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Edited by:
Vitaliy V. Khutoryanskiy, Ph.D., is Professor of Formulation Science, Reading School of Pharmacy, University of Reading, Whiteknights, Reading, UK.
Theoni K. Georgiou, Ph.D., is a Senior Lecturer in Polymer Chemistry, Department of Materials, Imperial College London, UK.
About the Editors xiii
List of Contributors xv
Preface xix
Part I Chemistry 1
1 Poly(N-isopropylacrylamide): Physicochemical Properties and Biomedical Applications 3Marzieh Najafi, Erik Hebels,WimE. Hennink, and Tina Vermonden
1.1 Introduction 3
1.2 PNIPAM as Thermosensitive Polymer 4
1.3 Physical Properties of PNIPAM 5
1.3.1 Phase Behavior of PNIPAM in Water/Alcohol Mixtures 5
1.3.2 Effect of Concentration and Molecular Weight of PNIPAM on LCST 5
1.3.3 Effect of Surfactants on LCST 7
1.3.4 Effect of Salts on LCST 7
1.4 Common Methods for Polymerization of NIPAM 8
1.4.1 Free Radical Polymerization 8
1.4.2 Living Radical Polymerization 9
1.4.2.1 ATRP of NIPAM 10
1.4.2.2 RAFT Polymerization of NIPAM 11
1.5 Dual Sensitive Systems 12
1.5.1 pH and Thermosensitive Systems 12
1.5.2 Reduction-Sensitive and Thermosensitive Systems 13
1.5.3 Hybrid-Thermosensitive Materials 13
1.6 Bioconjugation of PNIPAM 15
1.6.1 Protein-PNIPAM Conjugates 16
1.6.2 Peptide-PNIPAM Conjugates 18
1.6.3 Nucleic Acid-PNIPAM Conjugates 21
1.7 Liposome Surface Modification with PNIPAM 21
1.8 Applications of PNIPAM in Cell Culture 22
1.9 Crosslinking Methods for Polymers 23
1.9.1 Crosslinking in PNIPAM-Based Hydrogels 23
1.9.2 Crosslinking of PNIPAM-Based Micelles 26
1.9.2.1 Shell Crosslinked (SCL) 26
1.9.2.2 Core Crosslinked (CCL) 27
1.10 Conclusion and Outlook of Applications of PNIPAM 27
Acknowledgments 28
References 28
2 Thermoresponsive Multiblock Copolymers: Chemistry, Properties and Applications 35Anna P. Constantinou and Theoni K. Georgiou
2.1 Introduction 35
2.2 Chemistry of Thermoresponsive Block-based Copolymers 35
2.3 Architecture, Number of Blocks and Block Sequence 38
2.3.1 Why the Block Structure? 38
2.3.2 Triblock Copolymers 39
2.3.2.1 Micelles 40
2.3.2.2 Gels 45
2.3.2.3 Films and Membranes 52
2.3.3 Tetrablock Copolymers 53
2.3.4 Pentablock Copolymers 54
2.3.4.1 Pluronic®Based 54
2.3.4.2 Non-pluronic Based 56
2.3.5 Multiblock Copolymers 57
2.4 Applications 59
2.5 Conclusions 61
Acknowledgments 61
References 61
3 Star-shaped Poly(2-alkyl-2-oxazolines): Synthesis and Properties 67Andrey V. Tenkovtsev, Alina I. Amirova, and Alexander P. Filippov
3.1 Introduction 67
3.2 Synthesis of Star-shaped Poly(2-alkyl-2-oxazolines) 68
3.3 Properties of Star-shaped Poly(2-alkyl-2-oxazolines) 78
3.4 Conclusions 87
References 88
4 Poly(N-vinylcaprolactam): FromPolymer Synthesis to Smart Self-assemblies 93Fei Liu, Veronika Kozlovskaya, and Eugenia Kharlampieva
4.1 Introduction 93
4.2 Synthesis of PVCL Homo- and Copolymers 93
4.2.1 Synthesis of Statistical PVCL Copolymers 95
4.2.2 Synthesis of PVCL Block Copolymers 97
4.2.3 Other PVCL-based Copolymers 99
4.3 Properties of PVCL in Aqueous Solutions 99
4.3.1 Dependence of the LCST of PVCL on Molecular Weight and Polymer Concentration 99
4.3.2 LCST Dependence on Chemical Composition 100
4.3.3 The Effect of Salt on the PVCL Temperature Response 102
4.3.4 The Effect of Solvent on PVCL Temperature Response 102
4.4 Assembly of PVCL-based Polymers in Solution 102
4.4.1 PVCL Interpolymer Complexes 102
4.4.2 PVCL-based Micelles 103
4.4.3 Self-assembly of PVCL-based Copolymers into Polymersomes 105
4.5 Templated Assemblies of PVCL Polymers 107
4.5.1 Hydrogen-bonded PVCL-based Multilayers 107
4.5.1.1 pH-sensitive Hydrogen-bonded PVCL Multilayers 107
4.5.1.2 Enzymatically Sensitive Hydrogen-bonded PVCL Multilayers 108
4.5.2 Multilayer Hydrogels of PVCL 110
4.6 Outlook and Perspectives 113
Acknowledgment 113
References 114
5 Sodium Alginate Grafted with Poly(N-isopropylacrylamide) 121Catalina N. Cheaburu-Yilmaz, Cornelia Vasile, Oana-Nicoleta Ciocoiu, and Georgios Staikos
5.1 Alginic Acid 121
5.1.1 Monomeric and Polymeric Structure of Alginates 121
5.2 Poly(N-Isopropylacrylamide) and Thermoresponsive Properties 122
5.3 Synthesis and Characterization of Alginate-graft-PNIPAM Copolymers 123
5.4 Solution Properties 124
5.4.1 Turbidimetry 124
5.4.2 Fluorescence 124
5.4.3 Rheology 126
5.4.4 Degradability 130
5.4.5 Biocompatibility 131
5.4.5.1 Cytotoxicity 132
5.4.5.2 Pharmaceutical and Medical Applications 135
5.5 Conclusions and Perspectives 137
References 138
6 Multi-stimuli-responsive Polymers Based on Calix[4]arenes and Dibenzo-18-crown-6-ethers 145SzymonWiktorowicz, Heikki Tenhu, and Vladimir Aseyev
6.1 Introduction 145
6.2 Single-stimuli-responsive Polymers 146
6.2.1 Thermo-responsive Polymers in Polar Media 147
6.2.2 pH-responsive Polymers 148
6.2.3 Photoresponsive Polymers 148
6.2.4 Other Single-stimuli-responsive Polymers 150
6.3 Multi-stimuli-responsive Polymers 150
6.4 Poly(azocalix[4]arene)s and Poly(azodibenzo-18-crown-6-ether)s 151
6.4.1 Calixarenes 151
6.4.2 Crown Ethers 152
6.4.3 Structural Units of Poly(azocalix[4]arene)s 153
6.4.4 Structural Units of Poly(azodibenzo-18-crown-6-ether)s 154
6.5 Photoisomerization 154
6.6 Host-guest Interactions 156
6.7 Thermo-responsiveness 158
6.7.1 LCST: Tegylated Poly(azocalix[4]arene)s inWater 158
6.7.2 UCST: Tegylated Poly(azocalix[4]arene)s in Alcohols 159
6.7.3 UCST and Photoisomerization of Tegylated Poly(azocalix[4]arene)s 160
6.7.4 UCST and Poly(azodibenzo-18-crown-6-ether)s 161
6.7.5 UCST and Photoisomerization of Poly(azodibenzo-18-crown-6-ether)s 162
6.7.6 UCST in Water-alcohol Mixtures 162
6.8 Solvatochromism and pH Sensitivity 163
6.9 Summary and Outlook 164
Acknowledgments 165
References 165
Part II Characterization of Temperature-responsive Polymers 175
7 Small-Angle X-ray and Neutron Scattering of Temperature-Responsive Polymers in Solutions 177Sergey K. Filippov, Martin Hruby, and Petr Stepanek
7.1 Introduction 177
7.2 Temperature-responsive Homopolymers 179
7.3 Hydrophobically Modified Polymers 182
7.4 Cross-Linked Temperature-Sensitive Polymers and Gels 184
7.5 Temperature-Responsive Block Copolymers 185
7.6 Hybrid Nanoparticles 187
7.7 Gradient Temperature-Responsive Polymers 188
7.8 Multi-responsive Copolymers 189
7.9 Concluding Remarks 191
Acknowledgments 191
References 191
8 Infrared and Raman Spectroscopy of Temperature-Responsive Polymers 197Yasushi Maeda
8.1 Introduction 197
8.2 Experimental Methods to Measure IR and Raman Spectra of Aqueous Solutions 198
8.3 Poly(N-substituted acrylamide)s 200
8.3.1 Overall Spectral Change 200
8.3.2 Amide Bands 202
8.3.3 C-H Stretching Bands 204
8.3.4 C-D Stretching Band 206
8.4 Poly(vinyl ether)s 207
8.5 Poly(meth)acrylates 208
8.6 Effects of Additives on Phase Behavior 210
8.7 Temperature-Responsive Copolymers and Gels 217
References 222
9 Application of NMR Spectroscopy to Study Thermoresponsive Polymers 225Jirí Spevácek
9.1 Introduction 225
9.2 Coil-Globule Phase Transition and Its Manifestation in NMR Spectra 225
9.3 Temperature Dependences of High-Resolution NMR Spectra: Phase-Separated Fraction p 227
9.4 Multicomponent Polymer Systems 230
9.5 Effects of Low-Molecular-Weight Additives on Phase Transition 234
9.6 Behavior of Water at the Phase Transition 236
9.7 Conclusion 242
Acknowledgment 242
References 242
10 Polarized Luminescence Studies of Nanosecond Dynamics of Thermosensitive Polymers in Aqueous Solutions 249Vladimir D. Pautov, Tatiana N. Nekrasova, Tatiana D. Anan'eva, and Ruslan Y. Smyslov
10.1 Introduction 249
10.2 Theoretical Part 250
10.2.1 Polarization of Luminescence 250
10.2.2 The Use of Polarized Luminescence in the Studies of Nanosecond Dynamics of Macromolecules 253
10.3 Experimental Part 258
10.3.1 Methods of Synthesis of Polymers Containing Luminescent Markers 258
10.3.2 Technique for Measurement of Luminescence Polarization 260
10.3.3 Thermosensitive Water-Soluble Polymers 263
10.3.4 pH and Thermosensitive Water-Soluble Polymers 268
10.3.5 Temperature-Induced Transitions in Polymers in Nonaqueous Solutions 271
10.4 Conclusion 272
References 273
Part III Applications of Temperature-responsive Polymers 279
11 Applications of Temperature-Responsive Polymers Grafted onto Solid Core Nanoparticles 281Edward D. H. Mansfield, Adrian C.Williams, and Vitaliy V. Khutoryanskiy
11.1 Introduction 281
11.2 Silica Nanoparticles 282
11.2.1 pNIPAM-functionalised Silica Nanoparticles 282
11.2.2 Poloxamer-functionalised Silica Nanoparticles 284
11.2.3 Other Polymers 286
11.3 Metallic Nanoparticles 286
11.3.1 pNIPAM-functionalised Metallic Nanoparticles 287
11.3.2 Poloxamer-functionalised Metallic Nanoparticles 288
11.3.3 Elastin-functionalised Metallic Nanoparticles 288
11.3.4 Other Polymer-functionalised Metallic Nanoparticles 289
11.4 Magnetic Nanoparticles 290
11.4.1 pNIPAM-functionalised Magnetic Nanoparticles 290
11.4.2 Poloxamer-functionalised Magnetic Nanoparticles 291
11.4.3 Other TRP-functionalised Magnetic Nanoparticles 293
11.4.4 Summary 293
11.5 Conclusions 294
References 294
12 Temperature-responsive Polymers for Tissue Engineering 301Kenichi Nagase, Masayuki Yamato, and Teruo Okano
12.1 Introduction 301
12.1.1 Thermo-responsive Cell Culture Dishes and Cell Sheets 301
12.1.2 Thermo-responsive Cell Culture Dishes Prepared by Electron-beam-induced Polymerization 302
12.1.3 Thermo-responsive Cell Culture Dishes for Enhancing Cell Adhesion and Proliferation by Immobilized Biological Ligands 303
12.1.4 Thermo-responsive Cell Culture Dish Prepared by Living Radical Polymerization 304
12.1.5 Patterned Thermo-responsive Cell Culture Substrates 306
12.1.6 Thermo-responsive Surfaces for Cell Separation 309
12.2 Conclusions 309
Acknowledgments 309
References 311
13 Thermogel Polymers for Injectable Drug Delivery Systems 313VidhiM. Shah, Duc X. Nguyen, Deepa A. Rao, Raid G. Alany, and AdamW.G. Alani
13.1 Introduction 313
13.2 Pluronics® 314
13.3 Polyester-based Polymers 315
13.4 Chitosan and Derivatives 317
13.5 Polypeptides 318
13.6 Clinical Application of Thermogel Polymers 319
13.6.1 Ocular Delivery 319
13.6.2 Nasal Delivery 320
13.6.3 Antitumor Delivery/Drug Delivery Systems 321
13.7 Summary 323
References 323
14 Thermoresponsive Electrospun Polymer-based (Nano)fibers 329Mariliz Achilleos and Theodora Krasia-Christoforou
14.1 Introduction 329
14.2 Basic Principles of Electrospinning 330
14.3 PNIPAM-based Electrospun (Nano)fibers 332
14.3.1 Temperature-triggered Wettability 332
14.3.2 Biomedicine 335
14.3.2.1 Drug Delivery 336
14.3.2.2 Tissue Engineering 339
14.3.2.3 Biosensing 341
14.3.2.4 Solid-phase Microextraction 341
14.3.2.5 Molecular Recognition 342
14.3.2.6 Organic-Inorganic PNIPAM-based Electrospun (Nano)fibers 342
14.3.3 Sensing 343
14.3.4 Other Applications 344
14.4 Other Types of Thermoresponsive Electrospun (Nano)fibers 345
14.5 Conclusions and Outlook 348
References 348
15 Catalysis by Thermoresponsive Polymers 357Natalya A. Dolya and Sarkyt E. Kudaibergenov
15.1 Introduction 357
15.2 Metal Complexes Immobilized Within Thermosensitive Polymers 358
15.3 Thermoresponsive Polyampholytes 358
15.4 Thermosensitive Hydrogels in Catalysis 361
15.5 Thermoresponsive Catalytically Active Nano- and Microgels, Spheres, Capsules, and Micelles 364
15.6 Thermosensitive Self-Assemblies 367
15.7 Mono- and Bimetallic Nanoparticles Stabilized by Thermoresponsive Polymers 368
15.8 Enzymes-Embedded Thermoresponsive Polymers 369
15.9 Immobilization of Magnetic Nanoparticles into the Matrix of Thermoresponsive Polymers for Efficient Separation of Catalysts 369
15.10 Summary 370
Acknowledgments 371
References 371
Index 379
Marzieh Najafi, Erik Hebels, Wim E. Hennink and Tina Vermonden
Department of Pharmaceutics, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 3508 TB Utrecht, The Netherlands
Poly(N-isopropylacrylamide) (PNIPAM) (Figure 1.1) has attracted a lot of attention during the past decades because of its thermoresponsive behavior in a biomedically interesting temperature window. This polymer exhibits inverse solubility in aqueous media and precipitates upon increasing the temperature [1, 2]. The temperature at which this polymer converts from a soluble state to an insoluble state, known as the cloud point (CP) or the lower critical solution temperature (LCST), is 32?°C [3]. The first study on the PNIPAM phase diagram was reported by Heskins and Guillet [2] Since then this polymer has been known as a thermosensitive polymer. PNIPAM has been prepared by a wide range of polymerization techniques such as free radical polymerization (FRP) [4], redox polymerization [5], ionic polymerization [6], radiation polymerization [7], and living radical polymerization [8].
Figure 1.1 Chemical structure of poly(N-isopropylacrylamide) (PNIPAM).
The focus of this chapter is on polymerization techniques, and examples are given addressing PNIPAM's potential applications as biomaterial in drug and gene delivery and bioseparation. For other applications of PNIPAM in, e.g. membranes, sensors, thin films, and brushes, the reader is referred to reviews published elsewhere [9-12].
After introducing the general physicochemical properties of PNIPAM, an overview of the most frequently used polymerization techniques (free and living radical polymerization) is given, and a variety of copolymers and structures obtained by these methods are highlighted. Copolymerization with other monomers or conjugation/grafting of PNIPAM with other stimuli-responsive polymers/materials results in dual responsive materials, of which the physical properties can be changed by several stimuli, e.g. changes in pH or redox conditions, light, and magnetic field. Examples of these systems along with the effect of copolymer composition on the LCST of PNIPAM are provided in this chapter. In addition, different methods of chemical and physical crosslinking and their effects on properties of the final materials are discussed.
Also, the potential of designing complex bioconjugates provided by recent developments in polymerization methods is discussed. Conjugation of responsive polymers to biomolecules (e.g. proteins, peptides, and nucleic acids) is a sophisticated method because the attached PNIPAM imparts responsiveness to these biomolecules. Furthermore, conjugation to biomolecules induces changes in stability and bioactivity as a result of altering the (surface) properties and solubility of materials. Here, we will review examples of grafting PNIPAM to biomolecules or growing polymeric chains from their surfaces. Finally, the future prospects of PNIPAM in biomedical and pharmaceutical applications are outlined.
Thermosensitive polymers are by definition polymers whose physical properties can change in response to temperature changes, usually occurring in aqueous media [13]. This transition is most often drastic and follows upon passing a certain threshold that may be, in context of miscibility in a solvent, either an upper critical solution temperature (UCST) or lower critical solution temperature (LCST). LCST behavior indicates the temperature above which the polymer will no longer be soluble, while UCST behavior indicates the temperature below which immiscibility is reached. It should be noted that in literature the terms CP and LCST are often mixed up. The CP of a polymer solvent mixture is the temperature at which separation into a polymer-rich and polymer-poor phase occurs. The LCST is defined as the minimum of the CP in a temperature versus polymer concentration plot. So by definition, below the LCST, only one phase is observed independent of the polymer concentration (see Section 1.3) [14].
PNIPAM is an especially interesting thermosensitive polymer for application in biomedical and pharmaceutical sciences because of its sharp LCST of 32?°C in aqueous media. This transition is reversible, and PNIPAM solubilizes again when the temperature drops below its LCST [3].
The exact mechanism by which PNIPAM self-assembles in water above the LCST is still not fully clear but believed to be because of the entropic gain of water molecules that dissociate from the hydrophobic isopropyl side-chain moieties above the LCST. The enthalpy gain of water molecules associated via hydrogen bonds with the amide groups of the polymer becomes smaller than the counter effect of entropic gain of the system with water being dissociated when passing the LCST [3]. Since the extent of hydration of polymers is dependent on the characteristics of the monomer units, the LCST of PNIPAM may be varied by copolymerizing NIPAM with monomers differing in hydrophobicity or hydrophilicity. Furthermore, hydrophobic interactions between the polymer segments themselves have also been suggested to be crucial to the LCST transition from isolated extended coils of PNIPAM to collapsed chains [3, 15, 16].
Water molecules form hydrogen bonds with the carbonyl group, accepting two hydrogen bonds, and the nitrogen atom of the amide group can donate one hydrogen bond in the hydrated state below LCST [16]. During this transition, it has been shown that the number of hydrogen bonds between PNIPAM and water is reduced and intra-chain hydrogen bonds are formed instead, of which some remain, even when cooled again below LCST. This explanation is used to rationalize why the aggregated chains swell upon cooling and do not immediately dissociate slightly below the LCST and hence cause hysteretic behavior [17]. Computer simulations confirmed that besides a reduction of intermolecular hydrogen bonds, there is a substantial decrease in the solvent accessible surface area, and it has been even suggested that a decrease in torsional energy of the isopropyl groups occurs during this thermal transition. The model also predicted the decrease in LCST upon copolymerizing with hydrophobic tert-butylacrylamide (tBAAM), which is in line with experimental results [18].
The carbon backbone has shown to play an important role in the hydrophobic contribution of phase transition. To investigate this effect, Lai and Wu [19] used N-isopropylpropionamide (NIPPA) as a small molecular model compound for PNIPAM. They observed that at high concentration (40?wt%), the NIPPA solution shows a higher LCST of 39?°C with a broader phase transition temperature range. They explained that the carbonyl group in the small molecule of NIPPA has more interaction with water molecules, which explains the higher LCST. Yet, the presence of the hydrophobic main chain in PNIPAM interferes with hydrogen bonding between the carbonyl groups and water molecules [19]. On the other hand, the presence of a-methyl groups in the main chain (poly(N-isopropylmethacrylamide) (pNIPMAM)) results in increased hydrophobicity; however, surprisingly the LCST of this polymer is not lower than that of PNIPAM but even increased by about 15?°C. The authors speculated that the higher CP for pNIPMAM is due to the methyl groups that induce steric hindrance for the hydrophobic groups to self-assemble in the most favorable manner [20].
This section briefly describes some of the physical properties of PNIPAM by highlighting the effect of composition of the media on its phase transition temperature.
In water/organic solvent mixtures (e.g. alcohols/acetone), the LCST of PNIPAM is dependent on the type of cosolvent and its volume fraction. In general, first a decrease in a CP is found upon increasing the volume fraction of organic solvent, while after a certain volume ratio an increase in a CP is observed. The less polar the cosolvent, the lower the volume fraction at which the increase in the transition temperature occurs. For example, for acetone the minimum transition temperature is found at a molar fraction of 0.15, while for methanol this mole fraction is 0.34 (see Figure 1.2). At low volume ratios, the cosolvent molecules and PNIPAM compete for water molecules, resulting in less hydration of PNIPAM and thus a lower CP. Upon increasing the volume fraction of a cosolvent, these solvent molecules interact with the polymer chains and increase their solubility. Remarkably, for some alcoholic cosolvents such as ethanol and 1-propanol, a coexistence of LCST and UCST behavior is observed. In contrast, UCST behavior is not observed in water only or methanol-water mixtures [15, 21, 22].
Figure 1.2 Comparison between phase transition temperatures of PNIPAM in water-methanol (open symbols) and water-acetone (filled symbols) solutions.
Source: Costa and Freitas 2002 [22]. Reproduced with permission of...
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