated surface. In an in-situ comparison experiment, it was found that UPy-based

110

4.  Photoresponsive Polymers C13H27 N

O

N

C13H27

H

H

O

O

N

N

H

H

C6H12

N

N

H

H

(A)

N

O

n

NO2

N O

N

O N H

C13H27

C13H27 NO2

N

N

CH2O

N

N

O N

N

H

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C4H9

O

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H

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H

H

C4H9

81

O N H

Si

O

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82 NH O

Silicon

(B)

caged UPy-modified

UV

Silicon

O

N

N H

N H

UPy-modified

FIG. 4.10  (A) Supramolecular polymer consisting of two UPy units and monofunctional UPy unit with and without a photolabile protected group. (B) Silanizing agent containing o-nitrobenzyl protected UPy compound and its dimerization underwater. Adapted with permission from Folmer, B.J.B., Cavini, E., Sijbesma, R.P., Meijer, E.W., 1998. Chem. Commun. 1847–1848; Cui, J., del Campo, A., 2012. Chem. Commun. 48, 9302–9304.

copolymer can stably bond to the activated substrate even underwater. Based on this observation, UPy-based self-healing hydrogel was prepared (Cui and del Campo, 2012; Jeon et al., 2016). The sample idea was further expended to photoresponsive hydrogel thin film (Cui et al., 2013b). Another strategy to design photoresponsive supramolecular polymers is based on the host-guest interactions. Polymer 83 shows a typical ­system with stiff-stilbene as guest and bispillar[5]arene as host. Stiff-stilbene can transfer between Z and E configuration under 360 and 387 nm irradiation, respectively. The Z-configuration is favorable for forming a self-­ complexing structure with the bispillar[5]arene, whereas E-one prefers a linear supramolecular structure (Wang et al., 2014a). The formation and disassembly of the supramolecular polymer were reversible by alternating irradiation between 387 nm and 360 nm light (Fig. 4.11) (Wang et al., 2017). The same idea was also demonstrated by the system of stiff-stilbene and pillar[6]arene/pillar[7]arene (Xia et al., 2016; Chi et al., 2015) or used to prepare a multiresponsive gel (Xu et al., 2013). Fig.  4.12 presents a different example of photosensitive supramolecular polymers based on the host-guest interaction between CD- and adamantine-terminated dimers (Polymer 84) (Kuad et  al., 2007). The ­ ­stilbene spacer undergoes a light-induced reversible trans-cis photoisomerization and changes the orientation and the distance between CD units. In trans conformation, the monomers self-assemble into dimers or short ­oligomers. Upon irradiation with UV light of 350 nm, stilbene is converted into its cis conformation and allows the formation of supramolecular linear polymers with high molecular weights. A similar host-guest



4.3  Key Types and Properties of Photoresponsive Polymers

111

FIG. 4.11  (A) Chemical structures of light-responsive stiff-stilbene-bridged symmetrical guests (Z-G/E-G). (B) Photocontrolled assembly and disassembly of an AA/BB supramolecular polymer. Adapted with permission from Wang, Y., Sun, C.-L., Niu, L.-Y., Wu, L.-Z., Tung, C.-H., Chen, Y.-Z., Yang, Q.-Z., 2017. Polym. Chem. 8, 3596–3602.

interaction was exploited to prepare photoresponsive supramolecular hyperbranched polymer 85 using an azobenzene dimer and a β-CD trimer (Fig. 4.12B) (Dong et al., 2011). Light-induced trans-to-cis transition of the azobenzene results in a bended conformation of the guest and disfavored its host-guest interaction with β-CD. As a consequence, depolymerization occurs. Recent studies on azobenzene-based polymers with different terminal groups such as chiral binaphthyl (Sun et  al., 2013), adamantine (Liu et  al., 2014b; Nachtigall et  al., 2014), and other functional moieties (Xia et  al., 2014; Mazzier et  al., 2014; Endo et  al., 2016; Concellón et  al., 2016; Wang et  al., 2016a) have led to various novel multifunctional

112

4.  Photoresponsive Polymers

FIG.  4.12  (A) Structures of stilbene bis(β-CD) dimer and C3 guest dimer and the photoswitched transition between dimer and polymer. (B) Schematic representation of the photocontrolled polymerization and depolymerization of a β-CD3/Diazo supramolecular hyperbranched polymer based on host-guest interactions. (C) Chemical structures of the azobenzene-bridged pillar[5]arene dimer (H4) and switching between the assembly and disassembly of a supramolecular polymer by alternating between UV and visible light irradiation. A: Adapted with permission from Kuad, P., Miyawaki, A., Takashima, Y., Yamaguchi, H., Harada, A., 2007. J. Am. Chem. Soc. 129, 12630–12631; B: Adapted with permission from Dong, R., Liu, Y., Zhou, Y., Yan, D., Zhu, X., 2011. Polym. Chem. 2, 2771–2774; C: Adapted with permission from Ogoshi, T., Yoshikoshi, K., Aoki, T., Yamagishi, T.A., 2013. Chem. Commun. 49, 8785–8787.

­ hotoresponsive supramolecular polymers. One interesting example is p to trigger the reversible folding of the linear supramolecular polymer 86 (Fig.4.12C) (Adhikari et al., 2017). It was constructed via step-growth polymerization of azobenzene-bridged pillar[5]arene dimer (host molecule) and ­di-­pyridinium (guest molecule) (Ogoshi et al., 2013; Yang et al., 2014a), and its degree of polymerization increases exponentially with the concentrations of the building blocks. By using UV and visible light, the assembly and disassembly of the supramolecular 86 can be controlled. Tweezer/guest complexation is a novel method to build supramolecular polymer systems. Fig. 4.13 shows an example with ­bis[alkynylplatinum(II)]

4.3  Key Types and Properties of Photoresponsive Polymers

guest complexation.Adapted with permission from Gao, Z., Han, Y., Chen, S., Li, Z., Tong, H., Wang, F., 2017. ACS Macro Lett. 6, 541–545.

113

FIG. 4.13  Schematic representation for the formation of supramolecular polymer networks via hydrogen bond-assisted molecular tweezer/

114

4.  Photoresponsive Polymers

terpyridine as molecular tweezer and trans-azobenzene as recognition motif. In the assembled state 87, intermolecular O−H···N hydrogen bond forms, which enhance the cross-linking strength. Taking advantage of the trans-cis transition of the azobenzene moieties, the supramolecular network is photoresponsive (Gao et al., 2017).

4.4 APPLICATIONS Light-induced changes at polymer level can be reflected on the macroscopic level of material properties, which has been used in various applications.

4.4.1  Controlled Drug Delivery Polymer micelles or vesicles formed through self-assembly of photoresponse block copolymers can be applied as carriers for controlled drug delivery. Fig.  4.14 schematically illustrates the general mechanism for photocontrolled polymer micelles; light exposure induces solubility changes in the block modified with the photochromic group and, as a consequence, the micelles disassemble (Zhao, 2009; Zhao, 2012). Fig. 4.15 present a typical example of reversible photoregulated micelles (Lee et al., 2007). The diblock copolymer 54 self-assembles into micelles with the hydrophobic spiropyran-based block in the core. Light exposure switches hydrophobic spiropyran to its charged MC form, which enhances the solubility of polymer chains and, consequently, the micelles disassemble. When the micelle was loaded with a hydrophobic dye, UV exposure allowed the release of the dye, which could be re-entrapped by irradiation with visible light. Moreover, other functional groups can be incorporated into the s­ piropyran-related polymers to design multiresponsive micelles (Lee et al., 2014; Son et al., 2014; Shen et al., 2015). Fig. 4.16 shows a specific example of using photoresponsive polymers to control drug delivery (Shao et  al., 2014; Ji et  al., 2013; Barman et  al., 2015). In this system, coumarin was incorporated into linear dendritic copolymers to form photocross-linkable nanocarriers to load drug molecules. Obtained nanocarriers can be triggered to degrade to release the drug molecules in vivo by taking advantage of the photoinduced reversible dimerization of coumarin. In addition, azobenzene was another good host-guest inclusion candidate for self-assembling stable vesicles and rapid releasing of anticancer drugs (Xia et al., 2014; Li et al., 2014a; Zhang et al., 2015a; Xiao et al., 2015). Light excitation in the NIR is more convenient for drug delivery because it is able to penetrate the tissue and it does not cause cell damage. Although two-photon excitation can, in principle, extend the activation



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FIG. 4.14  Schematic illustration of various types of light-responsive block copolymer micelles. Adapted with permission from Zhao, Y., 2012. Macromolecules 45, 3647–3657; Gohy, J.F., Zhao, Y., 2013. Chem. Soc. Rev. 42, 7117–7129; Yan, Q., Han, D., Zhao, Y., 2013. Polym. Chem. 4, 5026–5037.

wavelength of a chromophore to the NIR region, most chromophores have low two-photon-absorption cross-sections, and the photoreaction occurs with low efficiency and requires high-power femtosecond pulse lasers. To overcome this limitation, Lanthanide-doped upconverting nanoparticles (UCNPs) have been proposed for building NIR light-response micelles (Fig. 4.17) (Yan et al., 2011). UCNPs can absorb NIR light and then convert it into higher-energy photons in the UV and visible regions, which is absorbed by the photochromic moieties of polymer 59 in the core-forming block. As a consequence of the photocleavage reaction, the core becomes hydrophilic, and the micelles dissociate and release their payload. This strategy can be applied to different photoliable groups and material systems (Song et al., 2013; Yu et al., 2015).

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FIG. 4.15  AFM images of (A) a micellar solution spin-coated on mica (a1 and a2 are height and volume distributions of micellar aggregates, respectively), (B) dissociated micelles after 30 min UV exposure (365 nm). (C) Reformed micelles after subsequent visible light (620 nm) exposure for 30 min, and (D) for 120 min (d1 and d2 are height and volume distributions of reformed micellar aggregates, respectively). Adapted with permission from Lee, H.-i., Wu, W., Oh, J.K., Mueller, L., Sherwood, G., Peteanu, L., Kowalewski, T., Matyjaszewski, K., 2007. Angew. Chem. Int. Ed., 46, 2453–2457.

4.4.2  Functional Micropatterns Site-selective exposure of thin films of photosensitive polymers using masks or scanning lasers can be applied to make functional patterns onto substrates, like the examples presented in Fig.  4.18 (Anastasiadis et  al., 2008; Barille et  al., 2011; Matsumoto et  al., 2008; Kim et  al., 2012). Thin



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FIG.  4.16  Illustration of the cross-linking and decross-linking process of the c­ oumarin-containing photosensitive phase-segregated micelle nanocarriers. Adapted with permission from Shao, Y., Shi, C., Xu, G., Guo, D., Luo, J., 2014. ACS Appl. Mater. Interfaces 6, 10381–10392.

films of the main-chain conjugated polymer 7 spin-coated on an electrode generate a color conductive pattern when irradiated through a mask with parallel micrometric stripes (Fig.  4.18A). The dark areas represent the masked, highly conductive region. The bright areas correspond to the light-exposed resistive region where diarylethene adopt open forms with lower conductivity (Kim and Lee, 2006). Azobenzene-based polymers have been repeatedly used for creating surface microreliefs or graftings when an interfering laser is used for illumination (Gong et al., 2011; Lomadze et al., 2011; Wang et al., 2011). Fig. 4.18B presents atomic force microscopy (AFM) images of the surface relief grating formed on films of epoxy-based polymers containing azobenzene groups at side chains after irradiation at 488 nm. Light exposure with high-energy interfering laser induces mass transport in the polymeric film, which involves the scission of covalent bonds and mass transition. The mechanism of the laser-induced periodic surface structure is still unclear, but the investigation of these surface relief graftings still attract great attention (Rocha et al., 2014; Koskela et al., 2014; Rianna et al., 2015; Landry et al., 2017; Zong et al., 2016). One of the interesting examples published recently is to create hierarchical surface patterns on azo-containing multilayer films. Large-area surface wrinkling was induced in the multilayer-based film/substrate system through external stimuli of heating/cooling processing. When the formed wrinkle morphologies were selectively exposed to visible light through copper grids, the wrinkle wavelength reduced gradually with the light irradiation and finally reached a saturated value. In contrast, the unexposed region evolved into highly ordered wrinkles, leading to microstructure patterns (Zong et al., 2016). Compared to the reversible chromophore system, thin films made from the irreversible photoresponsive system of polymer 43 can ­generate

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FIG.  4.17  (A) Photosensitive micelles that encapsulate upconversion nanoparticles (UCNPs) and allow excitation in the NIR; (B) Photo-triggered reaction occurred in the polymers of the micelles. Adapted with permission from Yan, B., Boyer, J.-C., Branda, N.R., Zhao, Y., 2011. J. Am. Chem. Soc. 133, 19714–19717.

FIG.  4.18  Patterns of (A) polymer 7, (B) azobenzenyl polymer, and (C) polymer 22. Adapted with permission from Kim, E., Lee, H.W., 2006. J. Mater. Chem. 16, 1384–1389; Gong, Y.-H., Li, C., Yang, J., Wang, H.-Y., Zhuo, R.-X., Zhang, X.-Z., 2011. Macromolecules 44, 7499–7502; Lomadze, N., Kopyshev, A., Rühe, J.r., Santer, S., 2011. Macromolecules 44, 7372– 7377; Wang, X., Yin, J., Wang, X., 2011. Macromolecules 44, 6856–6867; Cui, J., Huong, N.T., Ceolín, M., Berger, R.d., Azzaroni, O., del Campo, A., 2012. Macromolecules 45, 3213–3220.

a chemical pattern with regions of different wettability upon light exposure (Fig.  4.18C). The light-induced release of the o-nitrobenzyl photolabile protecting group from the polymer structure generates a polyelectrolyte and, consequently, makes exposed regions hydrophilic and pH-sensitive (Cui et al., 2012a). In contact with water or in a humid



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a­ tmosphere, the exposed regions can uptake water and swell, generating a surface relief with a pH-tunable height difference between irradiated and nonirradiated regions. o-Nitrobenzyl-based photoresponsive polymers are also good candidates for making hydrogel and cell patterns (Radl et  al., 2017; Li et  al., 2014b; Tsang et al., 2015; Ding et al., 2017). Fig. 4.19 shows a typical example that combines both photoinduced formation of thiol-ene network and photoinduced degradation of nitrobenzyl spacers. The hydrogel was prepared by photoinduced “click” reactions with visible light (λ > 400 nm), which does not induce any photocleavage of the nitrobenzyl links. Upon irradiation of UV light (λ < 400 nm), the cleavage of covalent links occurs. It can be used to create the second pattern (Fig. 4.19A and B) (Radl et al., 2017). Furthermore, the functional o-nitrobenzyl-ester-based polymres could be modified on the surface of the material and used for cell patterns. A novel strategy for constructing cell patterns on titanium substrates have been developed by combining o-nitrobenzyl with UCNP (Fig. 4.19C and D). The o-nitrobenzyl was used as a photolabile spacer to link the bioadhesive ligand arginine-glycine-aspartic acid (RGD) to UCNP. Upon an irradiation of the NIR light (980 nm) through a photomask, the UCNP could transfer NIR light into UV light in situ, which results in the photocleavage and detachment of the unsheltered cells for the formation of cell pattern (Ding et al., 2017). Photoreactive chromophores incorporated into polymer films can be used for inducing site-specific surface reactions and generation of chemical patterns. The chromophore 2-napthoquinone-3-methide generates highly reactive radicals upon exposure, which can selectively react with vinyl groups with electron-donating substituents, or turn back to their ground state and regenerate the photochemical precursor (Fig.  4.20) (Arumugam and Popik, 2009, 2011a,b; Arumugam et  al., 2012). This chromophore has been incorporated into the side chain of a poly(N-hydroxysuccinimidyl 4-vinylbenzoate) backbone and used for the surface immobilization of different species. An azide and an alkyne-terminated vinyl ether were photopatterned onto the polymer surface and then reacted with an alkyne or azide-terminated fluorophore using the azide-alkyne click-reaction (Arumugam et  al., 2012). A fluorescent pattern was obtained. This simple method can be extended to attach any molecule or biomolecule to the surface with a high yield and a good selectivity. In addition, copolymers containing 2-­ methacryloyloxyethyl phosphorylcholine (MPC) and N-methacryloyl-(L)-tyrosinemethylester (MAT) groups were also used for region-specific immobilization of proteins and cells (Tanaka et al., 2017). When the copolymer-P(MPC/MAT) was modified on the silicon or gold surfaces, photoinduced oxidation of the MAT units generates catechol groups that could react with the amine or the thiol groups

120 4.  Photoresponsive Polymers

FIG. 4.19  Photoinduced formation and light-triggered cleavage of thiol-ene networks for the design of switchable hydrogel patterns in (A) and (B). The process of the construction of cell patterned surface in (C) and (D). Adapted with permission from Radl, S.V., Schipfer, C., Kaiser, S., Moser, A., Kaynak, B., Kern, W., Schlögl, S., 2017. Polym. Chem. 8, 1562–1572; Ding, T., Yang, W., Luo, Z., Liu, J., Zhang, J., Cai, K., 2017. Mater. Lett. 209, 392–395.



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FIG.  4.20  Generation of chemical patterns with photoreactive polymers: PhotoDiels−Alder surface anchoring followed by Azide-Alkyne Click-Reaction to immobilize Fluorescent Dyes. Adapted with permission from Arumugam, S., Orski, S.V., Locklin, J., Popik, V.V., 2012. J. Am. Chem. Soc. 134, 179–182.

of proteins. Compared to the high adhesion of the irradiated region, the nonUV-­ irradiated P(MPC/MAT) surface is protein-­ repellent. Therefore, cell/protein patterns can be made.

4.4.3  Responsive Hydrogels Stimulus-responsive polymeric hydrogels are useful materials with applications in drug/gene delivery, photography, paints/coatings, scaffolds for tissue-engineered prostheses, biosensors, or actuators (Chaterji et  al., 2007; Tokarev and Minko, 2010; Lyon et  al., 2009). In most cases, the stimulus causes a molecular change (ionization, cross-linking) that affects the swelling degree of the hydrogel. In 1967, Lovrien et  al. suggested a strategy to prepare photoresponse hydrogels with photochromic dyes (Lovrien, 1967), and this was first experimentally realized by Van der Veen and Prins in 1971. A poly(2-hydroxyethyl methacrylate) hydrogel was mixed with sulfonated bisazostilbene dye, which decreased the hydrophilicity of the polymer chain by physical bonding in trans form

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(Van Der Veen and Prins, 1971). However, the first relevant example of light-responsive polymeric hydrogel was not reported until 1984 (Irie and Kungwatchakun, 1984). The chromophore triphenylmethane leuco was introduced into polyacrylamide or poly(N-isopropylacrylamide) (PNIPAM) hydrogels to obtain a photoregulated swelling and shrinkage due to the reversible light-induced ionization of the chromophore (Irie and Kunwatchakun, 1986; Mamada et al., 1990). Recently, the complexes of azobenzene derivatives and CD have been integrated into hydrogels as responsive engines to light-induced swelling changes. For example, α-CD, a dodecyl-modified poly(acrylic acid) and 4,4′-azodibenzoic acid have been combined to generate a hydrogel with the light-controlled gelsol transition. In the trans form, this system does not form a gel because azobenzene has a great higher affinity with CD than dodecyl and consumes most of CD by forming azobenzene/CD complexes. Under irradiation, the azobenzene derivative undergoes trans-to-cis isomerization; it is released from the α-CD site and allows self-assembly of the dodecyl groups and transition to the gel form (Tomatsu et al., 2005). Azobenzene/ CD-based polymers with different functional groups have been investigated for the reversible sol-gel transition (Wang et al., 2016a; Zhou et al., 2013; Samai et al., 2016). A similar strategy was adapted to dextran hydrogels and applied to control the release of a protein (Fig. 4.21) (Peng et al., 2010). The host-guest molecules, azobenzenyl and β-CD, were attached to the dextran backbone via thiol-ene click reactions. In the trans form, the azobenzenyl group forms the host-guest complex with the β-CD, and this results in effective cross-linking of the dextran and formation of the hydrogel. The green fluorescent protein (GFP) was encapsulated in this system. In the cross-linked system, GFP remains inside the gel, but after UV light irradiation, GFP can diffuse out of the gel and is released. This strategy only works with big molecules (i.e., protein, DNA, or a drug with high molecular weight) that are not able to diffuse outside of the polymer network in the cross-linked form. Azobenzene-containing photoresponsive hydrogels could also be used as models to explore the possibility of applying light to regulate a material's elastic modulus (Rosales et al., 2015). The ability to regulate modulus is attractive for hydrogel materials as it allows for the investigation of the effect of dynamic matrix stiffness on adhered cell behavior. In the study of poly(ethylene glycol)-based hydrogels with azobenzene-­ containing ­cross-linker, reversibly stiffening and softening was achieved by light-­ triggered isomerization. The cis configuration leads to a softening of the hydrogel up to 100-200 Pa (shear storage modulus), and the modulus can recover upon irradiation with visible light. Phototriggered shrinkage has been realized in a PNIPAm hydrogel modified with 1 mol% spirobenzopyran-modified acrylate (Szilagyi et al., 2007). An acidic aqueous solution of this polymer maintained in the dark



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FIG.  4.21  (A) Modification of dextran with azobenzene and CD through the thiol-­ maleimide reaction and (B) schematic representation of phototriggered protein release from the gel. Adapted with permission from Peng, K., Tomatsu, I., Kros, A., 2010. Chem. Commun. 46, 4094–4096.

forms a highly hydrated gel, because most of the spirobenzopyran is present in the positively charged open-ring form. Irradiation with blue light causes the transition to the closed and uncharged form of spirobenzopyran, leading to collapse of the hydrogel in the exposed area. Such shrinkage has been applied to generate a rewritable microrelief (Fig. 4.22). Recently, it was found that changing the spiropyran derivatives ­embedded

124 4.  Photoresponsive Polymers

FIG. 4.22  Left: Chemical structure of a cross-linked PNIPAm hydrogel functionalized with spiropyran and a schematic illustration of the photoinduced shrinking of the hydrogel. Right: (A) Images of the hydrogel layer just after the micropatterned light irradiation. (B) Irradiation times were (red dot) 0, (diamond) 1, and (green rectangle) 3 s. (C) Thickness change of the hydrogel layer in (dot) nonirradiated and (ring) irradiated region (3 s blue light irradiation) vs. time. Adapted with permission from Szilagyi, A., Sumaru, K., Sugiura, S., Takagi, T., Shinbo, T., Zrinyi, M., Kanamori, T., 2007. Chem. Mater. 19, 2730–2732.



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in a PNIPAm hydrogel could induce a significant improvement of the isomerization speed and reversible swelling/shrinking behavior. These spiropyran-based hydrogels could be applied in microfluidic devices (ter Schiphorst et  al., 2015), reversible biomaterials (Wang et  al., 2014b; Sun et al., 2016), actuator designing (Tudor et al., 2016; Delaney et al., 2017), novel stimuli-responsive gel systems (Filipcsei et  al., 2014; Moriyama et al., 2016), and multipurpose microfluidic devices (Stumpel et al., 2014; Ziółkowski et al., 2015). Molecular motors are one class of interesting photoswitches because of their monodirectional rotation. Recently, a light-driven motor has been integrated into hydrogels to induce a macroscopic contraction (Fig. 4.23A) (Li et  al., 2015). The motor was incorporated into polymer networks by connected with four hydrophilic polymer chains. Under UV irradiation, the irreversible monodirectional rotation of the motor can induce continual entanglement and thus macroscopic contraction of the hydrogel. A maximum contraction of nearly 80% was observed by measuring the surface reduction. It is interesting that the gel ruptured after a longer period of irradiation (170 min, Fig. 4.23B). It was attributed to the high tension that can break the double bonds in motor under irradiation (Fig. 4.23C). Phototriggered delivery of Ca2+ cations has been used as a light-induced approach to cross-link alginate hydrogels (Augst et al., 2006; Park and Lee, 2008). Photolabile Ca2+ cages are chelators that change their affinity for Ca2+ upon light exposure from a Kd of several to hundreds nM to several mM (Ellis-Davies, 2008). The affinity change is a consequence of a light-­ induced change in the molecular structure and can be used to change the local concentration of Ca2+ (Mayer and Heckel, 2006; Ellis-Davies, 2008). Cage compound nitr-T has been developed for this purpose and embedded in alginate solution (Cui et al., 2012b). Irradiation at 360 nm released Ca2+ cations, which bond to adjacent α-L-guluronic acid (G) residues of alginate with the chelating interaction of the carboxylic groups (Stokke et  al., 2000). This interaction results in gelation and resulting hydrogel display higher rheological modulus compared to the alginate hydrogel prepared by mixing CaCl2 solution directly (Fig. 4.24) (Cui et al., 2013c). Besides synthetic polymer systems, photoresponsive proteins are also used to prepare photoresponsive hydrogels. One of the examples is based on the combination of tax-interacting protein (TIP-1) and their recombinant protein, arabidopsis thalian protein UVR8. UVR8 is one kind of interesting protein that not only bonds to TIP-1 but also undergoes an ongoing change from homodimer to monomer upon UV irradiation. This unique property allows its derivative UVR8-1 to act as a cross-linker to bond TIP1-based nanofibers. The photoinduced dimer-to-monomer transformation leads to a gel-sol phase transition of the hydrogel of TIP-1-based nanofibers. This material could be applied to protein delivery and cell separation (Zhang et al., 2015b).

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FIG. 4.23  Macroscopic contraction of hydrogel with light-driven molecular motors. (A) Chemical structures of the motor gels. (B) Snapshots of time-dependent macroscopic contraction of gels upon UV irradiation (0.96 mW cm-2). (C) Overview of macroscopic contraction during irradiation. (D) Small-angle X-ray scattering (SAXS) data obtained before and after irradiation of gels. Adapted with permission from Li, Q., Fuks, G., Moulin, E., Maaloum, M., Rawiso, M., Kulic, I., Foy, J.T., Giuseppone, N., 2015. Nat. Nanotechnol. 10, 161–165.

4.4.4  Photodegradable Materials Polymers with photolabile groups in the main chain undergo chain breakage upon light illumination and can be classified as photodegradable materials. Most of the recent works use the o-nitrobenzyl chromophore, but a few other photopolymerization strategies have also been applied. Silicon-containing polyureas undergo photodegradation upon irradiation at λ >300 nm due to the photoinduced single-electron transfer from the σ C-Si to the adjacent π C = O bond, followed by silyl group migration and solvolysis (Hwu and King, 2005). Biocompatible polyketals and polyacetals have been synthesized and were photolyzed by UV light at 248 nm into carbonyl and hydroxyl product through zwitterionic intermediates and applied for making cell patterns (Pasparakis et  al., 2011). The photolysis requires low energy as a consequence of ionic photo intermediate instead of a radical one. This property makes this system interesting for biomaterial applications as the exposure conditions are compatible with

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sion from Cui, J., Wang, M., Zheng, Y., Rodríguez Muñiz, G., del Campo, A., 2013. Biomacromolecules 14, 1251–1256.

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FIG. 4.24  Model of phototriggering alginate hydrogel system with nitr-T(C12)-Ca2+ and its light-induced shrinking. Adapted with permis-

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living cells. Recently, commercially available o-nitrobenzyl-based photocleavable monomers were added into a polyurethane-based positive photoresist for making micropatterns by photolithography (Garcia-Fernandez et al., 2014). The diblock copolymer of polystyrene (PS) and poly(ethylene oxide) (PEO) with a photodegradable o-nitrobenzyl linker was applied to achieve ordered self-assembly nanostructures (Zhao et al., 2012; Kang and Moon, 2009). The copolymer self-assembled into highly ordered hexagonally packed cylinders oriented perpendicular to the substrate with PS as the continuous phase. UV irradiation cleaves the two blocks by the photolysis reaction of o-nitrobenzyl. The free PEO block was washed with water, which lead to the nanoporous template (Zhao et al., 2011b, 2012; Theato, 2011; Kang and Moon, 2009). Diblock photodegradable copolymers could be obtained by means of two kinds of click reactions and used as a potential for development of drug delivery system and biomaterials (Yamamoto et al., 2016). Polymers with a metal-metal bond (i.e., iron and molybdenum) in main chains of polyesters and polyamides are another kind of photodegradable polymers that are sensitive to visible light. Films of such photodegradable polymers are interesting for agriculture because polymer film degradation can occur with daily light, and the film does not need to be removed (Tyler, 2003). Several applications of nitrobenzenyl derivatives have been recently reported. Fig. 4.25 presents a photodegradable dendron with a hydrophilic and a lipophilic unit connected by the photocleavable group (Yesilyurt et  al., 2011). Micelles of this dendron have been used for encapsulating

FIG. 4.25  Schematic representation of the light-induced disassembly of dendritic micellar assemblies. Adapted with permission from Yesilyurt, V., Ramireddy, R., Thayumanavan, S., 2011. Angew. Chem., Int. Ed. 50, 3038–3042.



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and light-mediated delivering of Nile red. Similarly, different photodegradable polymer-based nanoparticles bearing nitrobenzenyl derivatives have been widely investigated for controlled drug delivery (Yang et al., 2013; Zhang et al., 2015c; Cui et al., 2015; Jalani et al., 2016). Photodegradable hydrogels containing poly(ethylene glycol) (PEG) chains cross-linked with photocleavable nitrobenzyl units have been applied as 3D scaffolds for cell growth with light-tunable mechanical properties (Fig. 4.26) (Kloxin et al., 2009a,b, 2010). Using scanning lasers and two-photon excitation, micrometric resolution of the photodegradation process was possible. 3D channels with reduced cross-linking were created inside the hydrogel to direct cell migration. The elasticity and mechanical properties of the photodegradable materials containing nitrobenzyl units with different functional groups could also be weighed before and after light irradiation (Tibbitt et al., 2013; Yanagawa et al., 2015a; Kharkar et al., 2015). A unique hydrogel-nanoparticle hybrid scaffold containing three distinct components provides a chemically defined, remotely triggerable, and on-demand release of small molecule drugs. Upon photoirradiation, the activation of the phototriggerable compound is designed to initiate a series of intramolecular chemical rearrangements, which would cleave the covalently bound drug and release it from the hydrogel (Shah et al., 2014). Moreover, a targeted, image-guided, and dually locked ­photodegradable

FIG.  4.26  Light-induced disassembly of dendritic micellar assemblies after light exposure. Adapted with permission from Yang, Y., Velmurugan, B., Liu, X., Xing, B., 2013. Small 9, 2937–2944.

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material could release the anticancer drug and be employed for the ­real-time monitoring of the prodrug and in  vitro cellular imaging by one- and two-photon excitation (Karthik et  al., 2015). Photodegradable hydrogels could also be formed by Michael-type addition reactions and orthogonal click reactions, and the photolithography region can be used to culture cells with high viability and proliferation rates, which can potentially be used to create 3D biomaterials for various tissue-engineering applications (Yanagawa et al., 2015b). Similar photodegradable biomaterials were recently applied for directed cell function and modulating valvular interstitial cell phenotype (Siltanen et al., 2013; Kirschner et al., 2014; Shin et  al., 2014; Yang et  al., 2014b; Arakawa et  al., 2017). Novelty, selective photodegradation on one side of this kind of hydrogel films leads to a class of self-folding structures that can be used for 3D cell culture (Kapyla et  al., 2016). Because of controllable degradation, it is possible to make ­gradient-patterned stiffness (Norris et al., 2016). In addition, nitrobenzyl group was also applied to prepare photodegradable dendrimers (Nazemi and Gillies, 2014; Lai et  al., 2016), miktoarm star polymers (Burts et  al., 2014), and so on (Rajendran et al., 2015; Hwang et al., 2016). In a bioinspired approach, nitrodopamine has been used to end-cap a star PEG and form covalently or metal-cross-linked networks (Fig. 4.27). Upon UV irradiation, the nitrophenylethyl group photolyzed, and the hydrogel degraded. This bioinspired material retains the underwater bonding properties of the mussel (due to the catechol moieties) and incorporates the possibility of light-induced debonding. It represents a new generation of photodegradable biomaterials that can be widely used in biocompatible coating, multiple cell, and medical applications (Shafiq et al., 2012). In addition to nitrobenzenyl, other photocleavable groups such as Irgacure-2959 and azo-motifs have also been applied to prepare photodegradable materials. Irgacure-2959 is a photoinitiator used for photoinduced polymerization. When it is incorporated as a cross-linker in a polymer network, it can act as a photodegradable spacer for controlling a material’s elasticity and swelling ratio (Fig. 4.28A) (Selen et al., 2016). The same strategy also works in azo compounds, which are also well-used radical initiators. One recent example based on poly(vinyl alcohol) with an azo-based cross-linker shows that the UV irradiation causes a degradation and thus triggers a solid-to-liquid phase transition (Fig. 4.28B) (Ayer et al., 2017). Besides the previously referred nitrobenzyl and azo groups, allyl sulfide is another photoresponsive group that can be used to prepare degradable hydrogels. Fig. 4.29 shows the example in which allyl sulfide bis(azide) is used as a photodegradable spacer to connect the PEG network. When the hydrogel is exposed to light in the presence of a photoinitiator, radical species generate and add directly to the allyl sulfide, which induces a radical addition fragmentation chain transfer process. In the case without

4.4 Applications

o-nitrophenyl ethyl moiety. (B) Different strategies used to trigger bonding and debonding upon light exposure of nitrodopamine derivatives. Adapted with permission from Shafiq, Z., Cui, J., Pastor-Pérez, L., Miguel, V.S., Gropeanu, R.A., Serrano, C., del Campo, A., 2012. Angew. Chem. Int. Ed. 124, 4408–4411.

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FIG.  4.27  Structure of nitrodopamine derivatives and their photocleavage mechanisms. (A) Photolytic reaction of the

132 4.  Photoresponsive Polymers

FIG. 4.28  (A) Photodecomposition of photoinitiator (Irgacue-2959)-based hydrogel under UV irradiation. (B) Formation of azo-cross-linked organogels and light-responsive properties upon UV irradiation. Adapted with permission from Selen, F., Can, V., Temel, G., 2016. RSC Adv. 6, 31692–31697; Ayer, M.A., Schrettl, S., Balog, S., Simon, Y.C., Weder, C., 2007. Soft Matter 13, 4017–4023.



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free thiol inside the system, significant photodegradation could occur due to the direct addition of the photoinitiator radical fragments to the allyl sulfide cross-linker. To increase the efficiency of the photodegradation reaction, free monothiol (mPEG-SH) was added to the system (Fig.  4.29). This radical-initiated thiol-ene exchange reaction made the allyl sulfide hydrogel system degrade. This system can be used for cell encapsulation and release (Brown et al., 2017). When the degradation is normally used to describe a decrease in molecular weight, the solid-to-liquid transition can be included as a specific “degradation” behavior. Fig.  4.30A shows a recent example of light-­ regulated solid-liquid transition (Zhou et al., 2017). The polymer has azobenzene side chains. In the trans state of the chromophore, the polymer has a glass transition temperature (Tg) above room temperature, whereas in the cis state, the polymer shows a Tg below room temperature because of the weak stacking interaction of cis form. Therefore UV light irradiation could induce a solid-to-liquid transition in this polymer at room temperature. Taking advantage of the mobility of the liquid state, this unique transition can be used to prepare smooth surface and self-healing fractures (Fig. 4.30C)

4.4.5  Photoswitchable Liquid Crystalline Elastomers (LCE) for Remote Actuation Photoswitchable units have been incorporated into liquid crystalline polymers. The chromophore is usually part of the mesogenic core, and the light-induced molecular changes directly affect the degree of order of the mesophase and, consequently, its properties such as Curie temperature (Beyer et al., 2007), molecular orientation, symmetry, transition temperatures, etc. (Seki, 2007). One issue of recent interest in photoresponsive liquid crystal elastomers is the possibility to generate photoswitchable actuators. Light exposure induces a change in the conformation of polymer chains from extended to a coiled one, which results in a macroscopic shape change. This actuating principle has been applied for bending LCE films and micropillars (Ohm et al., 2010; Qian et al., 2012). The first example of this kind was reported in 2003 with polymer 28 (Li et al., 2003). A 20-μm thin film of the LCE with the mesogens preferentially oriented in a direction parallel with long axis was obtained. Film contraction in the direction of mesogenic units was observed upon exposure to UV light at 75°C as a consequence of trans-to-cis transition of azobenyl, which ­induces ­nematic-isotropic phase transition. Light-driven flexural-­ torsional response in azobenzene functionalized LCE could be affected by key material parameters with polarized light, complex geometry, boundary conditions, and loading conditions (Smith et al., 2014).

134 4.  Photoresponsive Polymers

FIG. 4.29  Light-triggered radical network degradation in (A) and (B). (C) Incorporation of mPEG-SH allows controlled photodegradation of the gel and tuning of the storage modulus. Adapted with permission from Brown, T.E., Marozas, I.A., Anseth, K.S., 2017. Adv. Mater. 29, 1605001.

4.4 Applications

FIG.  4.30  Photoinduced solid-to-liquid transition of azopolymer-based films. (A) Chemical structure

135

and photoisomerization of azobenzene-containing polymers. (B) Schematic illustration (top) and confocal images (bottom) of surface roughness reduction by photoswtiching of solid-to-liquid transition. (C) Schematic illustration (top) and optical microscopy images (bottom) of scratches healing on a hard azopolymer coatings with different light wavelength. Adapted with permission from Zhou, H., Xue, C., Weis, P., Suzuki, Y., Huang, S., Koynov, K., et al., 2017. Nat. Chem. 9, 145–151.

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Fig.  4.31 presents a different example where a freestanding LCE film was bent upon irradiation (Ikeda et  al., 2007). Monodomain LCE films with the mesogens aligned in a parallel direction to the surfaces were generated by the method shown in Fig.  4.30A (Yu and Ikeda, 2011). In situ polymerization and cross-linking of the film was carried out in the liquid crystal (LC) phase. In the resulting self-supporting LCE films, the network structure retained the orientation of the mesogens. UV irradiation caused macroscopic bending of the film as a consequence of the contraction induced by the transition of the LC phase into the isotropic phase. Such deformation was reversible by irradiating with alternating UV and visible light sources (Fig. 4.31B). When a polarized light was used, direction-­ controllable bending was achieved in a polydomain LCE films, as shown in Fig. 4.31C (Yu et al., 2003). Recently, similar effects were observed with fibers, which can bend to any shiny direction, like a “sunflower” (Yoshino et  al., 2010). Multifunctional LCEs could be prepared by cross-linked azobenzene chromophores, liquid crystals, and dynamic ester bonds, which exhibits programmable material responses to external stimuli at the molecular level with photomechanical, shape memory, and self-healing properties (Li et al., 2016). Azobenzene moieties could also be modified to silicone elastomer to prepare photodriving LCE materials. The alignment of mesogens and macroscopic shapes can be controlled through the rearrangement of azobenzene groups on the network topology, showing various bending behaviors upon irradiation with UV or visible light (Ube et al., 2016; Ube et al., 2017). When the LCE was embedded with photothermal graphene oxide, a NIR-vis-UV light-controlled actuator can be obtained. The product exhibits excellent processability and mechanical properties (Cheng et  al., 2015). The responsiveness to both UV and visible light was recently applied to get a light-controlled shape-memory effect (Ban et al., 2017). The contraction and bending of LCE have inspired interesting application attempts (Fig. 4.32). An azobenzenyl-containing LCE layer was attached to a flexible polyethylene sheet and used as a photodriven belt (Fig. 4.32A) (Yamada et al., 2008). UV and visible lights were shined simultaneously from different directions and induced a rotation of the belt. This rotation was used to drive a motor device in a counterclockwise direction at room temperature. It represents the first realization of light-driven plastic motors in which light energy was directly converted into mechanically rotational energy. Exploiting bending and stretching effects of a LCE film, bioinspired propulsion was further demonstrated (Fig. 4.32B). The movement was driven by cyclic photoinduced bending and extension (Yamada et al., 2009; Yamada et al., 2009). Recently, molecular relaxation rate after irradiation is taken into ­account for designing novel shape change. Fig.  4.33 shows macroscopic



4.4 Applications

137

FIG. 4.31  Photoresponsive freestanding LCE film. (A) Scheme of the preparation process of freestanding LCE film using an azobenzene-based LC monomer and a cross-linker. (B) Phototriggerred bending mechanism of the monodomain LCE films. (C) Control the bending direction of LCE films by linearly polarized light and its plausible mechanism. Adapted with permission from Yu, H., Ikeda, T., 2011. Adv. Mater. 23, 2149–2180.

­ echanical waves under continual irradiation (Gelebart et  al., 2017). In m this example, molecular tautomerization and structure push-pull strategies were applied to increase the thermal relaxation rate of the azobenzene. The idea was shown by an asymmetric structure with planar alignment on one side but homeotropic alignment on another side. UV irradiation can induce the temperature of the irradiated region to a temperature higher

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than the Tg of the polymers with a short half-life (1-2s), because of the molecular tautomerization. Phase transition induces a fast contract on the planar alignment sider but an expending on the homeotropic alignment side, which causes a curve downward (planar up) or upward (homeotriopic up). Opposite stress on both sides pushes a crest away (planar up) or toward (homeotriopic up) the light resource and thus results in continuous travelling wave and repeating movement until the light is turned off (Fig. 4.33B and 4.33C). Azobenzenyl-based LCE shows not only the photoswitchable actuating but also macroscopic helical motioning (Tašič et  al., 2013; Lv et  al., 2014; Garcia-Amoros et al., 2014). Inspired by biological systems, a novel spring-like material has been fabricated for converting light energy into mechanical work at the macroscopic scale. It was found that light-­operated molecular-scale motion (cis-trans photoisomerization) can be converted into large macroscopic deformations of the springs. More than a single actuation mode encoded inherently in these chiral objects, the actuation can be reversed when changing from one handedness to the other (Fig. 4.34) (Iamsaard et al., 2014). Another interesting application of a photoresponsive LCE is to make cantilever actuators. To do so, a LCE polymer described by azobenzene monomer and azobenzene cross-linker was cast onto a low-density polyethylene film. The bilayer shows a photomechanical movement, which can drive attached copper coils to cut a magnetic line of force to generate electricity. This simple strategy was claimed to have potential in the applications of the capture and storage of light energy (Tang et al., 2015). Photoresponsive LCE materials are further expended to microfluidic systems recently. The idea is based on the photoinduced asymmetric deformation of tubular microactuators made from azobenzene-based LCE. In the multiple-layer tube, LCE layer would contract under irradiation, which shrinks the tube to offer a driving force to move the droplet in the tube (Fig. 4.35) (Lv et al., 2016). It greatly simplifies microfluidic devices and opens a new way in biomedical and chemical engineering. In addition to permanent covalent cross-linking, dynamic bonding is also able to make LCE. Because of the dynamic nature, these m ­ aterials show interesting properties such as easy-to-reshape, self-healing, fatigue resistance, etc. (Fang et al., 2013). Several interesting examples recently published are based on H-bonding. For example, a novel photodeformable LCE was fabricated by using multivalent hydrogen bonds as ­cross-linkers (Fig. 4.36A). This LCE not only exhibits self-healing properties at low temperature but also presents a reversible photoinduced ­deformation by alternate irradiation of UV and visible light (Fig.  4.36B and C) (Ni et al., 2016). In contrast to the photoinduced isomerization presented in the previous examples, the photothermal heating effect was also applied to get a



4.4 Applications

139

FIG.  4.32  Photoinduced sophisticated 3D motions of a LCE film laminated on a flexible polyethylene sheet. (A) Schematic illustration of a light-driven plastic motor and photographs of time profiles of the rotation. (B) Photographs of photoinduced inchworm walk and the plausible mechanism. A: Adapted with permission from Yamada, M., Kondo, M., Mamiya, J.-i., Yu, Y., Kinoshita, M., Barrett, C.J., Ikeda, T., 2008. Angew. Chem. Int. Ed. 47, 4986–4988; B: Adapted with permission from Yamada, M., Kondo, M., Miyasato, R., Naka, Y., Mamiya, J.-i., Kinoshita, M., Shishido, A., Yu, Y., Barrett, C.J., Ikeda, T., 2009. J. Mater. Chem. 19, 60–62.

­photoinduced deformation. Fig. 4.37 shows a dual-layer, dual-­composition, polysiloxane-based LCE strategy that was developed to mimic the organisms’ complex shape deformations. A NIR absorbing dye (YHD796) was mixed into the azobenzene-based network, and it could induce the LCto-isotropic phase transition because of the photothermal heating ­effect.

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FIG. 4.33  Waves in a photoactive polymer film. (A) Chemical structures of azo-­derivatives and liquid crystal mesogens. (B) Schematic of the experimental set-up under an oblique-­ incidence light source. (C) Simulation (left) and experimental (right) data for planar-up and homeotropic-up configurations. Adapted with permission from Gelebart, A.H., Mulder, D.J., Varga, M., Konya, A., Vantomme, G., Meijer, E.W., Selinger, R.L.B., Broer, D.J., 2017. Nature 546, 632–636.

To prepare the bilayer, two different kinds of precross-linked layers were fabricated (Fig. 4.37A) and slowly uniaxially stretched to a different angle for orientation. The films could be covalently bonded together to get ­dual-layer LCE that could perform not only bending but also chiral twisting (left-handed and right-handed) under irradiations of different light wavelengths (Fig. 4.37C) (Wang et al., 2016b).

4.5  CONCLUSIONS AND FUTURE TRENDS The future of photoresponsive polymers and smart materials derived from them will depend on the research development in different directions. The development of photoresponsive units acts as an engine of photoresponsive polymer systems. New and more efficient p ­ hotosensitive



141

4.5  Conclusions and Future Trends

dL

UV Visible

1.7

dR dR/dL

1.5 1.3 1.1 0.9 UV (l = 365 nm)

(B)

1

2

3

4

5 6 7 8 Number of cycles

9

10

Magnets

Visible light

UV (l = 365 nm) Magnets

(A)

(C)

FIG.  4.34  Light-driven mechanical device. (A) Deformation under alternate irradiation. (B) Cycles of helical ratio under alternating irradiation. (C) A magnet connected to the kink undergoes a push-pull shuttling motion. Adapted with permission from Iamsaard, S., Asshoff, S.J., Matt, B., Kudernac, T., Cornelissen, J.J., Fletcher, S.P., Katsonis, N., 2014. Nat. Chem. 6, 229–235.

FIG. 4.35  Design and photodeformation of tubular microactuator (TMA). (A) Schematics illustration of the motion of a slug confined in a TMA driven by photodeformation. (B) Lateral photographs of the light-induced motion of a silicone oil slug in a TMA fixed on a substrate. Adapted with permission from Lv, J.A., Liu, Y., Wei, J., Chen, E., Qin, L., Yu, Y., 2016. Nature 537, 179–184.

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FIG.  4.36  Photoinduced-deformable LCE with dynamic multivalent hydrogen bonds. (A) Schematic and chemical structure of the self-healing photoinduced deformable LCEs. (B) Self-healing process of a fractured fiber. (C) Photoinduced bending and unbending behavior of the healed fiber upon irradiation with UV light at 365 nm and visible light at 470 nm. Adapted with permission from Ni, B., Xie, H., Tang, J., Zhang, H., Chen, E., 2016. Chem. Commun. 52, 10257–10260.

molecular units and switching strategies are required, as well as chromophores sensitive to long wavelengths for compatibility with living organisms and tissues and applications in the biomedical area. The development of polymerization strategies able to incorporate the chromophores at a selected position in complex macromolecular architectures is also an important question, i.e., by mature living control radical polymerization techniques (Hawker et  al., 2001; Kamigaito et  al., 2001; Matyjaszewski and Xia, 2001). Controlled drug delivery will remain as the main application field of photosensitive polymers. Although many systems have been tested in vitro with a dye or a drug, in-vivo applications are scarce and require further development. Close cooperation between organic chemists, polymer chemists, biologists, and medical doctors will be required to push this research to interdisciplinary level (Cosa et al., 2009; Mizukami et al., 2010; Kim et al., 2006; Tanaka et al., 2010; Mal et al., 2003). Lighttriggered actuators will also be an issue for the future, which has been, up to now, mainly based on azobenzene-containing LCEs. However, indirect strategies can also achieve a similar effect and may also extend the irradiation wavelength to broader regions (Torras et al., 2011). All these areas will certainly further grow in the future and expand the application of these systems to unforeseen fields.



4.5  Conclusions and Future Trends

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FIG.  4.37  Phototunable bending and chiral twisting motion based on a dual-layer, ­ ual-composition, polysiloxane-based LCE. (A) The chemical compositions of the dual-layer d of LCE. (B) Schematic illustration of the preparation protocol of a same-sized-bilayer LCE ribbon material. (C) The bilayer LCE ribbon with a -45 degree angle between the top and bottom layer was irradiated under 365 nm UV light and an 808 nm NIR light, respectively. Adapted with permission from Wang, M., Lin, B., Yang, H., 2016. Nat. Commun. 7, 13981.

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C H A P T E R

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Enzyme-Responsive Polymers: Classifications, Properties, Synthesis Strategies, and Applications Anika B. Asha*, Shruti Srinivas*, Xiaojuan Hao†, Ravin Narain* ⁎

Department of Chemical and Materials Engineering, Donadeo Innovation Centre for Engineering, University of Alberta, Edmonton, AB, Canada, † CSIRO Manufacturing, Research Way, Clayton, VIC, Australia

5.1  INTRODUCTION The responsive or “smart” polymers are considered one of the promising materials in medicine in comparison to conventional polymers due to their bioresponsive physicochemical nature. Over the past 25 years, they have been proposed for numerous biomedical uses such as diagnostics, drug delivery, tissue engineering (regenerative medicine), bioimaging, biosensing, and cell culture (Hoffman, 2013; Ulijn, 2006). Smart or stimuli-responsive materials change their properties in response to pH, temperature, or light as external stimuli (Ulijn, 2006). Among a variety of stimuli-responsive or smart polymers, enzymeresponsive polymers show intriguing properties due to the precise selectivity and high efficiency of the enzymatic catalysis. Enzymes are an important category of biological machineries and one of the important constituents in the metabolic process (Heinemann and Sauer, 2010). Enzyme-responsive polymers are those polymers whose structure or functionality changes by the direct action of the enzyme even under mild conditions (aqueous, pH 5–8, 37°C) (Ulijn, 2006). Enzyme-responsive m ­ aterials ­undergo ­reversible

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macroscopic transitions triggered by selective enzyme catalysis (Zelzer and Ulijn, 2014). Enzyme-catalyzed reactions are highly selective and efficient toward specific substrates. The integration of enzyme-catalyzed reactions with responsive polymers triggers the intricate properties of responsive polymers expanding the range of its applications in biology and biomedicine. Enzyme-responsive polymers can exist in different states in the form of solution, gels, self-assembled aggregates, (multilayer) films, and bulk solids, exhibiting reversible or irreversible changes in chemical structures and/or physical properties. Enzyme-responsive polymeric systems can be designed by either using enzyme-degradable polymers or by modifying polymers with moieties responsive to specific enzymes. Both synthetic polymers (PEG, PNIPAAm, and PLL, etc.) and natural polymers (polypeptides, gelatin, and dextran, etc.) have been exploited for enzyme-responsive systems. A functional enzyme-responsive polymer consists of (i) a substrate mimic that can be specifically recognized by an enzyme or (ii) a component that directs and controls changes in noncovalent interactions that cause macroscopic transitions (Heinemann and Sauer, 2010). Enzyme-responsive polymers that have been described in recent years are usually based on supramolecular assemblies, chemically cross-linked gels, and (nanoparticle) surfaces that respond to a range of different enzymes including lipases, proteases, phosphatases, kinases, glycosidases, acyl transferases, and redox enzymes.

5.1.1  Rationale Behind Enzyme-Responsive Polymers Enzyme-responsive polymers are a new class of stimuli for responsive materials. The structure and functionality of these polymers change by the direct action of the enzyme even under mild conditions (Ulijn, 2006). The inherent biocompatibility of enzymes has triggered the exploitation of enzyme-responsive polymers in various fields, including drug or gene nanocarriers, regenerative medicine, diagnostics, smart actuators, adaptive coatings, and self-healing materials (Ulijn, 2006; Hu et al., 2012). More specifically, enzyme-responsive polymers show reversible or irreversible enzyme-induced changes in their chemical or physical properties. On the other hand, stimuli-responsive polymers exhibit changes in response to externally applied stimuli such as pH, temperature, light, solvent polarity, electric/magnetic field, and small (bio-)molecules (Ulijn, 2006; Whyte, 2010). However, external application of these stimuli may not be compatible with the biological environment. Moreover, some stimuli such as pH or temperature changes are not very specific or targeted to the material but may also affect other components of the biological environment. Conversely, a variety of naturally occurring enzymes in the body provides additional advantages over external stimuli such as pH or temperature as the stimulus does not need to be added externally but can be supplied by the biological environment itself, provided that the naturally present enzyme matches the triggering enzyme of the responsive material. Hence, enzymes are recently



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considered a highly attractive alternative to conventional stimuli for the development of functional biomaterials. Moreover, the activity of certain enzymes is often linked to specific locations in the body and/or specific conditions of the organism. For example, several diseases are found to have a high level of phosphatase activity (Whyte, 2010); azoreductases—the flavoenzymes can be found mainly in the digestive system (Miyata et al., 2002; Ryan, 2017) and the healing of wounds displays a complex sequence of enzyme activities that mark the different stages in the wound-healing process (Metcalfe and Ferguson, 2008). The incorporation of enzyme responsiveness into a material therefore goes beyond the addition of any other stimulus. The tightly controlled interplay between the biological environment and enzymatic actions makes enzyme-responsive materials more attractive for integrating artificial materials with biological entities.

5.2  HISTORICAL EVOLUTION OF ENZYMERESPONSIVE POLYMER Among other stimuli responsive polymers, research on enzymeresponsive polymers has been growing markedly over the last few years. Folk et  al. first discussed the catalyzing capability of transglutaminase enzyme to cross-link a naturally derived polypeptide—gelatin (Folk and Finlayson, 1977). Since then, the potential biological significance of enzyme-responsive materials has been drawing attention of the researchers. Following the research on transglutaminase, other naturally derived polymers, such as dextran hydrogels and gelatin, were highlighted in other prominent research (Kurisawa et al., 1997; Yamamoto et al., 1996). Sperinde et al. explored the cross-linking of transglutaminase to artificial polymers (Sperinde and Griffith, 1997). West and Hubbell (1999) first designed and developed protease-responsive polymer hydrogels. They introduced the enzyme-sensitive functionality separately into the material and developed the methods of incorporation of short peptide cross-links into a polymer hydrogel. This approach opened the potential to use a variety of different enzymes to degrade the polymer hydrogel. An overview of development of enzyme-responsive materials is given in Fig. 5.1. Later in 2003, Hubbell and coworkers first introduced the possibility of linking material properties with biological processes in living organisms. They demonstrated that native enzymes provided by skin cells could degrade an artificial polymer hydrogel (Lutolf et  al., 2003a). In 2007, Yang et al. expanded enzyme-responsive polymeric materials into a new area— supramolecular enzyme-responsive hydrogels (Yang et al., 2004). They coupled enzymatic dephosphorylation with hydrogelation to generate supramolecular hydrogels. Research on enzyme-responsive polymeric materials had then flourished and developed from polymer hydrogel-based materials to polymer micelles, biodegradable capsules, particles, polymer conjugates,

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FIG. 5.1  Development of enzyme-responsive polymers. Reproduced in part from Zelzer, M., Ulijn, R.V., 2014. Enzyme-responsive polymers: properties, synthesis and applications. In: Smart Polymers and Their Applications. Elsevier BV, pp. 166–203. (Chapter 6).

and self-immolative polymers (Harnoy et al., 2014; Itoh et al., 2006; Ghadiali and Stevens, 2008; Azagarsamy et  al., 2009; Kühnle and Börner, 2009). Currently, enzyme-responsive polymers can be assigned to one of four categories: enzyme-responsive polymer hydrogels; enzyme-responsive supramolecular polymers; enzyme-responsive particles; and enzyme-responsive self-immolative polymers (Fig. 5.2) (Zelzer and Ulijn, 2014).

FIG. 5.2  Enzyme-responsive polymers (Zelzer and Ulijn, 2014).



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5.3  ENZYME-RESPONSIVE MATERIALS 5.3.1  Supramolecular Assemblies of Enzyme-Responsive Polymers Enzyme-responsive polymer assemblies are one of the promising candidates for biomaterials, biomedicine, and biosensing. Conventionally, these assemblies are prepared by the self-assembly of polymer building blocks where enzyme-responsive moieties are noncovalently complexed with the polymer building blocks (Ding et  al., 2015). These supramolecular assemblies consist of molecules held together by noncovalent interactions such as electrostatic interactions, hydrogen bonding, p-stacking, van der Waals forces, hydrophobic interactions, or combinations thereof in aqueous or organic solvent systems (Ulijn, 2006). In addition to supramolecular strategy, another common strategy for imparting enzyme-responsiveness to polymer assemblies is to covalently link enzymatic substrates to amphiphilic copolymers (Ding et  al., 2015). Compared with covalent modification, the noncovalent incorporation is more efficient as chemical synthesis is not required (Wang et al., 2010). The interaction driving self-assembly is mainly electrostatic interaction upon the addition or removal of anionic phosphate groups (Ding et al., 2015). Enzymatic (de-)phosphorylation is commonly used in biology to alter both structural features and biological activity of proteins. The dephosphorylation reaction catalyzed by a phosphatase can be taken as a first example of enzymatic supramolecular hydrogelation (Yang et  al., 2004). Phosphatase-mediated dephosphorylation removes the hydrophilic phosphate group and changes the hydrophilic block to hydrophobic block. Consequently, this enzymatic conversion decreases the solubility of the molecules in solution and creates an amphiphile that can undergo self-assembly to form colloidal nanostructure or supramolecular hydrogels (Amir et al., 2009). Supramolecular polymers are usually based on small molecules such as peptides or peptide amphiphiles, and they are also found as precursors (gelators) to form supramolecular hydrogels. Peptides can be synthesized in a sequence-defined manner and through intermolecular interactions. They spontaneously form secondary structures such as α-helix, collagen, coiled-coils, and β-sheet under appropriate conditions for a predetermined amino acid sequence. Most of the rational design of self-assembly directing materials is based on these secondary peptide structures (Williams et  al., 2010). Burkoth et  al. (1999) first exploited that hybrid diblock copolymers consisting of β-amyloid peptide and PEG can spontaneously self-assemble into well-dispersed fibrils in a controlled manner, and the extent of aggregation can be facilely adjusted by concentration, pH, and ionic strength. Thus more sophisticated enzyme-triggered self-assembling

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FIG. 5.3  Schematic illustration of enzyme-triggered self-assembly due to the transformation of a water-soluble diblock copolymer into an amphiphilic diblock copolymer.

systems can be constructed from polymer-peptide hybrid block copolymers upon site-specific modification of the peptide block. Nongelling supramolecular assemblies have also attracted considerable attention for drug delivery and other biological applications. Introduction of phosphate group to side chains of one block of the polymer is another way to achieve enzyme-mediated assembly of polymer-based supramolecular structure. This kind of structure is achieved by decreasing the hydrophilicity of one polymer block of a doubly hydrophilic block polymer (Hu et al., 2012) (Fig. 5.3). Enzyme-mediated destruction of self-assembled supramolecular structures is another novel approach that does not require covalent synthesis. Kang et  al. constructed a phosphatase-responsive supra-amphiphile based on the electrostatic interactions of a double hydrophilic block copolymer and adenosine 5′- triphosphate (ATP) which can self-assemble to form spherical aggregates and be disassembled by the presence of active phosphatase (Kang et  al., 2012). Wang et  al. also constructed a “superamphiphile,” which was able to self-assemble into micelles and disassemble by the introduction of phosphatase (Wang et al., 2010). This new approach of enzyme-induced disassembly of supramolecular structures can be employed as a temporary support for cells or a drug delivery.

5.3.2  Enzyme-Responsive Polymer Hydrogels Enzymatically cross-linked hydrogels have been increasingly attracting researchers’ interest especially due to the mildness of enzymes catalyzing reactions. Most of the enzymes involved in the cross-linking are common to the enzymes catalyzing reactions naturally occurring in our body. Enzymatic reactions are catalyzed by most enzymes at neutral pH, in an aqueous media, and at moderate temperatures implying that they also can be used to develop in situ forming hydrogels. Enzymatic cross-linking of



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FIG. 5.4  Schematic presentation of enzyme-responsive materials based on (i) polymeric and (ii) supramolecular hydrogels. Reproduced in part from Abul-Haija, Y.M., Ulijn, R.V., 2014. Enzyme-responsive hydrogels for biomedical applications. In: Connon, C.J., Hamley, I.W. (Eds.), Hydrogels in Cell-Based Therapies. Series: RSC Soft Matter Series. Royal Society of Chemistry, Cambridge, pp. 112–134. ISBN 9781849737982. https://doi.org/10.1039/9781782622055-00112.

synthetic macromolecular precursors yields stronger covalent bonds between substrates. Enzymatic cross-linking also offers the potential for kinetic control of gel formation and thus for formation of homogeneous gels in situ via the simple control of enzyme concentration. Enzyme-responsive hydrogels can be classified into two classes: polymeric hydrogels and supramolecular hydrogels (Fig.  5.4) (Zelzer and Ulijn, 2014; Abul-Haija and Ulijn, 2014). Based on these classifications, ­enzyme-responsive polymer hydrogels can be designed for either hydrogel formation or controlled degradation (Zelzer and Ulijn, 2014). Enzymatically controlled swelling of hydrogel particles is an exception of enzyme action on enzyme-responsive polymer hydrogel systems. Upon enzymatic action, macroscopic transitions (swelling/collapse) take place while the overall cross-linked structure stays intact. Polymer hydrogels consist of hydrophilic polymeric networks, which can retain and absorb a very large quantity of water (up to 99%) (Zelzer and Ulijn, 2014; Wichterle and Lim, 1960). Both naturally derived (e.g., polypeptides and polysaccharides) and artificial polymers (e.g., PEG/poly(ethylene oxide) (PEO), poly(2-hydroxyethyl methacrylate) and poly(N-isopropylacrylamide)) enzyme-responsive hydrogels are mostly prepared by using enzyme systems like transglutaminase, tyrosinases, phosphatase, transferases, and lysyl oxidases (Teixeira et  al., 2012). Enzyme-sensitive functions are usually present in the side chains of an amino acid that will be covalently connected by the enzyme.

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Catalytic formation of a covalent bond linking two nonassembling components together to form a gelator is achieved by catalyzing the condensation reaction between two amino acid derivatives or peptide fragments. Sperinde and Griffith demonstrated the formation of a hydrogel network by the cross-linking of a polypeptide (poly(KF)) with synthetic polymers (PEG) using transglutaminase enzyme system and developed methods to predict gelation kinetics in these systems (Sperinde and Griffith, 1997). Sanborn and Messersmith designed a further sophisticated system where the enzymatic cross-linking of PEGpeptide conjugate was triggered thermally to release calcium from phospholipid vesicles (Sanborn et  al., 2002). Peptidic building blockbased biocatalytic self-assembly systems are mostly found in reports. Hydrogels based on peptidic building blocks are of particular interest due to several reasons: (1) their rich chemistry in noncovalent (hydrogen bonding, electrostatic, p-stacking, hydrophobic) interactions; (2) their sequence matches the target enzyme of choice whereas the response of naturally degradable polymers is restricted to one enzyme only; and (3) their ease of synthesis. Another approach to generate cross-links between polymer chains is the enzymatic conversion of side groups into more reactive species that are subsequently able to react with moieties in neighboring polymer chains. Kurisawa et  al. showed that the oxidative coupling of phenols using horseradish peroxidase (HRP) in the presence of H2O2 produced a hydrogel from hyaluronic acid/tyramine conjugates (Kurisawa et al., 2005). Catalytic cleavage of a covalent bond to transform a nonassembling precursor to a self-assembly building block can be achieved by removing a functional group through a hydrolysis reaction, which might affect the molecular packing ability due to its bulky size or by causing electrostatic repulsion between monomeric units. West and Hubbell were the first to design enzymatically cleavable cross-linkers, PEG molecules flanked at both sides with short peptides terminated with polymerizable groups (West and Hubbell, 1999). The degradation was conducted by collagenase and plasmin. Polymer hydrogels based on natural polymers can often be degraded directly (e.g., cross-linked dextran by dextranase) (Klinger et al., 2012). But artificial polymers require the incorporation of enzyme-­ sensitive moieties, typically in the form of enzyme cleavable cross-linkers such as short peptide sequences. Enzymes can also be exploited to control the morphology of hydrogel particles through their function of increasing pore sizes or sol-gel transitions. By changing the overall charge of the particles (Fig. 5.5), the degree of swelling can be modified using enzymes such as trypsin, thermolysin, elastase, and matrix metalloproteinases (MMPs) (Thornton et  al., 2005; McDonald et  al., 2009; Thornton et  al., 2008; Patrick and Ulijn, 2010).



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163

FIG. 5.5  Enzyme-induced morphological changes.

5.3.3  Enzyme-Responsive Polymer Nanoparticles Enzyme-responsive polymer nanoparticles are widely used as carriers in drug delivery and enzyme detection applications (De La Rica et  al., 2012). The enzyme-responsive strategies that have been exploited for polymer particles include the disintegration of polymeric spheres or capsules and induced swelling of polymer hydrogels to physically release entrapped molecules. The unique property of nanoparticle systems is their relatively small diameter ranging from 6 to 200 nm (Nguyen et al., 2015). Consequently, this nanometric size of polymer-based nanoparticles favors the circulation of these materials in the body and systematic transport, which are crucial features for their targeted delivery. For example, some tumors have relatively porous blood vessels that may facilitate the ingress of nanoparticles into the tissue. Thus site-specific controlled drug release without compromising in targeting efficiency and specificity can be achieved by nanoparticles integrated with site-specific enzyme-triggered moieties (Allen, 2002; Hu et al., 2014). Polymeric nanoparticles can be categorized into four classes: polymer micelles, hydrogel particles, solid particles, and polymer capsules (Zelzer and Ulijn, 2014). Nanomaterials can be rendered enzyme-responsive by containing moieties in their main chain or side groups, which can be cleaved by the enzyme. Apart from their role in hydrogel applications discussed in the previous section, solid particles can be achieved by the random aggregation of polymers into spherical structures and by cross-linking polymers in a spherical shape, for example, via emulsion-type polymerizations. Researchers have exploited amphiphilic block copolymers to achieve nanostructured micelles, for example, Ti-Hsuan et  al. designed spherical micellar nanoparticles from polymer-peptide block copolymer amphiphiles containing substrates for protein kinase A, protein phosphatase-1, and MMPs 2 and 9 (Ku et al., 2011). They exploited phosphorylation, dephosphorylation, and peptide cleavage mechanisms to modify the micelle morphology and aggregation behavior. Lastly, polymer capsules are materials where the polymer forms a solid cage around a hollow interior filled with solvent in which the cargo resides. Enzyme responsiveness of these

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polymer capsules is mostly restricted to direct degradation/disassembly of the polymer structure. One of the most widely used polymers in a nanostructured, enzyme-responsive system is polyethylene glycol (PEG) due to its flexible and hydrophilic chain. One such example of its use is synthesis of amphiphilic block copolymers by Harnoy et al. using a linear hydrophilic PEG and an enzyme-responsive hydrophobic dendron (Harnoy et  al., 2014). PEG-dendron hybrids self-assembled in water into micellar nanocontainers that could disassemble and release encapsulated hydrophobic cargo molecules upon enzymatic activation, and this process is depicted schematically in Fig. 5.6. Enzymes can also be exploited to alter the particle size for the potential applications of effective delivery. For example, Chien et al. also reported enzyme-responsive self-assembled micellar nanoparticles prepared from amphiphilic block copolymers bearing a simple hydrophobic block and a hydrophilic peptide brush (Chien et al., 2013). Enzymatic action changed the morphology from 20-nm spherical micelles to micrometer-scale aggregates, kinetically trapping them within the tumor. By taking advantage of the formation of a new assembly in response to the enzymatic cleavage of the substrate, the aggregates were retained in the targeted tumor tissues as long as 1 week, whereas nonresponsive nanoparticles would be degraded within 2 days. Enzymes can also be used to shrink the polymer nanoparticle size to facilitate diffusive transport of nanoparticles. Wong et al. engineered a 100nm nanoparticle with a core composed of gelatin and a surface covered with quantum dots (QDs), a model 10-nm nanoparticle (Wong et al., 2011). This size change was triggered by proteases highly expressed in the tumor microenvironment such as MMP-2, which degraded the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm QDs nanoparticles from

FIG. 5.6  Schematic representation of the encapsulation of hydrophobic guests in the hydrophobic core of a smart micellar nanocarrier (Harnoy et al., 2014).



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FIG. 5.7  Schematic representation of the size change of QDGelNPs and release of 10-nm QD NPs in the presence of MMP-2. Reproduced in part from Wong, C., Stylianopoulos, T., Cui, J., Martin, J., Chauhan, V.P., Jiang, W. et al., 2011. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl. Acad. Sci. U. S. A. 108 (6), 2426–2431.

their surface (Fig. 5.7). The resulting enhancement of diffusive transport overcoming multiple physical barriers to deep penetrate into tumor tissue allowed enzyme-responsive, multistage nanoparticle systems for additional tenability in the spatial control of drug delivery by changing in size.

5.3.4  Enzyme-Responsive Self-Immolative Polymers Enzyme-responsive self-immolative polymers are very recently developed unique macromolecules that typically undergo head-to-tail depolymerization in response to the cleavage of stimuli-responsive caps from their ends (Fan and Gillies, 2015). A spontaneous head-to-tail depolymerization often involves multitopic release of small-appended molecules and disassembling of complete polymer structure into its parental units (Fig.  5.8) (Zelzer et  al., 2013). These polymers have been designed in which self-immolative dendrimers and oligomers can undergo cascades of cyclization and/or elimination reactions in response to the activation

FIG. 5.8  Schematic presentation of enzyme-responsive head-to-tail depolymerization of self-immolative polymer (Peterson et al., 2012).

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or cleavage of a trigger moiety. Conventional self-immolative polymers are carbamate- or carbonate ester-based polymers that comprise a kinetically stable polymer and a dormant chain end that responds to enzyme by triggering a head-to-tail depolymerization of the polymer main chain (Peterson et al., 2012). If other molecules are attached to the polymer via the same metastable chemistry, these multiple molecules will be released into the environment in response to a single enzyme-triggering event. This unique property makes self-immolative polymer a potential candidate for drug release, self-healing, and sensory application (Peterson et al., 2012). In 2003, Shabat and coworkers developed self-immolative dendrimers triggered by enzymes that could be cleaved by catalytic antibody 38C2 (Shamis et al., 2004). They developed first generation prodrugs by incorporating drug molecules as the tail units and an enzyme substrate as the trigger that was able to generate a multiprodrug unit activated with a single enzymatic cleavage. This kind of polymer is very recently introduced, and it still needs much more development for further potential biomedical applications.

5.4  PROPERTIES OF ENZYME-RESPONSIVE POLYMERS The structural changes in stimuli-responsive polymers can be altered through enzymatic actions. The assembly of micelles and other supramolecular structures from amphiphilic block copolymers is considered to be one of the most successful strategies. The functional groups of the responsive block are altered from double-hydrophilic to amphiphilic upon the addition of an external stimulus. The size and shape of the nanostructures can be controlled by altering their solubility, which results in great control over the triggering process and a high degree of selectivity through enzymatic action (Amir et al., 2009). According to Amir et  al., the self-assembly of block copolymers can be altered under physiological conditions by enzymatically triggering their self-assembly. The polymerization of vinyl monomers containing an ­enzyme-activated substrate with PEG macroinitiator yields water-soluble block copolymers. A hydrophobic block is formed by the removal of these soluble moieties from vinyl polymer backbone. This results in the polymer undergoing self-assembly to form colloidal nanostructures and becoming amphiphilic (Amir et al., 2009). Another attractive environmental trigger is temperature due to which reversible micellization and dissociation in response to temperature changes occur in the block copolymers. By the incorporation of a different monomer, the thermosensitive properties of the polymer, i.e., lower critical solution temperature (LCST) can be modified (Neradovic et al., 2001).



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Neradovic et al. reported the development of block copolymers based on poly-N-isopropylacrylamide (PNIPAAm) and PEG. The thermosensitive and hydrophilic block copolymers can self-assemble into nanoparticles above the cloud point (CP) of the thermosensitive block. The study here is based on NIPAAm and N-(2-hydroxypropyl) methacrylamide lactate (poly(NIPAAm-co-HPMAm-lactate)) as a thermosensitive block and PEG as a hydrophilic block. The CP of the thermosensitive block increases, resulting in the destabilization of the particles due to the hydrolysis of the lactic side groups. Based on this concept, Xu et al. developed complex polymeric micelles with a PLA core and a mixed PEG/PNIPAM shell from self-assembly of two block copolymers: poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) and poly(N-isopropyl acrylamide)-b-poly(lactic acid) (PNIPAM-b-PLA) (Xu et al., 2012). Complex micelles with a PLA core and a mixed PEG/PNIPAM shell showed a protective effect against enzymatic degradation in aqueous solutions at temperatures above the phase transition temperature of the PNIPAM block. At higher temperatures, the PNIPAM block collapsed onto the PLA core and formed a hydrophobic layer, which prevented the micellar core from enzyme degradation (Fig. 5.9). In addition, the enzymatic degradation rate of the micellar core can be tuned by changing the ratio of PEG to PNIPAM in the mixed shell. With increasing content of PNIPAM, the conformation of the collapsed PNIPAM changes from patchy domains to a continuous and dense layer, and the enzyme accessibility to the PLA core is changed. This represents the first example of the micelle model, which can balance the biodegradability and the circulation time of polymeric micelles as a drug carrier. The significant change in the solution viscosity of natural polymers, which occurs due to their enzymatic hydrolysis, is considered to be a complex phenomenon, as a result of which the macromolecule degrades into smaller molecular units. The polymer concentration, solution viscosity, and the presence of appendages to the backbone play a major role in influencing the enzymatic access to polymer cleavage sites. Rheological properties of the biopolymer solutions can be employed to control the enzymatic hydrolysis (Tayal et al., 1999). Tayal et  al., employed a water-soluble polysaccharide, guar galactomannan, which consists of a linear backbone of â-1,4-linked mannose

Enzyme

PEG

T

PNIPAM

Enzyme

PLA

Enzyme

FIG.  5.9  Schematic illustration of complex micelles with different temperature (Tayal et al., 1999).

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units with R-1,6-linked galactose units as side chains. To be used to form synergistic gels with biopolymers, the chemical architecture and the chain size of the guar molecule needs to be modified. This was achieved by investigating the molecular properties of guar galactomannan during enzymatic degradation and relating them to its rheological characteristics. The rheological properties of guar exhibited a decrease in zero-shear viscosity of several orders of magnitude and were sensitive to enzymatic hydrolysis. The guar solution viscosity as a function of degradation time and enzyme concentration could be made by collapsing the viscosity-time profiles onto a single curve by shifts along the time axis. A unique correlation between degradation time, molecular weight, and viscosity resulted in the superposition of the data (Tayal et al., 1999).

5.5  FABRICATION MECHANISMS OF ENZYMERESPONSIVE POLYMERS 5.5.1  Living Polymerization The polymeric molecules undergo three processes before forming a polymer: initiation, propagation, and termination; these processes are regulated during polymerization. The death of the polymer occurs during the termination process, and when the termination does not occur, the polymeric molecules live for an indefinite period of time, which results in the increase in its molecular weight beyond limits. The constant supply of monomer to the polymer is essential for its growth, which when exhausted interrupts the growth of the polymer. The living free-radical polymerization mechanism is classified into three categories: (i) living anionic polymerization, (ii) living cationic polymerization, and (iii) living free-radical polymerization (LFRP). 5.5.1.1  Living Anionic Polymerization Szwarc et  al. first reported the living anionic polymerization mechanism in 1956, which involved the polymerization of styrene and dienes. The synthesis of model polymers with controlled architecture and narrow molecular weight distribution (MWD) has been achieved by living anionic polymerization for about 40 years. The anionic polymerization is due to the formation of carbanions at the ends of the polymer chain ends. It is one of the most reliable and versatile methods for synthesis due to its efficient generation of polyanions that undergo termination or chain transfer reactions. One of the most remarkable features of this mechanism is that the termination step is not involved and, as a result, the carbanion in the absence of impurities is active and capable of adding another monomer, due to which the chains are inadvertently active. This makes it easier to



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calculate the average molecular weight Mn from the amount of monomer consumed by the polymer. This proves that polymer synthesis can be performed in a controlled manner in terms of molecular weight as all the chains are initiated at the same time (Hong et al., 1999). 5.5.1.2  Living Cationic Polymerization The living cationic polymerization mechanism was first reported in the 18th century, and different kinds of monomers and initiators were examined during this period. The process of controlling the reaction had always been a challenge in the case of cationic polymerization due to highly active and unstable growing species caused by side reactions. The discovery of styrene derivatives in the late 1970s shattered the pessimistic outlook of long-lived cationic species in polymerization. However, it was in the 1980s that Higashimura and Sawamoto made their first breakthrough with living polymerization of alkyl vinyl ethers followed with living polymerization of isobutene by Kennedy and Faust. Thus the first controlled living polymerization reaction that permitted precision synthesis of various functional polymers is living cationic polymerization (Aoshima and Kanaoka, 2009). The scheme of living cationic polymerization is shown in Fig. 5.10.

FIG. 5.10  Scheme of living cationic polymerization mechanism.

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Though perfect control over the molecular architecture has been established by living ionic (anionic or cationic) polymerization, it still holds a lot of disadvantages. The growing carbanion reacts with oxygen, water, or carbon dioxide resulting in a lot of impurities, which can affect the polymerization reaction. The optimum temperature requirement for the reaction varies from 20°C to 78°C as high temperatures affect the rate of reaction. The functional moieties are rarely compatible with ions and counterions formed during polymerization and, as a result, functional monomers are difficult to polymerize (Bisht and Chatterjee, 2001). 5.5.1.3  Living Free-Radical Polymerization Living free-radical polymerization is a chain-growth polymerization where the end chain is a free radical and has a number of advantages over traditional free radical procedures. One of the advantages is the ability to prepare block copolymers in the presence of different monomers by the sequential activation of the dormant end chain (Bisht and Chatterjee, 2001). The scheme of living free-radical polymerization is shown in Fig. 5.11. Niu et  al. (2017) reported the synthesis of structurally defined synthetic polymers using the light-mediated CRP techniques. A visible lightmediated PET-RAFT process was developed from initiators attached covalently or noncovalently into the cell surface. These initiators were used to achieve cytocompatibility and cell-surface initiated polymerization, which led to an increase in the amount of grafted polymers on the surface of the cell. The implementation of a biocompatible CRP process is essential for the generation of polymer brushes on a biotic substrate. PEG-based acrylamides were chosen due to their excellent hydrolytic stability in biological environments in addition to high propagation rates in aqueous solutions at room temperature (Fig.  5.12). The chosen acrylamides were impermeable to cell membranes with a molecular weight of 1 kDa. The catalyst chosen for polymerization was Eosin Y; 2-(butylthiocarbonothioyl) propionic acid (BTPA) is the chain transfer agent; and the co-catalyst is triethanolamine for the PET-RAFT process. The aggregation of polymer-modified yeast cells was mediated by introducing tannic acid, which can bind through hydrophobic interactions to PEG. This led to an increased efficiency of polymer grafting in these systems and also enabled the phenotype of the cell when compared to traditional approaches. This results in the generation of glycopolymers with controlled spatial and temporal distributions and high density (Niu et al., 2017). A–B

hv/D

Asymmetric iniferter (unimolecular initiator)

A× High-reactivity radical

B×

+

Low-reactivity stable radical

FIG. 5.11  Scheme of living free-radical polymerization.



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5.5 Fabrication Mechanisms of Enzyme-Responsive Polymers O x

O

MeO

S

N H

24

S

S

HO

BTPA

PEGA-1k

Triethanolamine

+

RT, 5 min, hv (465 nm)

O O y

R

O 24

N H

Functional PEGA R = –N3, biotin

O

Br HO

S

O

COOH

Br

O

x O

r

y O

S S

NH

NH O O

R OMe

24

24

OH Br

Br Eosin Y

FIG.  5.12  Scheme of synthesis of polymer brushes using the CRP technique (Niu et al., 2017).

5.5.2  Reversible Addition-Fragmentation Chain-Transfer Polymerization One of the living free radical polymerization mechanisms is the Reversible Addition-Fragmentation chain Transfer (RAFT). The RAFT polymerization can be used to control the molecular weight of polymers with low polydispersity indices (PDI