Temperature-Responsive Polymers E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 835

Veröffentlichungsjahr: 2018

Beschreibung

An authoritative resource that offers an understanding of the chemistry, properties and applications of temperature-responsive polymers

With contributions from a distinguished panel of experts, Temperature-Responsive Polymers puts the focus on hydrophilic polymers capable of changing their physicochemical properties in response to changes in environmental temperature. The contributors review the chemistry of these systems, and discuss a variety of synthetic approaches for preparation of temperature-responsive polymers, physicochemical methods of their characterisation and potential applications in biomedical areas.

The text reviews a wide-variety of topics including: The characterisation of temperature-responsive polymers; Infrared and Raman spectroscopy; Applications of temperature-responsive polymers grafted onto solid core nanoparticles; and much more. The contributors also explore how temperature-responsive polymers can be used in the biomedical field for applications such as tissue engineering. This important resource:

• Offers an important synthesis of the current research on temperature-responsive polymers
• Covers the chemistry, the synthetic approaches for presentation and the physiochemical method of temperature-responsive polymers
• Includes a review of the fundamental characteristics of temperature-responsive polymers

• Explores many of the potential applications in biomedical science, including drug delivery and gene therapy

Written for polymer scientists in both academia and industry as well as postgraduate students working in the area of stimuli-responsive materials, this vital text offers an exploration of the chemistry, properties and current applications of temperature-responsive polymers.

Leseprobe

Table of Contents

Cover

Copyright

About the Editors

List of Contributors

Preface

References

Part I: Chemistry

Chapter 1: Poly(

N

‐isopropylacrylamide): Physicochemical Properties and Biomedical Applications

1.1 Introduction

1.2 PNIPAM as Thermosensitive Polymer

1.3 Physical Properties of PNIPAM

1.4 Common Methods for Polymerization of NIPAM

1.5 Dual Sensitive Systems

1.6 Bioconjugation of PNIPAM

1.7 Liposome Surface Modification with PNIPAM

1.8 Applications of PNIPAM in Cell Culture

1.9 Crosslinking Methods for Polymers

1.10 Conclusion and Outlook of Applications of PNIPAM

Acknowledgments

References

Chapter 2: Thermoresponsive Multiblock Copolymers: Chemistry, Properties and Applications

2.1 Introduction

2.2 Chemistry of Thermoresponsive Block‐based Copolymers

2.3 Architecture, Number of Blocks and Block Sequence

2.4 Applications

2.5 Conclusions

Acknowledgments

References

Chapter 3: Star‐shaped Poly(2‐alkyl‐2‐oxazolines): Synthesis and Properties

3.1 Introduction

3.2 Synthesis of Star‐shaped Poly(2‐alkyl‐2‐oxazolines)

3.3 Properties of Star‐shaped Poly(2‐alkyl‐2‐oxazolines)

3.4 Conclusions

References

Chapter 4: Poly(

N

‐vinylcaprolactam): From Polymer Synthesis to Smart Self‐assemblies

4.1 Introduction

4.2 Synthesis of PVCL Homo‐ and Copolymers

4.3 Properties of PVCL in Aqueous Solutions

4.4 Assembly of PVCL‐based Polymers in Solution

4.5 Templated Assemblies of PVCL Polymers

4.6 Outlook and Perspectives

Acknowledgment

References

Chapter 5: Sodium Alginate Grafted with Poly(

N

‐isopropylacrylamide)

5.1 Alginic Acid

5.2 Poly(

N

‐Isopropylacrylamide) and Thermoresponsive Properties

5.3 Synthesis and Characterization of Alginate

‐graft

‐PNIPAM Copolymers

5.4 Solution Properties

5.5 Conclusions and Perspectives

References

Chapter 6: Multi‐stimuli‐responsive Polymers Based on Calix[4]arenes and Dibenzo‐18‐crown‐6‐ethers

6.1 Introduction

6.2 Single‐stimuli‐responsive Polymers

6.3 Multi‐stimuli‐responsive Polymers

6.4 Poly(azocalix[4]arene)s and Poly(azodibenzo‐18‐crown‐6‐ether)s

6.5 Photoisomerization

6.6 Host–guest Interactions

6.7 Thermo‐responsiveness

6.8 Solvatochromism and pH Sensitivity

6.9 Summary and Outlook

Acknowledgments

References

Part II: Characterization of Temperature‐responsive Polymers

Chapter 7: Small‐Angle X‐ray and Neutron Scattering of Temperature‐Responsive Polymers in Solutions

7.1 Introduction

7.2 Temperature‐responsive Homopolymers

7.3 Hydrophobically Modified Polymers

7.4 Cross‐Linked Temperature‐Sensitive Polymers and Gels

7.5 Temperature‐Responsive Block Copolymers

7.6 Hybrid Nanoparticles

7.7 Gradient Temperature‐Responsive Polymers

7.8 Multi‐responsive Copolymers

7.9 Concluding Remarks

Acknowledgments

References

Chapter 8: Infrared and Raman Spectroscopy of Temperature‐Responsive Polymers

8.1 Introduction

8.2 Experimental Methods to Measure IR and Raman Spectra of Aqueous Solutions

8.3 Poly(

N

‐substituted acrylamide)s

8.4 Poly(vinyl ether)s

8.5 Poly(meth)acrylates

8.6 Effects of Additives on Phase Behavior

8.7 Temperature‐Responsive Copolymers and Gels

References

Chapter 9: Application of NMR Spectroscopy to Study Thermoresponsive Polymers

9.1 Introduction

9.2 Coil–Globule Phase Transition and Its Manifestation in NMR Spectra

9.3 Temperature Dependences of High‐Resolution NMR Spectra: Phase‐Separated Fraction

p

9.4 Multicomponent Polymer Systems

9.5 Effects of Low‐Molecular‐Weight Additives on Phase Transition

9.6 Behavior of Water at the Phase Transition

9.7 Conclusion

Acknowledgment

References

Chapter 10: Polarized Luminescence Studies of Nanosecond Dynamics of Thermosensitive Polymers in Aqueous Solutions

10.1 Introduction

10.2 Theoretical Part

10.3 Experimental Part

10.4 Conclusion

References

Part III: Applications of Temperature‐responsive Polymers

Chapter 11: Applications of Temperature‐Responsive Polymers Grafted onto Solid Core Nanoparticles

11.1 Introduction

11.2 Silica Nanoparticles

11.3 Metallic Nanoparticles

11.4 Magnetic Nanoparticles

11.5 Conclusions

References

Chapter 12: Temperature‐responsive Polymers for Tissue Engineering

12.1 Introduction

12.2 Conclusions

Acknowledgments

References

Chapter 13: Thermogel Polymers for Injectable Drug Delivery Systems

13.1 Introduction

13.2 Pluronics®

13.3 Polyester‐based Polymers

13.4 Chitosan and Derivatives

13.5 Polypeptides

13.6 Clinical Application of Thermogel Polymers

13.7 Summary

References

Chapter 14: Thermoresponsive Electrospun Polymer‐based (Nano)fibers

14.1 Introduction

14.2 Basic Principles of Electrospinning

14.3 PNIPAM‐based Electrospun (Nano)fibers

14.4 Other Types of Thermoresponsive Electrospun (Nano)fibers

14.5 Conclusions and Outlook

References

Chapter 15: Catalysis by Thermoresponsive Polymers

15.1 Introduction

15.2 Metal Complexes Immobilized Within Thermosensitive Polymers

15.3 Thermoresponsive Polyampholytes

15.4 Thermosensitive Hydrogels in Catalysis

15.5 Thermoresponsive Catalytically Active Nano‐ and Microgels, Spheres, Capsules, and Micelles

15.6 Thermosensitive Self‐Assemblies

15.7 Mono‐ and Bimetallic Nanoparticles Stabilized by Thermoresponsive Polymers

15.8 Enzymes‐Embedded Thermoresponsive Polymers

15.9 Immobilization of Magnetic Nanoparticles into the Matrix of Thermoresponsive Polymers for Efficient Separation of Catalysts

15.10 Summary

Acknowledgments

References

Index

End User License Agreement

List of Tables

Chapter 02

Table 2.1 The main thermoresponsive units, the block architecture in which they have been incorporated, the comonomer(s) used and the main application tested (if any).

Chapter 04

Table 4.1 Chain transfer agents used in synthesis of PVCL.

Chapter 05

Table 5.1 Hematological, immune system parameters, and serum biochemical parameters (mean ± standard deviation) in mice following ip injections with 99/1, 80/20, and 75/25 of PNIPAM/Alg hydrogel suspensions.

Table 5.2 Hematological and immune system parameters (mean ± standard deviation) in mice following ip injection with Alg‐

g

‐PNIPAM copolymer containing 25% PNIPAM suspensions.

Chapter 07

Table 7.1 Models used for fitting of various polymers.

Chapter 09

Table 9.1 Thermodynamic parameters Δ

H

and Δ

S

and size of cooperative unit

N

characterizing the phase transition in D

2

O solutions of PNIPMAm, PVCL, and PVME; DP is the average degree of polymerization [18, 26, 27].

Chapter 10

Table 10.1 Formula of PAMAs containing up to c. 0.2 mol% anthracene moieties per monomeric units.

List of Illustrations

Chapter 01

Figure 1.1 Chemical structure of poly(

N

‐isopropylacrylamide) (PNIPAM).

Figure 1.2 Comparison between phase transition temperatures of PNIPAM in water–methanol (open symbols) and water–acetone (filled symbols) solutions.

Figure 1.3 Phase diagram showing the concentration dependence of the cloud point temperatures of PNIPAM,

M

w

 = 3.9 × 10

5

dissolved in water. The three curves are from three parallel measurements.

Figure 1.4 Dependence of Newtonian viscosity on temperature (heating system). Effect of the addition of SDS to 5 wt% PNIPAM (39k) solutions. The depicted lines are a guide to the eye.

Figure 1.5 Dependence of Newtonian viscosity on temperature (heating system). Effect of anions in 5 wt% PNIPAM (20k) solutions. The depicted lines are a guide to the eyes. The Hofmeister series is depicted above the figure.

Figure 1.6 Reversible activation process in living radical polymerization.

Figure 1.7 General structure of the RAFT chain transfer agent.

Figure 1.8 Temperature‐ and redox‐responsive gelation of triblock copolymers prepared by RAFT. (a) Molecularly dissolved unimers of PNIPAM‐

b

‐PDMA‐

b

‐PNIPAM or PDEGA‐

b

‐PDMA‐

b

‐PDEGA; (b) hydrogels are formed upon heating above the LCST of the responsive PNIPAM or PDEGA blocks; (c) free‐flowing micellar solutions of PNIPAM‐

b

‐PDMA‐SH or PDEGA‐

b

‐PDMA‐SH resulting from trithiocarbonate aminolysis at

T

 > LCST; and (d) hydrogels formed from PNIPAM‐

b

‐PDMA‐S‐S‐PDMA‐

b

‐PNIPAM or PDEGA‐

b

‐PDMA‐S‐S‐PDMA‐

b

‐PDEGA upon oxidation of the thiol‐terminated diblock aminolysis products.

Figure 1.9 Schematic illustration of conjugation of a stimuli‐responsive polymer close to binding pocket of a protein. In the hydrated random coil state, the polymer interferes minimally with ligand binding to the receptor binding pocket. Upon increasing temperature, the collapsed polymer blocks access to the binding pocket.

Figure 1.10 Synthesis of streptavidin‐[biotin]4 macroinitiator and streptavidin‐[biotin‐PNIPAM] bioconjugate.

Figure 1.11 Illustration of well‐defined unimeric channels formed upon heating a solution of cyclic peptide−PNIPAM up to an intermediate temperature of 35 °C in the presence of large unilamellar vesicles (LUVs).

Figure 1.12 Schematic illustration of design of temperature‐sensitive liposomes using a thermosensitive polymer. The liposome is stabilized by hydrated polymer chains below its LCST. However, above the LCST, the dehydrated and contracted polymer chains cause destabilization of the liposome, an increase in hydrophobicity of the liposome surface, and/or exposure of the bare liposome surface.

Figure 1.13 Schematic representation of the adhesion above the LCST and detachment below the LCST of a cell on a PNIPAM‐grafted surface.

Figure 1.14 Native chemical ligation of thioester and N‐terminal cysteine.

Figure 1.15 Hydrogel fabrication process. A double‐barrel syringe in which one barrel contains the PNIPAM‐hydrazide‐coated SPIONs and the others contain the dextran–aldehyde hydrogel precursor was used to prepare the composite disks for testing. Both materials are dissolved/suspended in PBS, with a pharmaceutical agent of interest dissolved in both barrels if desired. Upon injection, the solutions are intimately mixed in a static mixing channel before being injected into a silicone mold through a needle tip for the formation of the test composite magnetic disks.

Chapter 02

Figure 2.1 The chemical structures, the names and the abbreviations of the main thermoresponsive units that are discussed in this chapter.

Figure 2.2 The phase separation taking place in (a) spherical micelles, (b) films and (c) gels. The hydrophobic and hydrophilic parts of the block copolymers are coloured in dark grey and light grey, respectively.

Chapter 03

Figure 3.1 Structure of tetrakis‐4‐(3′‐tosyloxypropoxy)phenylporphyrin.

Figure 3.2 Structure of 1,7‐dihydroxy‐4‐oxa‐2,2,6,6‐tetra(hydroxymethyl)heptanes hexanosylate.

Figure 3.3 Structure of pertosylated hyperbranched polyglycidol.

Figure 3.4 Structures of hepta‐7‐tosyl‐β‐cyclodextrin (a) and hepta‐7‐tosyl‐β‐cyclodextrin‐star‐polylactide (b).

Figure 3.5 Living chain (a) and termination–reinitiation (b) mechanisms of oxazoline polymerization.

Figure 3.6 Structure of methyl‐resorcinarene octa‐(3‐bromopropionate).

Figure 3.7 Structure of

tert

‐butylcalix[8]arene‐octa‐ω‐bromoalkanoyl ester.

Figure 3.8 Structure of 2,3,6,7,10,11‐hexa(6‐bromohexyloxy)triphenylene.

Figure 3.9 Synthesis of hexa‐(4‐bromomethylphenoxy)cyclotriphosphazene.

Figure 3.10 Synthesis of Fe tris(bipyridine)‐centered six‐arm poly‐2‐ethyl‐2‐oxazoline‐star polymer.

Figure 3.11 Synthesis of Cu bis(bipyridine)‐centered four‐arm poly‐2‐ethyl‐2‐oxazoline‐star polymer.

Figure 3.12 Arm‐first approach to star‐shaped polymer with polypropyleneimine dendrimer cores. Application of the living oligomer endcapping.

Figure 3.13 Polymer analogous way to a star‐shaped polymer with polypropyleneimine dendrimer generation 4 core.

Figure 3.14 Application of Huisgen click reaction in synthesis of star‐shaped oxazolines with cyclodextrin core.

Figure 3.15 The self‐organization and assembly of PMOX‐

b

‐PEOX molecules in water/chloroform solutions.

Figure 3.16 The self‐organization and assembly of PMOX‐

b

‐PEOX molecules in chloroform/water solutions.

Figure 3.17 Turbidity curves of 0.1 wt% aqueous solutions of anionic star polymer in the presence of different salts (NaSCN, NaNO

3

, and Na

2

SO

4

) (top to bottom) at different concentrations (0, 0.01, 0.1, and 1 M) (left to right) and pH 3, 7, and 11 (light gray, dark gray, black).

Figure 3.18 The temperature diagram of PiPOX solutions and the corresponding light scattering intensity distribution on hydrodynamic radius (narrow gray zone is the phase transition interval).

Chapter 04

Figure 4.1 RAFT/MADIX polymerization of VCL.

Figure 4.2 Schematic illustration of the dynamic hydration behavior of PVCL and the structural comparison between “spongelike” PVCL mesoglobules and “cotton‐ball‐like” PNIPAM mesoglobules. The gray color represents the distribution density of water.

Figure 4.3 Scheme of temperature responsive micelles P(MVCL‐

co

‐VCL)‐

b

‐P(VCL‐

co

‐VPON) with double LCSTs.

Figure 4.4 TEM images of micelles (a, b) and vesicles (c, d) obtained from PVCL

156

‐

b

‐PVPON

785

and PVCL

155

‐

b

‐PVPON

164

block copolymers, respectively.

Figure 4.5 Scheme of the temperature‐responsive polymersomes PVCL‐

b

‐PDMS

65

‐

b

‐PVCL.

Figure 4.6 SEM images of (silk/PVCL‐80)

10

spherical capsules (a, b) before and (c, d) after 72 h of enzymatic degradation.

Figure 4.7 Optical microscopy images of (PVCL)

7

‐coated MnCO

3

cubical particles before (a) and after (b) carbonate core dissolution. The scale bars are 5 μm. (c) SEM image of (PVCL)

15

hydrogel cubical hollow capsules.

Chapter 05

Scheme 5.1 Chemical structure of mannuronic and guluronic acid.

Scheme 5.2 Chemical structure of alginate.

Scheme 5.3 Poly(

N

‐isopropylacrylamide) (PNIPAM).

Figure 5.1 Temperature dependence of light transmittance for water solutions of grafted with PNIPAM copolymers of sodium alginate (▪) and chitosan (•)

c

 ∼ 1 g l

−1

.

Figure 5.2 Variation of the pyrene fluorescence intensity ratio

I

1

/

I

3

as a function of temperature for PNIPAM, G33, G51, G61, G78, and graft copolymers of NaAl with PNIPAM, in 1 g dl

−1

solutions in water.

Figure 5.3 Dependence of apparent viscosity on the share rate.

Figure 5.4 Variation of the viscosity versus temperature for SA, PNIPAM, and the SA‐

g

‐PNIPAM copolymers G27, G38, G51, and G65.

Figure 5.5 Dependence of the sol–gel transition temperature on copolymers composition, as determined by different experiments from the crossover point of the dynamic moduli (

G

′ = 

G

″), from particle size analysis and from

η

 − 

T

variation.

Figure 5.6 Relative complex viscosity,

η

rel

, for 10 wt% aqueous solutions of SA‐

g

‐PNIPAM‐L (▪), SA‐

g

‐PNIPAM‐H (•), and SA‐

g

‐P(NIPAM‐

co

‐N

t

BAM) (▴) copolymers.

Figure 5.7 DNA contents of encapsulated hBMSCs in AAlg‐

g

‐PNIPAAm hydrogels. Values represent means ± standard deviation (

n

 = 5).

p

 < 0.05, blank control group vs the other three groups.

Chapter 06

Figure 6.1 Examples of photo‐switches: (a) azobenzene; (b) spiropyran; (c) fulgide; and (d) diarylethene.

Figure 6.2 Structure and possible conformations of calix[4]arenes.

Figure 6.3 Examples of crown ethers: (a) with increasing ring size: 12‐crown‐4, 15‐crown‐5, and 18‐crown‐6 ether; (b) benzo‐18‐crown‐6 and dibenzo‐18‐crown‐6‐ether.

Figure 6.4 Illustration of poly(azocalix[4]arene)s in the all‐

trans

form. Nitroderivatives of calix[4]arene locked in the cone conformation are connected through a reductive coupling protocol. Here R is for the side chains, TEGOMe is for tetraethyleneglycol monomethyl ether, and Red‐Al is for sodium bis(2‐methoxyethoxyaluminum hydride).

Figure 6.5 Illustration of poly(azodibenzo‐18‐crown‐6‐ether) in the

trans

form.

Figure 6.6 Graph depicts flattening of the pinched cone conformation of the calix[4]arene unit in poly(azocalixa[4]arene)s upon

trans

‐to‐

cis

photoisomerization.

Figure 6.7 Difference in interaction between pyridinium‐based low molar mass guests (•) and poly(azocalix[4]arene)s in

trans

and

cis

conformations with aliphatic C

4

and C

12

side chains in chloroform. Photoisomerization provides a possibility to tune the degree of dynamic complex formation and release of the guest molecules: (1) shows

trans

–

cis

–

trans

isomerization under irradiation; (2) shows slow thermal

cis

‐to‐

trans

relaxation either at room temperature or faster relaxation at 40 °C.

Figure 6.8 Transmittance plots as a function of temperature for aqueous solutions of AZTEGOMe10 (DP = 10) at

c

 = 0.5 and 1.5 g l

−1

and AZTEGOMe7 (DP = 7) at

c

 = 1.5 g l

−1

obtained with a heating rate of 1 °C min

−1

. Photographic inserts represent the clear solution of AZTEGOMe7before (left) and the cloudy solution after (right) the LCST phase transition.

Figure 6.9 (a) Transmittance versus temperature plots for AZTEGOMe20 in ethanol (

c

 = 2.5 g l

−1

) upon irradiation with 365 nm wavelength light to different photostationary states (

trans

content). Cooling rate = 1 °C min

−1

. (b) Plot of the cloud point temperature as a function of photo‐induced

trans

content from measurements done with a cooling rate of 1 °C min

−1

.

Figure 6.10 Photo‐tunable UCST‐type phase separation of AZTEGOMe20 (DP = 20) in ethanol (

c

 = 2.5 g l

−1

). Photographs are taken (a) at 20 °C before irradiation for “relaxed”

trans

‐rich polymer; (b) at 20 °C after photo‐assisted writing with 365 nm wavelength light; (c) at 40 °C for thermally “relaxed” polymer; and (d) at 20 °C after thermal relaxation/erasing (complete reversibility).

Figure 6.11 (a) UV–Vis spectra of poly(azodibenzo‐18‐crown‐6‐ether) in various solvents (DP = 12,

c

 = 0.08 g l

−1

); (b) UV–Vis spectra in THF (DP = 18,

c

 = 0.2 g l

−1

) upon addition of HCl.

Chapter 07

Figure 7.1 A classical design of a typical SAS experiment.

Figure 7.2 The typical SAXS/SANS curves. The curves are vertically shifted for clarity.

Figure 7.3 (a) The SAXS scattering data for star‐4 pNIPAM as a function of temperature; (b) temperature dependence of the gyration radius

R

g

for starlike pNIPAM.

Figure 7.4 (a) The SAXS scattering data for PEA as a function of temperature; (b) temperature dependence of the gyration radius

R

g

.

Figure 7.5 Temperature dependence of the correlation length.

Figure 7.6 (a) SAXS curves for modified PEO solutions taken at temperatures 25 and 45 °C for

tel

‐PEO; The solid lines are fits. (b) Temperature dependence of the Flory exponent

ν

, for

tel

‐PEO.

Figure 7.7 (a) SAXS curves for pNIPAM microgel particles below CPT. (b) SAXS curves for pNIPAM microgel particles above CPT. Decomposition of SAXS curves: solid dark gray, Porod term; dashed solid gray line, Ornstein–Zernike term; solid light gray line, Guinier term; and dashed light gray lines, pseudo‐Voight terms.

Figure 7.8 (a) SANS data for pNIPAM‐

b

‐PEO‐

b

‐pNIPAM polymer at 25 and 40 °C. Solid dark gray lines are fits by the Beaucage model. Inset: separated contributions according to the Beaucage model. (b) Hypothetical structure of nanoparticles above CPT.

Figure 7.9 Typical 2D patterns for molecularly dissolved polymers (a), concentrated micellar solutions (b), and hexagonal phase (c).

Figure 7.10 Block and gradient structure of MOVE–EOVE copolymers synthesized in ref [71].

Figure 7.11 Temperature dependence of core and shell sizes for diblock and gradient micelles obtained from core–shell model applied for SANS results.

Figure 7.12 “Reel‐in” mechanism suggested by Shibayama to describe thermosensitive behavior of gradient micelles.

Figure 7.13 (a) A phase diagram of PSPP‐

b

‐pNIPAM copolymers; (b) SANS data at different temperatures.

Figure 7.14 SANS curves of 5 wt% PSPP‐

b

‐pNIPAM copolymer in D

2

O in regime I (a) and III (b).

Chapter 08

Figure 8.1 Energy diagrams for IR absorption and Raman scattering.

Figure 8.2 Schematic drawings of (a) an FTIR spectrometer and (b) a confocal micro‐Raman spectrometer with a temperature‐controlled cell.

Figure 8.3 (a) The IR absorption spectra of PNiPAm in H

2

O (blue) and D

2

O (red) at 25 °C. (b) The difference spectra induced by phase transition. (c) The values of ΔΔ

A

for selected vibration modes are plotted against temperature at heating (top) and cooling (bottom). (d) DSC thermograms at heating (black) and cooling (gray).

Figure 8.4 (a) Optical microscopic image of the phase separated PNiPAm/H

2

O at 40 °C. (b) Raman spectra measured in the domain and matrix phases. (c) Chemical mapping produced by confocal micro‐Raman spectroscopic measurement.

Figure 8.5 The amide I band of (a) PNiPAm and (b) PdEA measured below and above

T

p

with the subbands assigned to doubly, singly, and non‐H‐bonding amide carbonyl groups. The fractions of the subbands of (c) PNiPAm and (d) PdEA are plotted against temperature.

Figure 8.6 (a) The structure and (b) the

ν

(CH) band of PEoEA measured at different temperatures (top) with a simulated spectrum (bottom) by a DFT calculation. The

ν

(CH) frequencies are plotted against (c) temperature and (d) polymer concentration.

Figure 8.7 Schematic drawing showing the direct CH⋯OH

2

H‐bonds and the indirect O (ether)⋯HOH H‐bonds affecting

ν

(CH) frequencies.

Figure 8.8 (a) The chemical structure of PAProMd

3

. (b) The IR absorption and (c) difference spectra induced by phase separation of PAProM (gray) and PAProMd

3

(black) in D

2

O.

Figure 8.9 (a) The

ν

(CH) and

ν

(CO) bands of PVME (5 wt%) in D

2

O measured at different temperatures (35.9 (thick solid line)–40.6 °C (broken line)). (b) The frequencies of the

ν

s

(CH

3

) and (c)

ν

(CO) bands of PVME measured at 30 °C (•) and 45 °C (▴) in H

2

O are plotted against polymer concentration.

Figure 8.10 (a) The area ratio of the

ν

(CH) and

ν

(OH) bands (

A

CH

/

A

OH

) and (b) the frequencies of the

ν

(CH

2

) (top) and

ν

as

(CH

3

) (bottom) bands in the Raman spectra of PVME/KF/H

2

O ternary mixtures with different of KF concentrations (0, 0.25, and 0.5 M) measured in the polymer‐rich phases (

T

 > 

T

p1

) or homogeneous phases (

T

 < 

T

p1

) at cooling.

Figure 8.11 (a) The

ν

(CO) band of PM2Ma measured at temperatures below (left) and above (right)

T

p

and different polymer concentrations with the subbands assigned to doubly, singly, and non‐H‐bonding carbonyl groups. (b) The molar fractions of the singly and non‐H‐bonding carbonyl groups are plotted against temperature (

W

p

 = 0.3).

Figure 8.12 The

ν

(CO)

E

and

ν

(CO)

A

bands of PAProM measured in D

2

O (a) at 10 °C and (b) 50 °C and the subbands with their assignments.

Figure 8.13 (a) MeOH concentration dependence of

T

p

of PNiPAm, PnPA, PdEA, PMiPA, PEoEA, and PTHFMA in MeOH/H

2

O mixtures. The amide I bands of (b) PNiPAm, (c) PEoEA, (d) PdEA, and (e) PTHFMA measured in methanol‐d

4

/D

2

O mixtures of different

W

alc

(weight fraction of methanol‐d

4

in the solvents) at

T

 < 

T

p

. (f) The area fractions of the subbands of PTHFMA assigned to doubly, singly, and non‐H‐bonding amide carbonyl groups are plotted against

W

alc

(25 °C).

Figure 8.14 (a) The

ν

(CH) spectra of PTHFMA in MeOH‐d

4

/D

2

O of different

W

alc

at 25 °C. (b) The wavenumbers of the peaks

a

–

d

measured in MeOH‐d

4

/D

2

O and 2PrOH‐d

8

/D

2

O at 25 °C are plotted against

W

alc

.

Figure 8.15 The LCST and UCST behaviors of PNiPAm in DMSO‐d/D

2

O mixtures (

x

DMSO

 = 0.06 for LCST and 0.74 for UCST). The amide I band of PNiPAm (a, e) below and above (b, f)

T

L

or

T

U

. (c, g) The area fractions of the subband‐1 and subband‐2 are plotted against temperature. (d, h) Temperature dependences of the concentrations of PNiPAm () and DMSO‐d () in the polymer‐rich phases (

T

 > 

T

L

or

T

 < 

T

U

) or homogeneous solutions (

T

 < 

T

L

or

T

 > 

T

U

) of (d) 20 wt% PNiPAm in DMSO‐d/H

2

O (

x

DMSO

 = 0.06) and (h) 10 wt% PNiPAm in DMSO‐d/H

2

O (

x

DMSO

 = 0.74).

Figure 8.16 (a) Raman spectra of PVME/MeOH‐d

4

/H

2

O. (b) The concentrations of PVME, water, and MeOH‐d

4

in the polymer‐rich phases are plotted against temperature. (c) Raman spectra of PVME/Et

4

NBr/H

2

O (top), PVME/ H

2

O (middle), and Et

4

NBr/H

2

O (bottom). (d) The concentrations of PVME and Et

4

N

+

in the polymer‐rich phases are plotted against temperature.

Figure 8.17

T

p

of the ternary mixture of PVME and the concentration of the additives in the polymer‐rich phases are shown for (a) alcohols and (b) R

4

NBr as additives.

Figure 8.18 (a) The

ν

(CO)

A

band of PAProM measured at 10 °C in 54 mM

L

‐MA/D

2

O (top) and

D

‐MA/D

2

O (bottom) and three subbands (broken lines, 1627, 1609, and 1595 cm

−1

). (b) The possible geometry of the complex between MA and a racemo dimer of PAProM.

Figure 8.19 (a) The

ν

(CO)

ester

band of P(NiPAm‐

ran

‐MAc

10

) measured in D

2

O at different temperatures and (b) the three subbands at 1703, 1720, and 1738 cm

−1

. (c) The relative areas of the subbands are plotted against temperature. (d) The IR

ν

(CN) band of P(NiPAm‐

ran

‐AN

20

) measured at different temperatures. (e) The molar fractions of the H‐bonding nitrile groups are plotted against temperature.

Figure 8.20 (a) IR absorption spectra (1120–1050 cm

−1

) of P(NiPAm‐

ran

‐VIm

10

) measured at

α

 = 0 (black: 30 °C, gray: 46 °C) and

α

 = 1 (35 °C) in D

2

O. (b) IR difference spectra (1120–1050 cm

−1

) of P(NiPAm‐

ran

‐ VIm10) at

α

 = 0 (Δ

A

46–30

) and

α

 = 1 (Δ

A

58.8

–

35

). (c) IR absorption spectra of PNiPAm, P(NiPAm‐

ran

‐dEA

50

) and PdEA in H

2

O and D

2

O. Solid and broken lines indicate spectra measured below and above

T

p

, respectively.

Figure 8.21 (a) The structure of PdMMAEAPS‐

b

‐PdEA. (b) Schematic drawing of the micellization. (c) IR absorption spectrum and (d) difference spectra during the UCST (top) and LCST (bottom) transitions. (e) The values of ΔΔ

A

for the

ν

(SO

3

−

),

ν

(CO)

ester

, and amide I modes are plotted against temperature.

Figure 8.22 (a) Schematic drawing of the two‐step VPT of PPGac‐core‐NiPAm‐shell microgel. (b) IR absorption spectra of the microgel. (c) Temperature dependences of the values of ΔΔ

A

, (d) hydrodynamic diameter, and DSC thermogram of the microgel.

Chapter 09

Figure 9.1 60 MHz broad line

1

H NMR spectra of linear PDEAAm containing 3 mol% of MNa units (

c

 = 10 wt%) in D

2

O measured at 313 and 333 K.

Figure 9.2 500.1 MHz

1

H NMR spectrum of PVME in D

2

O (

c

 = 4 wt%) measured at 312 K.

Figure 9.3 (a) Temperature dependence of

1

H NMR integrated intensity of CH

3

line for PVME/D

2

O solution (

c

 = 6 wt%). Dotted line shows the 1/

T

dependence. (b) Temperature dependences of phase‐separated fraction

p

for PNIPMAm/D

2

O solutions of various polymer concentrations during gradual heating.

Figure 9.4 Temperature dependences of

1

H spin–lattice relaxation time

T

1

and spin–spin relaxation time

T

2

of HDO in D

2

O solution of PNIPMAm (

c

 = 5 wt%).

Figure 9.5

1

H NMR spectra of PVME/D

2

O solutions with

c

 = 20 wt% (a) and

c

 = 60 wt% (b). Line of the bound HDO is marked by asterisk. The spectra were obtained using spin–echo pulse sequence 90°

x

‐

t

d

‐180°

y

‐

t

d

‐acquisition with

t

d

 = 5 ms to suppress the broad lines from protons of phase‐separated PVME that exist at 309.5 K.

Figure 9.6 HDO signals in

1

H NMR spectra of PNIPMAm/PNIPAm (43/57) (a), PVCL/PNIPAm (50/50) (b), and PNIPAm/PAAm (78/22) (c) hydrogels in D

2

O measured at various temperatures during gradual heating [46, 72].

Chapter 10

Figure 10.1 The oscillator model. Vectors show directions of transition moments for absorption, fluorescence, and phosphorescence of anthracene.

Figure 10.2 To the calculation of limit polarization of luminescence.

Figure 10.3 Dependence of 1/

P

on

T

/

η

for luminescently labeled polymer in solution.

Scheme 10.1 Variants of location of LMs in a polymer chain: in main chain (I), in side chain (II), and at the chain end (III).

Figure 10.4 Block diagram of the setup intended for measurements of luminescence polarization of polymer solutions in steady‐state mode. LS is the excitation light source (mercury lamp, light‐emitting diode, laser);

F

1

and

F

2

are the light filters;

C

1

and

C

2

are the condensers (in the case of using mercury lamp); BP is the birefringent prism (or polarizers); PM

1

, PM

2

are the photomultipliers; A is the direct‐current amplifier; AD is the analog–digital converter unit connected to PC; TCC is the thermostatically controlled cuvette compartment.

Scheme 10.2 Chemical structure of luminescent marker 9‐anthryl‐methyl‐1,2‐dimethoxyethylene as contained (c. 0.2 mol%) in PDME.

Figure 10.5 Dependence of

on temperature for PDME in water. MM of polymers are 8000 (1), 25 000 (2).

Scheme 10.3 Chemical structure of LM 9‐anthryl‐methyl methacrylamide (9‐AMMA) as contained up to c. 0.2 mol% in PAMAs.

Figure 10.6 Dependence of

on temperature for PAMA‐3‐lin in water. Effect of chemical structure of for PAMA‐

n

‐lin, where

n

 = 1 (1),

n

 = 2 (2),

n

 = 3 (3) on binding low molecular weight indicator AO upon heating aqueous solutions. MM of polymers are 44 000 (4) and 10 000 (5).

C

AO

 = 6 × 10

−6

 M.

Figure 10.7 Dependence of

on temperature for PAMA‐3‐iso of various MM in water. MM of polymers are 50 000 (1), 30 000 (2), 13 000 (3), and 10 000 (4);

c

pol

 = 0.02 mass%.

Figure 10.8 Dependence of

for PAMA‐3‐lin (

M

n

 = 44 000) in aqueous solution previously heated and thermostatically controlled at 70 °C for 7 h on cooling duration at 25 °C (1); dependence of

for PAMA‐3‐lin (

M

n

 = 14 000) in aqueous solution, cooled, and thermostatically controlled at 25 °C for 1 h on the duration of preheating at 60 °C (2).

Scheme 10.4 Chemical structure of acridine orange.

Scheme 10.5 Chemical structure of copolymer and luminescent marker 9‐anthryl‐methyl methacrylamide.

Figure 10.9 Temperature dependences of the

relaxation times for copolymers with different contents of DEAEMA units: 67.8 (1), 40.5 (2), and 26.2 mol% (3).

Figure 10.10 Temperature dependences of

values for non‐protonated (1) and partially protonated (

α

 = 0.1) (2) copolymer with 40.5 mol% DEAEMA units.

Figure 10.11 Dependence of the

for main chain (1) and for side chains (2), contribution of high‐frequency motions of LM (3), reduced viscosity (4), and optical rotation (5) on temperature for cholesterol ester of poly(methacryloyl‐ω‐oxy‐undecanoic acid in heptane.

Chapter 11

Figure 11.1 Porous silica nanoparticles functionalised with pNIPAM can undergo phase transition, allowing the globular hydrophobic form of pNIPAM (above the LCST) to block the pores, thus not allowing the release of any encapsulated molecules. Below the LCST (in its hydrophilic coil conformation), pNIPAM allows molecules to be readily released from the pores.

Figure 11.2 Properties of the fluorescent particles developed by Wu et al. [19]. (1) and (3) show the dispersions after exposure to visible light (588–595 nm) for 4 mins at 20 °C (1) and 35 °C (3). (2) and (4) show the dispersions after exposure to UV radiation (365 nm) for 4 min at 20 °C (2) and 35 °C (4).

Figure 11.3 Image shows how upon heating via NIR radiation, the polymer shell collapses and exposes a polypeptide chain able to interact with a target cell.

Figure 11.4 T2‐weighted MR phantom images of KB cells after incubation with various concentrations of a magnetic nanoparticle composite for 3 h.

Chapter 12

Figure 12.1 Schematic of a thermo‐responsive cell culture dish. (a) Mechanism of thermally modulated cell adhesion and detachment. (b) Temperature‐modulated cell sheet harvest.

Figure 12.2 Preparation of a thermo‐responsive cell culture dish by electron‐beam‐induced polymerization.

Figure 12.3 Preparation scheme of thermo‐responsive polymer brushes by surface‐initiated ATRP. (a) PIPAAm brush on polystyrene, (b) PIPAAm with various brush lengths, (c) PIPAAm with various brush densities.

Figure 12.4 Preparation of thermo‐responsive polymer brushes by surface‐initiated RAFT polymerization.

Figure 12.5 Preparation of terminally functionalized, thermo‐responsive polymer brushes by surface‐initiated RAFT polymerization and subsequent replacement of terminal groups.

Figure 12.6 Preparation of a patterned thermo‐responsive cell culture dish by EB‐induced polymerization with a metal mask.

Figure 12.7 (a) Preparation of stripe‐patterned thermo‐responsive polymer brushes using photolithography. (b) Strips of cell sheets.

Figure 12.8 Cell separations using thermo‐responsive polymer brushes. (a) PIPAAm brush for separations of cardiovascular tissue engineering. (b) P(IPAAm‐co‐BMA) brush for separation of endothelial and fibroblast cells. (c) P(IPAAm‐

co

‐DMAPAAm‐

co

‐

t

BAAm) for purification of human bone marrow mesenchymal stem cells.

Chapter 13

Figure 13.1 General structure of poly(ethylene oxide)‐

b

‐poly(propylene oxide)‐

b

‐poly(ethylene oxide) polymers.

Figure 13.2 Chemical structures of PLGA‐based polymers. (a) PEG–PLGA–PEG; (b) PLGA–PEG–PLGA.

Figure 13.3 General structure of mPEG‐PCL polymer.

Figure 13.4 Vitreous DEX concentrations in rabbits treated with the DEX‐loaded thermogel or DEX suspension. Polymer concentration is 25% in the thermogel matrix and DEX concentration is 1 mg ml

−1

. Both the thermogel and suspension had injection volumes of 100 µl.

Figure 13.5 Postoperative observation in rabbit glaucoma filtration surgery models. (a) Group with filtration surgery only. (b) Group injected with 0.1 ml 5% w/v PTMC

15

‐F127‐PTMC

15

/MMC (0.1 mg ml

−1

) hydrogel in glaucoma filtration surgery. (c) Group treated with 0.5 mg ml

−1

MMC for 5 min during glaucoma filtration surgery. (d) Group with 0.1 ml 5% w/v PTMC

15

‐F127‐PTMC

15

injected in glaucoma filtration surgery.

Figure 13.6 Systemic distribution of DOX after (a) repeated injections of free DOX (0.4 mg) and (b) a single injection of DOX (0.4 mg)‐loaded mPEG‐PCL gel in xenograft‐bearing mice. Drug levels in each tissue (tumor, intestine, stomach, lung, kidney, liver, spleen, and heart) were measured by HPLC using reference to solutions containing defined concentrations of DOX [69].

Chapter 14

Figure 14.1 Schematic presentation of the electrospinning setup.

Figure 14.2 Thermoresponsive fibrous surfaces undergoing a phase transition upon temperature change.

Figure 14.3 Fabrication approaches for the development of (nano)fiber drug delivery systems by electrospinning.

Figure 14.4 “On”–“off”‐controlled drug release from thermoresponsive electrospun fibers

via

consecutive heating–cooling cycles [78].

Figure 14.5 Cell detachment from electrospun fibrous mats upon temperature decrease.

Figure 14.6 Aggregation phenomena induced between PNIPAM chains and magnetic nanoparticles at temperatures above the LCST of PNIPAM in aqueous media.

Chapter 15

Figure 15.1 Influence of benzylacrylamide content and salt concentration on the phase separation temperature of a benzylacrylamide–sulfobetaine copolymer.

Figure 15.2 Effect of temperature on the UV–Vis transmittance (solid black, heating curve) and the hydrodynamic radius (gray solid circles) of a solution of poly(NIPAM

114

‐

b

‐MPDSAH

228

) (0.1% w/w) in ultrapure water. The dotted lines indicate the approximate temperature regions at which each solubility transitions occurs.

Figure 15.3 Reversible changing of size (a) and catalytic activity of PNIPAM/PVP‐Pd(0) (b) at 25–40 °C.

Figure 15.4 Temperature‐dependent catalytic activity of PNIPAM in electron‐transfer reaction between hexacyanoferrate(III) and borohydride ions (a) and core–shell structure of the catalyst (b).

Figure 15.5 Asymmetric aldol reaction in water catalyzed by thermoresponsive polymer‐supported

L

‐proline micelle.

Figure 15.6 Shuttling “in” and shuttling “off” mechanism of living radical miniemulsion polymerization catalyzed by thermoresponsive ligand for efficient catalysis and removal.

Chapter 05

Figure 1.11 Different types of phase separation in solutions of temperature‐responsive polymers: formation of stable colloidal suspensions (a), physical gels with different degrees of transparency (b), and precipitates (c) in response to increase in environmental temperature.

Figure 1.22 Publications on temperature‐responsive or temperature‐sensitive polymers (Web of Science).

Guide

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Copyright

This edition first published 2018\hb

© 2018 John Wiley & Sons Ltd

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About the Editors

Prof. Vitaliy V. Khutoryanskiy has been professor of formulation science since 2014, having previously been associate professor (reader) in pharmaceutical materials (2010–2014) and lecturer in pharmaceutics (2005–2010) at the Reading School of Pharmacy, University of Reading. Prior to his appointment at the University of Reading, he worked as a postdoctoral research associate at the School of Pharmacy and Pharmaceutical Sciences, The University of Manchester (2004–2005) and as a postdoctoral research fellow at the Department of Pharmaceutical Sciences, University of Strathclyde (2002–2004). From 2000 to 2002, he worked at the Department of Macromolecular Chemistry (Al‐Farabi Kazakh National University) as a lecturer/senior lecturer in polymer chemistry. He received his PhD in Polymer Chemistry in 2000 from Kazakh National Technical University, Kazakhstan. Prof. Khutoryanskiy has researched broadly in the area of biomaterials for pharmaceutical and biomedical applications with a particular emphasis on drug delivery, mucoadhesive materials, hydrogels, nanoparticles, and stimuli‐responsive polymers. He was the recipient of the 2012 McBain Medal from SCI and RSC for his imaginative use of colloid, polymer, and interface science in the development of novel biomedical materials. He has published over 130 original papers and 17 reviews and edited 2 books.

Dr. Theoni K. Georgiou is currently a senior lecturer in polymer chemistry at the Department of Materials at Imperial College. She obtained a BSc in Chemistry and a PhD in Polymer Chemistry from the Department of Chemistry at the University of Cyprus in 2001 and 2006, respectively. Following her PhD studies, she joined Professor Antonios Mikos' group at Rice University in the United States as a postdoctoral fellow where she gained experience in biomaterials and tissue engineering. Then in October 2007, she moved to the United Kingdom when she was awarded a 5‐year RCUK fellowship in colloidal nanotechnology at the Department of Chemistry at the University of Hull that led to a lectureship in November 2012. In January 2014, she joined Imperial College as a lecturer and was promoted to senior lecturer in September 2016. Since September 2014 she has also been a member of the Macro Group UK committee. In 2016 she was also awarded with the 2016 Macro Group UK Young Researchers Medal for “contributions to polymer science which show outstanding promise for the future.” She has published over 40 peer‐reviewed papers and 4 book chapters. Her current research interests lie in the area of polymer chemistry and in particular in designing well‐defined polymeric materials and in investigating how the structural characteristics of the polymers affect the material's end properties and applications.

List of Contributors

Mariliz Achilleos

Department of Mechanical and Manufacturing Engineering

University of Cyprus

Nicosia

Cyprus

Adam W.G. Alani

College of Pharmacy

Oregon State University

USA

Raid G. Alany

School of Pharmacy and Chemistry Drug Discovery, Delivery and Patient Care (DDDPC) Theme

Kingston University London

UK

Alina I. Amirova

Institute of Macromolecular Compounds of Russian Academy of Sciences

St Petersburg

Russia

Tatiana D. Anan'eva

Institute of Macromolecular Compounds of Russian Academy of Sciences, Laboratory of Luminescence, Relaxation and Electrical Properties of Polymer Systems

The Federal Agency for Science and Education

St Petersburg

Russia

Vladimir Aseyev

Department of Chemistry

University of Helsinki

Finland

Catalina N. Cheaburu‐Yilmaz

Department of Physical Chemistry of Polymers, “Petru Poni” Institute of Macromolecular Chemistry

Romanian Academy

Iasi

Romania

and

Department of Chemical Engineering

University of Patras

Patras

Greece

Oana‐Nicoleta Ciocoiu

Department of Physical Chemistry of Polymers, “Petru Poni” Institute of Macromolecular Chemistry

Romanian Academy

Iasi

Romania

and

Department of Chemical Engineering

University of Patras

Patras

Greece

Anna P. Constantinou

Department of Materials

Imperial College London

UK

Natalya A. Dolya

Leibnitz Institute of Polymer Chemistry

Dresden

Germany

Alexander P. Filippov

Institute of Macromolecular Compounds of Russian Academy of Sciences

St Petersburg

Russia

Sergey K. Filippov

Department of Supramolecular Polymer Systems

Institute of Macromolecular Chemistry AS CR

Prague

Czech Republic

Theoni K. Georgiou

Department of Materials

Imperial College London

UK

Erik Hebels

Department of Pharmaceutics, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS)

Utrecht University

The Netherlands

Wim E. Hennink

Department of Pharmaceutics, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS)

Utrecht University

The Netherlands

Martin Hruby

Department of Supramolecular Polymer Systems

Institute of Macromolecular Chemistry AS CR

Prague

Czech Republic

Eugenia Kharlampieva

Chemistry Department

University of Alabama at Birmingham

Birmingham

USA

Vitaliy V. Khutoryanskiy

School of Pharmacy

University of Reading

Whiteknights, Reading

UK

Veronika Kozlovskaya

Chemistry Department

University of Alabama at Birmingham

Birmingham

USA

Theodora Krasia‐Christoforou

Department of Mechanical and Manufacturing Engineering

University of Cyprus

Nicosia

Cyprus

Sarkyt E. Kudaibergenov

Laboratory of Engineering Profile

and

Institute of Polymer Materials and Technology

K.I. Satpayev Kazakh National Research Technical University

Almaty

Kazakhstan

Fei Liu

Chemistry Department

University of Alabama at Birmingham

Birmingham

USA

Yasushi Maeda

Department of Applied Chemistry and Biotechnology, Graduate School of Engineering

University of Fukui

Japan

Edward D. H. Mansfield

School of Pharmacy

University of Reading

Whiteknights, Reading

UK

Kenichi Nagase

Institute of Advanced Biomedical Engineering and Science

Tokyo Women's Medical University (TWIns)

Shinjuku

Japan

Marzieh Najafi

Department of Pharmaceutics, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS)

Utrecht University

The Netherlands

Tatiana N. Nekrasova

Institute of Macromolecular Compounds of Russian Academy of Sciences, Laboratory of Luminescence, Relaxation and Electrical Properties of Polymer Systems

The Federal Agency for Science and Education

St Petersburg

Russia

Duc X. Nguyen

College of Pharmacy

Oregon State University

USA

Teruo Okano

Institute of Advanced Biomedical Engineering and Science

Tokyo Women's Medical University (TWIns)

Shinjuku

Japan

Vladimir D. Pautov

Institute of Macromolecular Compounds of Russian Academy of Sciences Laboratory of Luminescence, Relaxation and Electrical Properties of Polymer Systems

The Federal Agency for Science and Education

St Petersburg

Russia

Deepa A. Rao

School of Pharmacy

Pacific University

USA

Vidhi M. Shah

College of Pharmacy

Oregon State University

USA

Ruslan Y. Smyslov

Institute of Macromolecular Compounds of Russian Academy of Sciences Laboratory of Luminescence, Relaxation and Electrical Properties of Polymer Systems

The Federal Agency for Science and Education

St Petersburg

Russia

Jiří Spěváček

Institute of Macromolecular Chemistry

Academy of Sciences of the Czech Republic

Prague

Czech Republic

Georgios Staikos

Department of Physical Chemistry of Polymers, “Petru Poni” Institute of Macromolecular Chemistry

Romanian Academy

Iasi

Romania

and

Department of Chemical Engineering

University of Patras

Patras

Greece

Petr Stepanek

Department of Supramolecular Polymer Systems

Institute of Macromolecular Chemistry AS CR

Prague

Czech Republic

Heikki Tenhu

Department of Chemistry

University of Helsinki

Finland

Andrey V. Tenkovtsev

Institute of Macromolecular Compounds of Russian Academy of Sciences

St Petersburg

Russia

Cornelia Vasile

Department of Physical Chemistry of Polymers, “Petru Poni” Institute of Macromolecular Chemistry

Romanian Academy

Iasi

Romania

and

Department of Chemical Engineering

University of Patras

Patras

Greece

Tina Vermonden

Department of Pharmaceutics, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS)

Utrecht University

The Netherlands

Szymon Wiktorowicz

Department of Chemistry

University of Helsinki

Finland

Adrian C. Williams

School of Pharmacy

University of Reading

Whiteknights

UK

Masayuki Yamato

Institute of Advanced Biomedical Engineering and Science

Tokyo Women's Medical University (TWIns)

Shinjuku

Japan

Preface

Temperature‐responsive polymers are polymeric materials exhibiting reversible changes in their physicochemical properties in response to changes in temperature. In solutions these polymers may undergo phase separation forming colloidal suspensions, precipitates, or gels (Figure 1.1). Weakly cross‐linked temperature‐responsive polymers swell in water and form hydrogels, which may undergo changes in their volume upon changes in environmental temperature.

Figure 1.11 Different types of phase separation in solutions of temperature‐responsive polymers: formation of stable colloidal suspensions (a), physical gels with different degrees of transparency (b), and precipitates (c) in response to increase in environmental temperature.

Source: Panel (a): Reprinted with permission from [1]. Copyright (2008) American Chemical Society. Panels (b) and (c): Source: Reprinted from [2] under ®2017 by MDPI (http://www.mdpi.org).

There are two main behaviors of temperature‐responsive polymers in solution. The first type of polymers includes the systems that exhibit a lower critical solution temperature (LCST); these undergo phase transitions above certain temperature. The second type of systems has upper critical solution temperature (UCST) and shows the opposite behavior as they undergo phase separation below certain temperature.

A simple search in Web of Science database using “temperature‐responsive polymer” or “temperature‐sensitive polymer” reveals the continuous growth of interest in these materials (Figure 1.2).

Figure 1.22 Publications on temperature‐responsive or temperature‐sensitive polymers (Web of Science).

This book represents a collection of 15 chapters focusing on various aspects of temperature‐responsive polymers, including their various chemistries, physicochemical properties, and methods to study their phase transitions, and structure of self‐assemblies as well as their various applications.

Chapter 1 focuses on poly(N‐isopropylacrylamide) (PNIPAAM) as one of the most common and widely researched temperature‐responsive polymers. It discusses its physicochemical properties, phase behavior in water/alcohol mixtures, effects of polymer concentration, molecular weight, surfactants, and inorganic salts on LCST, methods of synthesis of PNIPAAM, design of dual responsive systems, PNIPAAM‐based bioconjugates, and PNIPAAM‐functionalized liposomes. This chapter also discusses some applications of PNIPAAM.

Chapter 2 discusses the chemistry, properties, and applications of thermoresponsive multi‐block copolymers. It summarizes the studies on the effects of molecular architecture of block copolymers on their temperature‐responsive behavior and self‐assembly and also describes some potential applications of these systems.

Chapter 3 describes the synthesis and properties of star‐shaped poly(2‐alkyl‐2‐oxazolines). It provides overview on the selection of multifunctional initiators used for synthesis of star‐shaped poly(2‐alkyl‐2‐oxazolines) and discusses their molecular and conformational characteristics as well as self‐assembly in solutions.

Chapter 4 presents the studies of poly(N‐vinylcaprolactam), describing approaches used for the synthesis of its homo‐ and copolymers, properties of these materials in aqueous solutions, and formation of interpolymer complexes, micelles, polymersomes, and multilayers.

Chapter 5 deals with the studies of PNIPAAM grafted onto sodium alginate. It presents some approaches used for synthesis and characterization of graft copolymers, describes some studies of their solution properties and discusses their degradability, biocompatibility, and cytotoxicity, and provides overview of their pharmaceutical and biomedical applications.

Chapter 6 focuses on multi‐stimuli responsive polymers based on calix[4]arenes and dibenzo‐18‐crown‐6‐ethers. It discusses various responsive systems such as temperature, pH, and photo stimuli and presents some examples on the use of poly(azocalix[4]arene)s and poly(azodibenzo‐18‐crown‐6‐ether)s in the design of these materials.

Chapter 7 looks into the applications of small angle X‐ray and neutron scattering in the studies of temperature‐responsive polymers in solutions. It provides overview on the nature of these experimental techniques and discusses their applicability to study temperature‐responsive polymers of different architectures.

Chapter 8 presents the use of infrared and Raman spectroscopy in the studies of temperature‐responsive polymers. It discusses some experimental methods to measure infrared and Raman spectra of aqueous solutions and gels and presents some interpretation of spectral data.

Chapter 9 reviews the use of NMR spectroscopy to study thermoresponsive polymers in aqueous solutions and gels. It discusses the coil–globule phase transition in solutions of thermoresponsive polymers and its manifestation in NMR spectra; it also considers the applications of NMR techniques to study polymers of various architectures.

Chapter 10 discusses the studies of nanosecond dynamics of thermosensitive polymers in aqueous solutions using polarized luminescence techniques. It provides the introduction into the basics of polarization of luminescence and discusses examples of using this technique in the studies of nanosecond dynamics of macromolecules. Additionally this chapter presents some methodologies for the synthesis of polymers containing luminescent markers.

Chapter 11 discusses the synthesis and applications of temperature‐responsive polymers grafted onto solid core nanoparticles. It includes examples of using silica, metal, and magnetic nanoparticles and presents some potential applications for these systems.

Chapter 12 considers the application of thermoresponsive polymers for tissue engineering, in particular, for cell culture substrates to fabricate cell sheets. It describes the preparation of different surfaces functionalized with thermoresponsive polymers and reviews the applications of these materials as cell culture substrates.

Chapter 13 deals with injectable drug delivery systems based on thermogelling polymers. It provides overview of different thermogelling materials and discusses potential for their clinical applications.

Chapter 14 reviews the development of thermoresponsive polymer‐based nano‐ and microfibers via electrospinning. It presents basic principles of electrospinning and discusses the properties and applications of various electrospun temperature‐responsive systems.

Chapter 15 looks into the application of temperature‐responsive polymers in catalysis. Due to their temperature‐dependent reversible “on–off” behavior, these materials are promising for the regulation of catalytic processes by controlling the heat or mass transfers of reactants/products in liquid media. The combination of these materials with metal nanoparticles and complexes, molecularly imprinting polymers, and enzymes is discussed.

References

1 Khutoryanskaya, O.V., Mayeva, Z.A., Mun, G.A., and Khutoryanskiy, V.V. (2008). Designing temperature‐responsive biocompatible copolymers and hydrogels based on 2‐hydroxyethyl(meth)acrylates.

Biomacromolecules

9: 3353–3361.

2 Constantinou, A.P., Zhao, H., McGilvery, C.M. et al. (2017). A comprehensive systematic study on thermoresponsive gels: beyond the common architectures of linear terpolymers.

Polymers

9 (1): 31. doi: 10.3390/polym9010031.

January 2018

Vitaliy V. Khutoryanskiy (Reading)

Theoni K. Georgiou (London)

Part IChemistry

Chapter 1Poly(N‐isopropylacrylamide): Physicochemical Properties and Biomedical Applications

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

1.1 Introduction

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.

1.2 PNIPAM as Thermosensitive Polymer

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].