Thermoresponsive copolymers: from fundamental studies to applications

Thermoresponsive copolymers have attracted considerable interest in both the polymer and biomaterial literature. They show interesting fundamental behaviour (thermally triggered contraction and aggregation) as well as potentially useful properties (reversible gelation). Biocompatible thermoresponsive copolymers are being developed for application in drug delivery and regenerative medicine. This review focuses on the fundamental aspects of thermally triggered conformational changes with an emphasis on copolymer design. Also, the ability to use these copolymers to produce thermoresponsive colloidal dispersions is discussed. Recent examples from within our group and elsewhere are considered in order to illustrate structure–property relationships. The review focuses on copolymers involving N-isopropylacrylamide. However, non-acrylamide thermoresponsive copolymers are also considered in detail. Emerging areas that appear likely to be actively pursued in the future are also discussed.

[1]  Li Liu,et al.  Controlled polymerization of 2‐(diethylamino)ethyl methacrylate and its block copolymer with N‐isopropylacrylamide by RAFT polymerization , 2008 .

[2]  M. Heskins,et al.  Solution Properties of Poly(N-isopropylacrylamide) , 1968 .

[3]  R. Issels,et al.  Hyperthermia-induced targeting of thermosensitive gene carriers to tumors. , 2008, Human gene therapy.

[4]  E. Denkbaş,et al.  A new temperature-sensitive polymer: Poly(ethoxypropylacrylamide) , 2005 .

[5]  Y. Tong,et al.  Preparation and characterization of temperature-sensitive poly(N-isopropylacrylamide)-b-poly(D,L-lactide) microspheres for protein delivery. , 2003, Biomacromolecules.

[6]  B. Mattiasson,et al.  Aqueous polymer two-phase systems formed by new thermoseparating polymers , 2000, Bioseparation.

[7]  Shiro Kobayashi,et al.  A Novel Thermo-Sensitive Polymer. Poly(2-iso-propyl-2-oxazoline) , 1992 .

[8]  J. Brash,et al.  Synthesis and Solution Properties of Fluorescently Labeled Amphiphilic (N-alkylacrylamide) Oligomers , 1998 .

[9]  R. Zhuo,et al.  Novel thermoresponsive nonviral gene vector: P(NIPAAm-co-NDAPM)-b-PEI with adjustable gene transfection efficiency. , 2008, Bioconjugate chemistry.

[10]  A. Hoffman,et al.  New antibody purification procedure using a thermally responsive poly(N-isopropylacrylamide)-dextran derivative conjugate. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[11]  D. Hourdet,et al.  Reversible Thermoassociation of Water-Soluble Polymers , 1997 .

[12]  T. Aoyagi,et al.  Synthesis and characterization of double thermo‐responsive block copolymer consisting N‐isopropylacrylamide by atom transfer radical polymerization , 2008 .

[13]  Allan S. Hoffman,et al.  Temperature-induced phase transition behaviors of random vs. graft copolymers of N-isopropylacrylamide and acrylic acid , 1995 .

[14]  W. Richtering,et al.  Copolymer Microgels from Mono- and Disubstituted Acrylamides: Phase Behavior and Hydrogen Bonds , 2008 .

[15]  K. Kubota,et al.  Phase transition of aqueous solutions of poly(N-isopropylacrylamide) and poly(N-isopropylmethacrylamide) , 1989 .

[16]  R. Audebert,et al.  Synthesis of thermoassociative copolymers , 1997 .

[17]  D. Hourdet,et al.  Positively Charged Amphiphilic Polymers Based on Poly(N-isopropylacrylamide): Phase Behavior and Shear-Induced Thickening in Aqueous Solution , 2000 .

[18]  D. Oupický,et al.  Temperature-controlled behavior of self-assembly gene delivery vectors based on complexes of DNA with poly(L-lysine)-graft-poly(N-isopropylacrylamide) , 2003 .

[19]  A. Tobolsky,et al.  A New Approach to the Theory of Relaxing Polymeric Media , 1946 .

[20]  Xian‐Zheng Zhang,et al.  Fabrication of thermosensitive PCL‐PNIPAAm‐PCL triblock copolymeric micelles for drug delivery , 2008 .

[21]  B. Saunders,et al.  Temperature-triggered gelation of aqueous laponite dispersions containing a cationic poly(N-isopropyl acrylamide) graft copolymer. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[22]  W. Richtering,et al.  Synergistic depression of volume phase transition temperature in copolymer microgels , 2006 .

[23]  T. Okano,et al.  Control of adriamycin cytotoxic activity using thermally responsive polymeric micelles composed of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(d,l-lactide) , 1999 .

[24]  M. Türk,et al.  In vitro transfection of HeLa cells with temperature sensitive polycationic copolymers. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[25]  Françoise M. Winnik,et al.  Microcalorimetric Study of the Temperature-Induced Phase Separation in Aqueous Solutions of Poly(2-isopropyl-2-oxazolines) , 2004 .

[26]  R. Pelton,et al.  The surface tension of aqueous poly(N-isopropylacrylamide-co-acrylamide) , 1999 .

[27]  Yi Yan Yang,et al.  Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide)-b-poly(D,L-lactide-co-glycolide) with varying compositions. , 2005, Biomaterials.

[28]  A. Domb,et al.  Exploiting EPR in polymer drug conjugate delivery for tumor targeting. , 2006, Current pharmaceutical design.

[29]  Y. Nakayama,et al.  In vivo evaluation of poly(N-isopropylacrylamide) (PNIPAM)-grafted gelatin as an in situ-formable scaffold , 2005, Journal of Artificial Organs.

[30]  A. Kondo,et al.  Development and application of thermo‐sensitive immunomicrospheres for antibody purification , 1994, Biotechnology and bioengineering.

[31]  H. G. Schild Poly(N-isopropylacrylamide): experiment, theory and application , 1992 .

[32]  E. Pişkin,et al.  Stimuli-responsive properties of conjugates of N-isopropylacrylamide-co-acrylic acid oligomers with alanine, glycine and serine mono-, di- and tri-peptides. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[33]  S. Aoshima,et al.  Synthesis of Stimuli-Responsive Polymers by Living Polymerization: Poly(N-Isopropylacrylamide) and Poly(Vinyl Ether)s , 2007 .

[34]  R. Audebert,et al.  Aqueous solution behavior of new thermoassociative polymers , 1995 .

[35]  T. Okano,et al.  Thermo-responsive drug delivery from polymeric micelles constructed using block copolymers of poly(N-isopropylacrylamide) and poly(butylmethacrylate). , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[36]  B. Saunders,et al.  A study of thermoassociative gelation of aqueous cationic poly(N-isopropyl acrylamide) graft copolymer solutions , 2009 .

[37]  M. J. Tiera,et al.  Synthesis, characterization and solution properties of amphiphilic N-isopropylacrylamide–poly(ethylene glycol)–dodecyl methacrylate thermosensitive polymers , 2005 .

[38]  Y. Tong,et al.  Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs. , 2007, Biomaterials.

[39]  E. Pişkin,et al.  Poly(N-isopropylacrylamide)/poly[(N-acetylimino)ethylene] thermosensitive block and graft copolymers , 2003 .

[40]  F. Lafuma,et al.  Small-Angle Neutron Scattering Study of Microphase Separation in Thermoassociative Copolymers , 1998 .

[41]  P. Wadgaonkar,et al.  Thermoreversible Behavior of Associating Polymer Solutions: Thermothinning versus Thermothickening , 2005 .

[42]  Chaoliang He,et al.  Novel temperature‐ and pH‐responsive graft copolymers composed of poly(L‐glutamic acid) and poly(N‐isopropylacrylamide) , 2008 .

[43]  E. Pişkin,et al.  A potential gene delivery vector: N‐isopropylacrylamide‐ethyleneimine block copolymers , 2002 .

[44]  H. Tenhu,et al.  Formation of Colloidally Stable Phase Separated Poly(N-vinylcaprolactam) in Water: A Study by Dynamic Light Scattering, Microcalorimetry, and Pressure Perturbation Calorimetry , 2004 .

[45]  F. Marcucci,et al.  Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress. , 2004, Drug discovery today.

[46]  E. Pişkin,et al.  Synthesis and Characterization of Stimuli-Responsive Poly(N-isopropylacrylamide-co-N-vinyl-2-pyrrolidone) , 2006 .

[47]  R. Zhuo,et al.  Self-assembled thermoresponsive micelles of poly(N-isopropylacrylamide-b-methyl methacrylate). , 2006, Biomaterials.

[48]  Yingli An,et al.  Synthesis and micellization of thermo- and pH-responsive block copolymer of poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) , 2007 .

[49]  E. Woo,et al.  Effects of chain configuration on UCST behavior in blends of poly(L‐lactic acid) with tactic poly(methyl methacrylate)s , 2008 .

[50]  Ho-Suk Choi,et al.  Hyperthermia-induced antitumor activity of thermosensitive polymer modified temperature-sensitive liposomes. , 2006, Journal of pharmaceutical sciences.

[51]  R. B. Grubbs,et al.  Synthesis and characterization of thermoresponsive amphiphilic block copolymers incorporating a poly(ethylene oxide-stat-propylene oxide) block , 2005 .

[52]  B. Saunders,et al.  Effect of added surfactant on temperature-induced gelation of emulsions. , 2004, Langmuir : the ACS journal of surfaces and colloids.

[53]  David Cunliffe,et al.  Thermo and pH responsive polymers as gene delivery vectors: effect of polymer architecture on DNA complexation in vitro. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[54]  Karim Amighi,et al.  Synthesis and characterization of thermosensitive copolymers for oral controlled drug delivery , 2004 .

[55]  N. Chourdakis,et al.  Poly(N‐isopropylacrylamide) grafted to a strongly charged backbone: Thermoresponsive behavior in aqueous solution , 2004 .

[56]  K. Ulbrich,et al.  Thermally Controlled Association in Aqueous Solutions of Diblock Copolymers of Poly[N-(2-hydroxypropyl)methacrylamide] and Poly(N-isopropylacrylamide) , 2000 .

[57]  B. Saunders,et al.  Cationic temperature-responsive poly(N-isopropyl acrylamide) graft copolymers: from triggered association to gelation. , 2008, Langmuir.

[58]  Ya Cao,et al.  Effects of Substitution Groups on the RAFT Polymerization of N-Alkylacrylamides in the Preparation of Thermosensitive Block Copolymers , 2007 .

[59]  Jean-François Lutz,et al.  Point by point comparison of two thermosensitive polymers exhibiting a similar LCST: is the age of poly(NIPAM) over? , 2006, Journal of the American Chemical Society.

[60]  Changyong Choi,et al.  Thermosensitive poly(N-isopropylacrylamide)-b-poly(ε-caprolactone) nanoparticles for efficient drug delivery system , 2006 .

[61]  Jae Chang Jung,et al.  The synthesis and thermal phase transition behavior of poly(N-isopropylacrylamide)-b-poly(ethylene oxide) , 1998 .

[62]  K. Shakesheff,et al.  Poly(D,L-lactide-co-glycolide) dispersions containing pluronics: from particle preparation to temperature-triggered aggregation. , 2008, Langmuir.

[63]  B. Saunders,et al.  Small-angle neutron scattering study of temperature-induced emulsion gelation: the role of sticky microgel particles. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[64]  T. Okano,et al.  Temperature-responsive polymeric carriers incorporating hydrophobic monomers for effective transfection in small doses. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[65]  I. Berlinova,et al.  Associative graft copolymers comprising a poly(N-isopropylacrylamide) backbone and end-functionalized polyoxyethylene side chains. Synthesis and aqueous solution properties , 2001 .

[66]  H. Winter Can the gel point of a cross-linking polymer be detected by the G′ – G″ crossover? , 1987 .

[67]  Allan S Hoffman,et al.  Poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH. , 2006, Biomacromolecules.

[68]  K. Zhu,et al.  Thermosensitive micelles self-assembled by novel N-isopropylacrylamide oligomer grafted polyphosphazene , 2004 .

[69]  S. Armes,et al.  Synthesis and characterization of biocompatible thermo-responsive gelators based on ABA triblock copolymers. , 2005, Biomacromolecules.

[70]  Z. Mustafaeva,et al.  Water-soluble covalent conjugates of bovine serum albumin with anionic poly(N-isopropyl-acrylamide) and their immunogenicity. , 2001, Biomaterials.

[71]  Howard G. Schild,et al.  Microcalorimetric detection of lower critical solution temperatures in aqueous polymer solutions , 1990 .

[72]  Yukiteru Katsumoto,et al.  Molecular understanding of the UCST-type phase separation behavior of a stereocontrolled poly(N-isopropylacrylamide) in bis(2-methoxyethyl) ether. , 2008, The journal of physical chemistry. B.

[73]  R. Freitag,et al.  Investigation of the LCST of polyacrylamides as a function of molecular parameters and the solvent composition , 1999 .

[74]  T. T. Chiu,et al.  Poly(2-ethyl-2-oxazoline): A New Water- and Organic-Soluble Adhesive , 1986 .

[75]  K. Yao,et al.  Toward an understanding of thermoresponsive transition behavior of hydrophobically modified N-isopropylacrylamide copolymer solution , 2005 .

[76]  Alain Durand,et al.  Synthesis and thermoassociative properties in aqueous solution of graft copolymers containing poly(N-isopropylacrylamide) side chains , 1999 .

[77]  D. Hourdet,et al.  Thermoassociative graft copolymers based on poly(N‐isopropylacrylamide): Relation between the chemical structure and the rheological properties , 2000 .

[78]  M. Diociaiuti,et al.  ATRP synthesis and association properties of thermoresponsive anionic block copolymers , 2008 .

[79]  H. Henning Winter,et al.  Analysis of Linear Viscoelasticity of a Crosslinking Polymer at the Gel Point , 1986 .

[80]  Howard G. Schild,et al.  Cononsolvency in mixed aqueous solutions of poly(N-isopropylacrylamide) , 1991 .

[81]  X. Zhu,et al.  Lower critical solution temperatures of N-substituted acrylamide copolymers in aqueous solutions , 1999 .

[82]  T. Okano,et al.  Preparation and characterization of thermally responsive block copolymer micelles comprising poly(N-isopropylacrylamide-b-DL-lactide). , 1998, Journal of controlled release : official journal of the Controlled Release Society.

[83]  R. Jordan,et al.  Effect of end group polarity upon the lower critical solution temperature of poly(2-isopropyl-2-oxazoline) , 2008 .

[84]  B. Saunders,et al.  A study of temperature-induced aggregation of responsive comb copolymers in aqueous solution , 2003 .

[85]  Julia S. Higgins,et al.  Polymers and Neutron Scattering , 1997 .

[86]  N. Seetapan,et al.  Linear viscoelasticity of thermoassociative chitosan-g-poly(N-isopropylacrylamide) copolymer , 2006 .

[87]  W. Hennink,et al.  Thermosensitive polymers as carriers for DNA delivery. , 1999, Journal of controlled release : official journal of the Controlled Release Society.

[88]  Baorui Liu,et al.  Novel thermosensitive polymeric micelles for docetaxel delivery. , 2007, Journal of biomedical materials research. Part A.

[89]  X. Kong,et al.  Thermoresponsive copolymers of methacrylic acid and poly(ethylene glycol) methyl ether methacrylate , 2005 .

[90]  Chaoliang He,et al.  Novel pH- and Temperature-Responsive Block Copolymers with Tunable pH-Responsive Range , 2008 .

[91]  Dennis E. Discher,et al.  Temperature‐Controlled Assembly and Release from Polymer Vesicles of Poly(ethylene oxide)‐block‐ poly(N‐isopropylacrylamide) , 2006 .

[92]  K. Bernaerts,et al.  Thermo‐Responsive and Emulsifying Properties of Poly(N‐vinylcaprolactam) Based Graft Copolymers , 2003 .

[93]  B Mattiasson,et al.  'Smart' polymers and what they could do in biotechnology and medicine. , 1999, Trends in biotechnology.

[94]  Tanii Hideji,et al.  In vitro neurotoxicity study with dorsal root ganglia for acrylamide and its derivatives. , 1991 .

[95]  Liqun Wang,et al.  Synthesis and characterization of temperature responsive graft copolymers of dextran with poly(N-isopropylacrylamide) , 2002 .

[96]  P. R. Rajamohanan,et al.  LCST in poly(N-isopropylacrylamide) copolymers: high resolution proton NMR investigations , 2000 .

[97]  Jia-cong Shen,et al.  The gene transfection efficiency of thermoresponsive N,N,N-trimethyl chitosan chloride-g-poly(N-isopropylacrylamide) copolymer. , 2007, Biomaterials.

[98]  J. Chiefari,et al.  Living free-radical polymerization by reversible addition - Fragmentation chain transfer: The RAFT process , 1998 .

[99]  I. Berlinova,et al.  Electrostatic self-assembly of thermally responsive zwitterionic poly(N-isopropylacrylamide) and poly(ethylene oxide) modified with ionic groups , 2005 .

[100]  Ian Soutar,et al.  Studies of the smart thermoresponsive behavior of copolymers of N-isopropylacrylamide and N, N-dimethylacrylamide in dilute aqueous solution , 2003 .

[101]  F. Lafuma,et al.  Responsive hybrid self-assemblies in aqueous media. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[102]  B. Saunders,et al.  Polymer stabilisers for temperature-induced dispersion gelation: versatility and control. , 2006, Journal of colloid and interface science.

[103]  Takao Yamamoto,et al.  Synthesis and phase behavior of aqueous poly(N-isopropylacrylamide-co-acrylamide), poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) and poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) , 2006 .

[104]  S. Yuk,et al.  pH/Temperature-Responsive Polymer Composed of Poly((N,N-dimethylamino)ethyl methacrylate-co-ethylacrylamide) , 1997 .

[105]  E. Pişkin,et al.  Poly(N-isopropylacrylamide-co-2-methacryloamidohistidine) Copolymers and Their Interactions with Human Immunoglobulin-G , 2003 .

[106]  S. Armes,et al.  The facile one-pot synthesis of shell cross-linked micelles in aqueous solution at high solids. , 2001, Journal of the American Chemical Society.

[107]  W. Vogt,et al.  N-Isopropylacrylamide andN-Isopropylmethacryl-amide: Cloud Points of Mixtures and Copolymers , 2001 .

[108]  P. Cremer,et al.  Specific ion effects on the water solubility of macromolecules: PNIPAM and the Hofmeister series. , 2005, Journal of the American Chemical Society.

[109]  R. Jordan,et al.  Modulation of the lower critical solution temperature of 2-Alkyl-2-oxazoline copolymers , 2008 .

[110]  A. Hoffman,et al.  A new temperature- and pH-responsive copolymer for possible use in protein conjugation , 1995 .

[111]  F. D. Prez,et al.  Block Copolymers of Methyl Vinyl Ether and Isobutyl Vinyl Ether With Thermo‐Adjustable Amphiphilic Properties , 2003 .

[112]  S. Hirotsu Critical points of the volume phase transition in N‐isopropylacrylamide gels , 1988 .

[113]  T. Aoyagi,et al.  Importance of bound water in hydration-dehydration behavior of hydroxylated poly(N-isopropylacrylamide). , 2006, Journal of colloid and interface science.

[114]  C. Vasile,et al.  Thermoresponsive behaviour in aqueous solution of poly(maleic acid‐alt‐vinyl acetate) grafted with poly(N‐isopropylacrylamide) , 2004 .

[115]  B. Saunders,et al.  Microgels: From responsive polymer colloids to biomaterials. , 2009, Advances in colloid and interface science.

[116]  D. Hourdet,et al.  Thermoassociative graft copolymers based on poly(N-isopropylacrylamide): effect of added co-solutes on the rheological behaviour , 2000 .