Poly(2-oxazoline)s as materials for biomedical applications

  • Victor R. de la Rosa


The conjunction of polymers and medicine enables the development of new materials that display novel features, opening new ways to administrate drugs, design implants and biosensors, to deliver pharmaceuticals impacting cancer treatment, regenerative medicine or gene therapy. Poly(2-oxazoline)s (POx) constitute a polymer class with exceptional properties for their use in a plethora of different biomedical applications and are proposed as a versatile platform for the development of new medicine. Herein, a global vision of POx as a platform for novel biomaterials is offered, by highlighting the recent advances and breakthroughs in this fascinating field.


Lower Critical Solution Temperature Rotigotine Drug Conjugate PropOx Perfluorophenyl 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I am grateful to Ghent Univerity for financial support, Dr. Bryn Monnery for helpful discussions and very especially to Prof. Richard Hoogenboom.


  1. 1.
    Staudinger H. Nobel lecture: macromolecular chemistry. (1953). Accessed 15 Sep 2012.
  2. 2.
    Ringsdorf HH. Hermann Staudinger and the future of polymer research jubilees-beloved occasions for cultural piety. Angew Chem Int Ed Engl. 2004;43(9):1064–76.CrossRefGoogle Scholar
  3. 3.
    Ringsdorf HH. Structure and properties of pharmacologically active polymers. J polym sci C. 1975;51(1):135–53. doi: 10.1002/polc.5070510111.Google Scholar
  4. 4.
    Haag R, Kratz F. Polymer therapeutics: concepts and applications. Angew Chem Int Ed Engl. 2006;45(8):1198–215.CrossRefGoogle Scholar
  5. 5.
    Lendlein A, Pierce B, Ambrosio L, Grijpma. Special issue: advanced functional polymers for medicine. Macromol Biosci. 2011;11(12):1613–768.CrossRefGoogle Scholar
  6. 6.
    Schlaad H, Hoogenboom R. Special issue: poly(2-oxazoline)s and related pseudo-polypeptides. Macromol Rapid Commun. 2012;33(19):1593–719.CrossRefGoogle Scholar
  7. 7.
    Leader B, Baca QJ, Golan DE. Protein therapeutics: a summary and pharmacological classification. Nat Rev Drug Discov. 2008;7(1):21–39.CrossRefGoogle Scholar
  8. 8.
    Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov. 2003;2(5):347–60.CrossRefGoogle Scholar
  9. 9.
    Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)–protein conjugates. Adv Drug Deliv Rev. 2003;55(10):1261–77.CrossRefGoogle Scholar
  10. 10.
    Jevševar S, Kunstelj M, Porekar VG. PEGylation of therapeutic proteins. Biotechnol J. 2010;5(1):113–28.CrossRefGoogle Scholar
  11. 11.
    Pasut G, Veronese FM. State of the art in PEGylation: the great versatility achieved after forty years of research. J Control Release. 2012;161(2):461–72.CrossRefGoogle Scholar
  12. 12.
    Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar SH, Scudiery D, Berger M, et al. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. J Pediatr. 1988;113(2):312–7.CrossRefGoogle Scholar
  13. 13.
    Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007;110(1):103–11.CrossRefGoogle Scholar
  14. 14.
    Tagami T, Nakamura K, Shimizu T, Yamazaki N, Ishida T, Kiwada H. CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes. J Control Release. 2010;142(2):160–6.CrossRefGoogle Scholar
  15. 15.
    Zhao Y, Wang C, Wang L, Yang Q, Tang W, She Z, et al. A frustrating problem: accelerated blood clearance of PEGylated solid lipid nanoparticles following subcutaneous injection in rats. Eur J Pharm Biopharm. 2012;81(3):506–13.CrossRefGoogle Scholar
  16. 16.
    Suzuki T, Ichihara M, Hyodo K, Yamamoto E, Ishida T, Kiwada H, et al. Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs. Int J Pharm. 2012;436(1–2):636–43.CrossRefGoogle Scholar
  17. 17.
    Ma Y, Yang Q, Wang L, Zhou X, Zhao Y, Deng Y. Repeated injections of PEGylated liposomal topotecan induces accelerated blood clearance phenomenon in rats. Eur J Pharm Sci. 2012;45(5):539–45.CrossRefGoogle Scholar
  18. 18.
    Arima Y, Toda M, Iwata H. Complement activation on surfaces modified with ethylene glycol units. Biomaterials. 2008;29(5):551–60.CrossRefGoogle Scholar
  19. 19.
    Moghimi SM, Hunter AC, Dadswell CM, Savay S, Alving CR, Szebeni J. Causative factors behind poloxamer 188 (Pluronic F68, Flocor™)-induced complement activation in human sera: a protective role against poloxamer-mediated complement activation by elevated serum lipoprotein levels. Biochim Biophys Acta. 2004;1689(2):103–13.CrossRefGoogle Scholar
  20. 20.
    Hamad I, Hunter AC, Szebeni J, Moghimi SM. Poly(ethylene glycol)s generate complement activation products in human serum through increased alternative pathway turnover and a MASP-2-dependent process. Mol Immunol. 2008;46(2):225–32.CrossRefGoogle Scholar
  21. 21.
    Knop K, Hoogenboom R, Fischer D, Schubert US. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed Engl. 2010;49(36):6288–308.CrossRefGoogle Scholar
  22. 22.
    Barz M, Luxenhofer R, Zentel R, Vicent MJ. Overcoming the PEG-addiction: well-defined alternatives to PEG, from structure–property relationships to better defined therapeutics. Polym Chem. 2011;2(9):1900–18.CrossRefGoogle Scholar
  23. 23.
    Veronese FM, editor. PEGylated protein drugs: basic science and clinical applications. Milestones in drug therapy. Basel: Springer; 2009.Google Scholar
  24. 24.
    Lee JS, Feijen J. Polymersomes for drug delivery: design, formation and characterization. J Control Release. 2012;161(2):473–83.CrossRefGoogle Scholar
  25. 25.
    Fleige E, Quadir MA, Haag R. Stimuli-responsive polymeric nanocarriers for the controlled transport of active compounds: concepts and applications. Adv Drug Deliv Rev. 2012;64(9):866–84.CrossRefGoogle Scholar
  26. 26.
    Duncan R, Vicent MJ. Polymer therapeutics-prospects for 21st century: the end of the beginning. Adv Drug Deliv Rev. 2012;65(1):60–70.CrossRefGoogle Scholar
  27. 27.
    Tomalia DA, Sheetz DP. Homopolymerization of 2-alkyl- and 2-aryl-2-oxazolines. J Polym Sci A. 1966;4(9):2253–65.CrossRefGoogle Scholar
  28. 28.
    Seeliger W, Aufderhaar E, Diepers W, Feinauer R, Nehring R, Thier W, et al. Recent syntheses and reactions of cyclic imidic esters. Angew Chem Int Ed Engl. 1966;5(10):875–88.CrossRefGoogle Scholar
  29. 29.
    Kagiya T, Narisawa S, Maeda T, Fukui K. Ring-opening polymerization of 2-substituted 2-oxazolines. J Polym Sci C. 1966;4(7):441–5.Google Scholar
  30. 30.
    Bassiri TG, Levy A, Litt M. Polymerization of cyclic imino ethers. I. Oxazolines. J Polym Sci C. 1967;5(9):871–9.Google Scholar
  31. 31.
    Hoogenboom R. Poly(2-oxazoline)s: a polymer class with numerous potential applications. Angew Chem Int Ed Engl. 2009;48(43):7978–94.CrossRefGoogle Scholar
  32. 32.
    Adams N, Schubert US. Poly(2-oxazolines) in biological and biomedical application contexts. Adv Drug Deliv Rev. 2007;59(15):1504–20.CrossRefGoogle Scholar
  33. 33.
    Hoogenboom R, Schlaad H. Bioinspired poly(2-oxazoline)s. Polymers. 2011;3(1):467–88.CrossRefGoogle Scholar
  34. 34.
    Schlaad H, Diehl C, Gress A, Meyer M, Demirel AL, Nur Y, et al. Poly(2-oxazoline)s as smart bioinspired polymers. Macromol Rapid Commun. 2010;31(6):511–25.CrossRefGoogle Scholar
  35. 35.
    Sedlacek O, Monnery BD, Filippov SK, Hoogenboom R, Hruby M. Poly(2-oxazoline)s—are they more advantageous for biomedical applications than other polymers? Macromol Rapid Commun. 2012;33(19):1648–62.CrossRefGoogle Scholar
  36. 36.
    Woodle MC, Engbers CM, Zalipsky S. New amphipatic polymer–lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes. Bioconjug Chem. 1994;5(6):493–6.CrossRefGoogle Scholar
  37. 37.
    Mero A, Pasut G, Via LD, Fijten MWM, Schubert US, Hoogenboom R, Veronese FM. Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: suitable alternatives to PEG-conjugates? J Control Release. 2008;125(2):87–95.CrossRefGoogle Scholar
  38. 38.
    Bauer M, Lautenschlaeger C, Kempe K, Tauhardt L, Schubert US, Fischer D. Poly(2-ethyl-2-oxazoline) as alternative for the stealth polymer poly(ethylene glycol): comparison of in vitro cytotoxicity and hemocompatibility. Macromol Biosci. 2012;12(7):986–98.CrossRefGoogle Scholar
  39. 39.
    Viegas TX, Bentley MD, Harris JM, Fang Z, Yoon K, Dizman B, et al. Polyoxazoline: chemistry, properties, and applications in drug delivery. Bioconjug Chem. 2011;22(5):976–86.CrossRefGoogle Scholar
  40. 40.
    Aoi K, Okada M. Polymerization of oxazolines. Prog Polym Sci. 1996;21(1):151–208.CrossRefGoogle Scholar
  41. 41.
    Kobayashi S. Polymerization of oxazolines. In: Krzysztof M, Martin M, editors. Polymer science: a comprehensive reference. Amsterdam: Elsevier; 2012. p. 397–426.CrossRefGoogle Scholar
  42. 42.
    Kobayashi S, Uyama H, Narita Y, Ishiyama J. Novel multifunctional initiators for polymerization of 2-oxazolines. Macromolecules. 1992;25(12):3232–6.CrossRefGoogle Scholar
  43. 43.
    Paulus RM, Becer CR, Hoogenboom R, Schubert US. Acetyl halide initiator screening for the cationic ring-opening polymerization of 2-ethyl-2-oxazoline. Macromol Chem Phys. 2008;209(8):794–800.CrossRefGoogle Scholar
  44. 44.
    Hoogenboom R, Fijten MWM, Kickelbick G, Schubert US. Synthesis and crystal structures of multifunctional tosylates as basis for star-shaped poly(2-ethyl-2-oxazoline)s. Beilstein J Org Chem. 2010;6:773–83.CrossRefGoogle Scholar
  45. 45.
    Luxenhofer R, Bezen M, Jordan R. Kinetic investigations on the polymerization of 2-oxazolines using pluritriflate initators. Macromol Rapid Commun. 2008;29(18):1509–13.CrossRefGoogle Scholar
  46. 46.
    Kowalczuk A, Kronek J, Bosowska K, Trzebicka B, Dworak A. Star poly(2-ethyl-2-oxazoline)s—synthesis and thermosensitivity. Polym Int. 2011;60(7):1001–9.CrossRefGoogle Scholar
  47. 47.
    Tasdelen MA, Kahveci MU, Yagci Y. Telechelic polymers by living and controlled/living polymerization methods. Prog Polym Sci. 2011;36(4):455–567.CrossRefGoogle Scholar
  48. 48.
    Glassner M, Kempe K, Schubert US, Hoogenboom R, Barner-Kowollik C. One-pot synthesis of cyclopentadienyl endcapped poly(2-ethyl-2-oxazoline) and subsequent ambient temperature Diels–Alder conjugations. Chem Commun. 2011;47(38):10620–2.CrossRefGoogle Scholar
  49. 49.
    Volet G, Lav T-X, Babinot J, Amiel C. Click-chemistry: an alternative way to functionalize poly(2-methyl-2-oxazoline). Macromol Chem Phys. 2011;212(2):118–24.CrossRefGoogle Scholar
  50. 50.
    Park J-S, Akiyama Y, Winnik FM, Kataoka K. Versatile synthesis of end-functionalized thermosensitive poly(2-isopropyl-2-oxazolines). Macromolecules. 2004;37(18):6786–92.CrossRefGoogle Scholar
  51. 51.
    Hoogenboom R, Wiesbrock F, Leenen MAM, Thijs HML, Huang H, Fustin C-A, et al. Synthesis and aqueous micellization of amphiphilic tetrablock ter- and quarterpoly(2-oxazoline)s. Macromolecules. 2007;40(8):2837–43.CrossRefGoogle Scholar
  52. 52.
    Fustin C-A, Thijs-Lambermont HML, Hoeppener S, Hoogenboom R, Schubert US, Gohy J-F. Multiple micellar morphologies from tri- and tetrablock copoly(2-oxazoline)s in binary water–ethanol mixtures. J Polym Sci A. 2010;48(14):3095–102.CrossRefGoogle Scholar
  53. 53.
    Krumm C, Fik CP, Meuris M, Dropalla GJ, Geltenpoth H, Sickmann A, et al. Well-defined amphiphilic poly(2-oxazoline) ABA-triblock copolymers and their aggregation behavior in aqueous solution. Macromol Rapid Commun. 2012;33(19):1677–82.CrossRefGoogle Scholar
  54. 54.
    Rossegger E, Schenk V, Wiesbrock F. Design strategies for functionalized poly(2-oxazoline)s and derived materials. Polymers. 2013;5(3):956–1011.CrossRefGoogle Scholar
  55. 55.
    Hoogenboom R. Polyethers and polyoxazolines. In: Dubois P, Coulembier O, Raquez J-M, editors. Handbook of ring-opening polymerization. Weinheim: Wiley; 2009. p. 141–64.CrossRefGoogle Scholar
  56. 56.
    Guillerm B, Monge S, Lapinte V, Robin J–J. How to modulate the chemical structure of polyoxazolines by appropriate functionalization. Macromol Rapid Commun. 2012;33(19):1600–12.CrossRefGoogle Scholar
  57. 57.
    Salzinger S, Huber S, Jaksch S, Busch P, Jordan R, Papadakis C. Aggregation behavior of thermo-responsive poly(2-oxazoline)s at the cloud point investigated by FCS and SANS. Colloid Polym Sci. 2012;290(5):385–400.CrossRefGoogle Scholar
  58. 58.
    Obeid R, Maltseva E, Thünemann AF, Tanaka F, Winnik FoM. Temperature response of self-assembled micelles of telechelic hydrophobically modified poly(2-alkyl-2-oxazoline)s in water. Macromolecules. 2009;42(6):2204–14.CrossRefGoogle Scholar
  59. 59.
    Diehl C, Schlaad H. Thermo-responsive polyoxazolines with widely tuneable LCST. Macromol Biosci. 2009;9(2):157–61.CrossRefGoogle Scholar
  60. 60.
    Huber S, Jordan R. Modulation of the lower critical solution temperature of 2-alkyl-2-oxazoline copolymers. Colloid Polym Sci. 2008;286(4):395–402.CrossRefGoogle Scholar
  61. 61.
    Hoogenboom R, Thijs HML, Jochems MJHC, van Lankvelt BM, Fijten MWM, Schubert US. Tuning the LCST of poly(2-oxazoline)s by varying composition and molecular weight: alternatives to poly(N-isopropylacrylamide)? Chem Commun. 2008;44:5758–60.CrossRefGoogle Scholar
  62. 62.
    Meyer M, Antonietti M, Schlaad H. Unexpected thermal characteristics of aqueous solutions of poly(2-isopropyl-2-oxazoline). Soft Matter. 2007;3(4):430–1.CrossRefGoogle Scholar
  63. 63.
    Park J-S, Kataoka K. Comprehensive and accurate control of thermosensitivity of poly(2-alkyl-2-oxazoline)s via well-defined gradient or random copolymerization. Macromolecules. 2007;40(10):3599–609.CrossRefGoogle Scholar
  64. 64.
    Park J-S, Kataoka K. Precise control of lower critical solution temperature of thermosensitive poly(2-isopropyl-2-oxazoline) via gradient copolymerization with 2-ethyl-2-oxazoline as a hydrophilic comonomer. Macromolecules. 2006;39(19):6622–30.CrossRefGoogle Scholar
  65. 65.
    Diab C, Akiyama Y, Kataoka K, Winnik FM. Microcalorimetric study of the temperature-induced phase separation in aqueous solutions of poly(2-isopropyl-2-oxazolines). Macromolecules. 2004;37(7):2556–62.CrossRefGoogle Scholar
  66. 66.
    Christova D, Velichkova R, Loos W, Goethals EJ, Prez FD. New thermo-responsive polymer materials based on poly(2-ethyl-2-oxazoline) segments. Polymer. 2003;44(8):2255–61.CrossRefGoogle Scholar
  67. 67.
    Chen FP, Ames AE, Taylor LD. Aqueous solutions of poly(ethyloxazoline) and its lower consolute phase transition. Macromolecules. 1990;23(21):4688–95.CrossRefGoogle Scholar
  68. 68.
    Bloksma MM, Weber C, Perevyazko IY, Kuse A, Baumgärtel A, Vollrath A, et al. Poly(2-cyclopropyl-2-oxazoline): from rate acceleration by cyclopropyl to thermoresponsive properties. Macromolecules. 2011;44(11):4057–64.CrossRefGoogle Scholar
  69. 69.
    Luxenhofer R, Han Y, Schulz A, Tong J, He Z, Kabanov AV, et al. Poly(2-oxazoline)s as polymer therapeutics. Macromol Rapid Commun. 2012;33(19):1613–31.CrossRefGoogle Scholar
  70. 70.
    Kempe K, Hoogenboom R, Jaeger M, Schubert US. Three-fold metal-free efficient (“Click”) reactions onto a multifunctional poly(2-oxazoline) designer Scaffold. Macromolecules. 2011;44(16):6424–32.CrossRefGoogle Scholar
  71. 71.
    Sosnik A, Gotelli G, Abraham GA. Microwave-assisted polymer synthesis (MAPS) as a tool in biomaterials science: how new and how powerful. Prog Polym Sci. 2011;36(8):1050–78.CrossRefGoogle Scholar
  72. 72.
    Hoogenboom R, Schubert US. Microwave-assisted polymer synthesis: recent developments in a rapidly expanding field of research. Macromol Rapid Commun. 2007;28(4):368–86.CrossRefGoogle Scholar
  73. 73.
    Bogdal D. Microwave-assisted polymerization. In: Krzysztof M, Martin M, editors. Polymer science: a comprehensive reference. Amsterdam: Elsevier; 2012. p. 981–1027.CrossRefGoogle Scholar
  74. 74.
    Hoogenboom R, Fijten MWM, Paulus RM, Thijs HML, Hoeppener S, Kickelbick G, et al. Accelerated pressure synthesis and characterization of 2-oxazoline block copolymers. Polymer. 2006;47(1):75–84.CrossRefGoogle Scholar
  75. 75.
    Wiesbrock F, Hoogenboom R, Leenen M, van Nispen SFGM, van der Loop M, Abeln CH, et al. Microwave-assisted synthesis of a 42-membered library of diblock copoly(2-oxazoline)s and chain-extended homo poly(2-oxazoline)s and their thermal characterization. Macromolecules. 2005;38(19):7957–66.CrossRefGoogle Scholar
  76. 76.
    Hoogenboom R, Wiesbrock F, Leenen MAM, Meier MAR, Schubert US. Accelerating the living polymerization of 2-nonyl-2-oxazoline by implementing a microwave synthesizer into a high-thrxoughput experimentation workflow. J Comb Chem. 2004;7(1):10–3.CrossRefGoogle Scholar
  77. 77.
    Kranenburg JM, Tweedie CA, Hoogenboom R, Wiesbrock F, Thijs HML, Hendriks CE, et al. Elastic moduli for a diblock copoly(2-oxazoline) library obtained by high-throughput screening. J Mater Chem. 2007;17(26):2713–21.CrossRefGoogle Scholar
  78. 78.
    U.S. Department of Health and Human Services. Food and Drug Administration. M3(R2) Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2010. Accessed 20 July 2013.
  79. 79.
    European Medicines Agency. ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals. 2009. EMA/CPMP/ICH/286/1995.Google Scholar
  80. 80.
    SciFinder. Chemical abstracts service: Columbus. (2012). Accessed 15 Sep 2012.
  81. 81.
    Luxenhofer R, Sahay G, Schulz A, Alakhova D, Bronich TK, Jordan R, et al. Structure-property relationship in cytotoxicity and cell uptake of poly(2-oxazoline) amphiphiles. J Control Release. 2011;153(1):73–82.CrossRefGoogle Scholar
  82. 82.
    Wang X, Li X, Li Y, Zhou Y, Fan C, Li W, et al. Synthesis, characterization and biocompatibility of poly(2-ethyl-2-oxazoline)–poly(d,l-lactide)–poly(2-ethyl-2-oxazoline) hydrogels. Acta Biomater. 2011;7(12):4149–59.CrossRefGoogle Scholar
  83. 83.
    Kronek J, Kroneková Z, Lustoň J, Paulovičová E, Paulovičová L, Mendrek B. In vitro bio-immunological and cytotoxicity studies of poly(2-oxazolines). J Mater Sci Mater Med. 2011;22(7):1725–34.CrossRefGoogle Scholar
  84. 84.
    Konradi R, Acikgoz C, Textor M. Polyoxazolines for nonfouling surface coatings—a direct comparison to the gold standard PEG. Macromol Rapid Commun. 2012;33(19):1663–76.CrossRefGoogle Scholar
  85. 85.
    Zalipsky S, Hansen CB, Oaks JM, Allen TM. Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes. J Pharm Sci. 1996;85(2):133–7.CrossRefGoogle Scholar
  86. 86.
    Pidhatika B, Rodenstein M, Chen Y, Rakhmatullina E, Mühlebach A, Acikgöz C, et al. Comparative stability studies of poly(2-methyl-2-oxazoline) and poly(ethylene glycol) brush coatings. Biointerphases. 2012;7(1):1–15.CrossRefGoogle Scholar
  87. 87.
    Goddard P, Hutchinson LE, Brown J, Brookman LJ. Soluble polymeric carriers for drug delivery. Part 2. Preparation and in vivo behaviour of N-acylethylenimine copolymers. J Control Release. 1989;10(1):5–16.CrossRefGoogle Scholar
  88. 88.
    Gaertner FC, Luxenhofer R, Blechert B, Jordan R, Essler M. Synthesis, biodistribution and excretion of radiolabeled poly(2-alkyl-2-oxazoline)s. J Control Release. 2007;119(3):291–300.CrossRefGoogle Scholar
  89. 89.
    Wang C-H, Hwang Y-S, Chiang P-R, Shen C-R, Hong W-H, Hsiue G-H. Extended release of bevacizumab by thermosensitive biodegradable and biocompatible hydrogel. Biomacromolecules. 2011;13(1):40–8.CrossRefGoogle Scholar
  90. 90.
    Duncan R. Polymer therapeutics as nanomedicines: new perspectives. Curr Opin Biotechnol. 2011;22(4):492–501.CrossRefGoogle Scholar
  91. 91.
    Mero A, Fang Z, Pasut G, Veronese FM, Viegas TX. Selective conjugation of poly(2-ethyl 2-oxazoline) to granulocyte colony stimulating factor. J Control Release. 2012;159(3):353–61.CrossRefGoogle Scholar
  92. 92.
    Tong J, Luxenhofer R, Yi X, Jordan R, Kabanov AV. Protein modification with amphiphilic block copoly(2-oxazoline)s as a new platform for enhanced cellular delivery. Mol Pharm. 2010;7(4):984–92.CrossRefGoogle Scholar
  93. 93.
    European Medicines Agency. Summary of the European public assessment report (EPAR) for Glybera. 2012. Accessed 20 July 2013.
  94. 94.
    Marshall E. Gene therapy death prompts review of adenovirus vector. Science. 1999;286(5448):2244–5.CrossRefGoogle Scholar
  95. 95.
    Boyce N. Trial halted after gene shows up in semen. Nature. 2001;414(6865):677.CrossRefGoogle Scholar
  96. 96.
    Check E. Gene therapy: a tragic setback. Nature. 2002;420(6912):116–8.CrossRefGoogle Scholar
  97. 97.
    Morille M, Passirani C, Vonarbourg A, Clavreul A, Benoit J-P. Progress in developing cationic vectors for non-viral systemic gene therapy against cancer. Biomaterials. 2008;29(24–25):3477–96.CrossRefGoogle Scholar
  98. 98.
    O’Rorke S, Keeney M, Pandit A. Non-viral polyplexes: scaffold mediated delivery for gene therapy. Prog Polym Sci. 2010;35(4):441–58.CrossRefGoogle Scholar
  99. 99.
    Wong SY, Pelet JM, Putnam D. Polymer systems for gene delivery—past, present, and future. Prog Polym Sci. 2007;32(8–9):799–837.CrossRefGoogle Scholar
  100. 100.
    Gosselin MA, Guo W, Lee RJ. Efficient gene transfer using reversibly cross-linked low molecular weight polyethylenimine. Bioconjug Chem. 2001;12(6):989–94.CrossRefGoogle Scholar
  101. 101.
    Breunig M, Lungwitz U, Liebl R, Fontanari C, Klar J, Kurtz A, et al. Gene delivery with low molecular weight linear polyethylenimines. J Gene Med. 2005;7(10):1287–98.CrossRefGoogle Scholar
  102. 102.
    Brissault B, Kichler A, Guis C, Leborgne C, Danos O, Cheradame H. Synthesis of linear polyethylenimine derivatives for DNA transfection. Bioconjug Chem. 2003;14(3):581–7.CrossRefGoogle Scholar
  103. 103.
    Lambermont-Thijs HML, van der Woerdt FS, Baumgaertel A, Bonami L, Du Prez FE, Schubert US, et al. Linear poly(ethylene imine)s by acidic hydrolysis of poly(2-oxazoline)s: kinetic screening, thermal properties, and temperature-induced solubility transitions. Macromolecules. 2009;43(2):927–33.CrossRefGoogle Scholar
  104. 104.
    Thomas M, Lu JJ, Ge Q, Zhang C, Chen J, Klibanov AM. Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc Natl Acad Sci USA. 2005;102(16):5679–84.CrossRefGoogle Scholar
  105. 105.
    Jeong JH, Song SH, Lim DW, Lee H, Park TG. DNA transfection using linear poly(ethylenimine) prepared by controlled acid hydrolysis of poly(2-ethyl-2-oxazoline). J Control Release. 2001;73(2–3):391–9.CrossRefGoogle Scholar
  106. 106.
    Hsiue G-H, Chiang H-Z, Wang C-H, Juang T-M. Nonviral gene carriers based on diblock copolymers of poly(2-ethyl-2-oxazoline) and linear polyethylenimine. Bioconjug Chem. 2006;17(3):781–6.CrossRefGoogle Scholar
  107. 107.
    Bauhuber S, Liebl R, Tomasetti L, Rachel R, Goepferich A, Breunig M. A library of strictly linear poly(ethylene glycol)–poly(ethylene imine) diblock copolymers to perform structure–function relationship of non-viral gene carriers. J Control Release. 2012;162(2):446–55.CrossRefGoogle Scholar
  108. 108.
    von Erlach T, Zwicker S, Pidhatika B, Konradi R, Textor M, Hall H, et al. Formation and characterization of DNA-polymer-condensates based on poly(2-methyl-2-oxazoline) grafted poly(l-lysine) for non-viral delivery of therapeutic DNA. Biomaterials. 2011;32(22):5291–303.CrossRefGoogle Scholar
  109. 109.
    Grayson SM, Cortez M, inventors; Polyplex Gene Delivery Vectors. International Patent WO 2011/116371. 2011.Google Scholar
  110. 110.
    Grayson SM. Polymer preprints (American Chemical Society, Division of Polymer Chemistry). 2012;53(1):370–1.Google Scholar
  111. 111.
    Canal F, Sanchis J, Vicent MJ. Polymer–drug conjugates as nano-sized medicines. Curr Opin Biotechnol. 2011;22(6):894–900.CrossRefGoogle Scholar
  112. 112.
    Greco F, Vicent MJ. Combination therapy: opportunities and challenges for polymer–drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev. 2009;61(13):1203–13.CrossRefGoogle Scholar
  113. 113.
    Moreadith RW, Viegas TX, Standaert DG, Bentley MD, Fang Z, Dizman B, Yoon K, Weimer R, Harris JM, Ravenscroft P, Johnston TH, Hill M, Brotchie JM. SER-214, a novel polymer-conjugated rotigotine formulation affords greatly extended duration of anti-Parkinsonian effect and enhanced plasma exposure following a single administration in rodents and primates. Proceedings of the 16th international conference of Parkinson’s disease and movement disorders, movement disorder society; Jun 17–21, 20125; Dublin, Ireland. Late breaking abstract 5, 2012.Google Scholar
  114. 114.
    Serina Therapeutics. US Patent and Trademark Office awards Serina Therapeutics key patent covering its lead clinical candidate for Parkinson’s disease and restless leg syndrome. 2013. Accessed 20 July 2013.
  115. 115.
    Wei H, Zhuo R-X, Zhang X-Z. Design and development of polymeric micelles with cleavable links for intracellular drug delivery. Prog Polym Sci. 2012;38(3–4):103–35.Google Scholar
  116. 116.
    Tyrrell ZL, Shen Y, Radosz M. Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers. Prog Polym Sci. 2010;35(9):1128–43.CrossRefGoogle Scholar
  117. 117.
    Chacko RT, Ventura J, Zhuang J, Thayumanavan S. Polymer nanogels: a versatile nanoscopic drug delivery platform. Adv Drug Deliv Rev. 2012;64(9):836–51.CrossRefGoogle Scholar
  118. 118.
    Matsumura Y, Kataoka K. Preclinical and clinical studies of anticancer agent-incorporating polymer micelles. Cancer Sci. 2009;100(4):572–9.CrossRefGoogle Scholar
  119. 119.
    Onaca O, Enea R, Hughes DW, Meier W. Stimuli-responsive polymersomes as nanocarriers for drug and gene delivery. Macromol Biosci. 2009;9(2):129–39.CrossRefGoogle Scholar
  120. 120.
    Nardin C, Thoeni S, Widmer J, Winterhalter M, Meier W. Nanoreactors based on (polymerized) ABA-triblock copolymer vesicles. Chem Commun. 2000;15:1433–4.CrossRefGoogle Scholar
  121. 121.
    Ben-Haim N, Broz P, Marsch S, Meier W, Hunziker P. Cell-specific integration of artificial organelles based on functionalized polymer vesicles. Nano Lett. 2008;8(5):1368–73.CrossRefGoogle Scholar
  122. 122.
    Broz P, Ben-Haim N, Grzelakowski M, Marsch S, Meier W, Hunziker P. Inhibition of macrophage phagocytotic activity by a receptor-targeted polymer vesicle-based drug delivery formulation of pravastatin. J Cardiovasc Pharmacol. 2008;51(3):246–52.CrossRefGoogle Scholar
  123. 123.
    Ranquin A, Versées W, Meier W, Steyaert J, Van Gelder P. Therapeutic nanoreactors: combining chemistry and biology in a novel triblock copolymer drug delivery system. Nano Lett. 2005;5(11):2220–4.CrossRefGoogle Scholar
  124. 124.
    Trzebicka B, Koseva N, Mitova V, Dworak A. Organization of poly(2-ethyl-2-oxazoline)-block-poly(2-phenyl-2-oxazoline) copolymers in water solution. Polymer. 2010;51(12):2486–93.CrossRefGoogle Scholar
  125. 125.
    Milonaki Y, Kaditi E, Pispas S, Demetzos C. Amphiphilic gradient copolymers of 2-methyl- and 2-phenyl-2-oxazoline: self-organization in aqueous media and drug encapsulation. J Polym Sci A. 2012;50(6):1226–37.CrossRefGoogle Scholar
  126. 126.
    Krumm C, Fik CP, Meuris M, Dropalla GJ, Geltenpoth H, Sickmann A, et al. Well-defined amphiphilic poly(2-oxazoline) ABA-triblock copolymers and their aggregation behavior in aqueous solution. Macromol Rapid Commun. 2012;33(19):1677–82.CrossRefGoogle Scholar
  127. 127.
    Persidis A. Cancer multidrug resistance. Nat Biotechnol. 1999;17(1):94–5.CrossRefGoogle Scholar
  128. 128.
    Luxenhofer R, Schulz A, Roques C, Li S, Bronich TK, Batrakova EV, et al. Doubly amphiphilic poly(2-oxazoline)s as high-capacity delivery systems for hydrophobic drugs. Biomaterials. 2010;31(18):4972–9.CrossRefGoogle Scholar
  129. 129.
    Han Y, He Z, Schulz A, Bronich TK, Jordan R, Luxenhofer R, et al. Synergistic combinations of multiple chemotherapeutic agents in high capacity poly(2-oxazoline) micelles. Mol Pharm. 2012;9(8):2302–13.Google Scholar
  130. 130.
    Lutolf MP. Biomaterials: spotlight on hydrogels. Nat Mater. 2009;8(6):451–3.CrossRefGoogle Scholar
  131. 131.
    Kelly AM, Hecke A, Wirnsberger B, Wiesbrock F. Synthesis of poly(2-oxazoline)-based hydrogels with tailor-made swelling degrees capable of stimuli-triggered compound release. Macromol Rapid Commun. 2011;32(22):1815–9.CrossRefGoogle Scholar
  132. 132.
    Dargaville TR, Forster R, Farrugia BL, Kempe K, Voorhaar L, Schubert US, et al. Poly(2-oxazoline) hydrogel monoliths via thiol-ene coupling. Macromol Rapid Commun. 2012;33(19):1695–700.CrossRefGoogle Scholar
  133. 133. Accessed 20 Oct 2012.
  134. 134.
    Hoogenboom R, Bender J, Van Hest J, inventors; Cross-linked polymers and implants derived from electrophilically activated polyoxazoline. International Patent WO 2012/057628. 2012.Google Scholar
  135. 135.
    Kelly AM, Wiesbrock F. Strategies for the synthesis of poly(2-oxazoline)-based hydrogels. Macromol Rapid Commun. 2012;33(19):1632–47.CrossRefGoogle Scholar
  136. 136.
    Del Pozo JL, Patel R. Infection associated with prosthetic joints. N Engl J Med. 2009;361(8):787–94.CrossRefGoogle Scholar
  137. 137.
    Werner C, Maitz MF, Sperling C. Current strategies towards hemocompatible coatings. J Mater Chem. 2007;17(32):3376–84.CrossRefGoogle Scholar
  138. 138.
    Krishnan S, Weinman CJ, Ober CK. Advances in polymers for anti-biofouling surfaces. J Mater Chem. 2008;18(29):3405–13.CrossRefGoogle Scholar
  139. 139.
    Vogler EA. Structure and reactivity of water at biomaterial surfaces. Adv Colloid Interface Sci. 1998;74(1–3):69–117.CrossRefGoogle Scholar
  140. 140.
    Vogler EA. In: Morra M, editor. Water in biomaterials surface science. 1st ed. New York: Wiley; 2001.Google Scholar
  141. 141.
    Roosjen A, de Vries J, van der Mei HC, Norde W, Busscher HJ. Stability and effectiveness against bacterial adhesion of poly(ethylene oxide) coatings in biological fluids. J Biomed Mater B. 2005;73B(2):347–54.CrossRefGoogle Scholar
  142. 142.
    Bozzini S, Petrini P, Tanzi MC, Zürcher S, Tosatti S. Poly(ethylene glycol) and hydroxy functionalized alkane phosphate mixed self-assembled monolayers to control nonspecific adsorption of proteins on titanium oxide surfaces. Langmuir. 2009;26(9):6529–34.CrossRefGoogle Scholar
  143. 143.
    Van Kuringen HPC, Lenoir J, Adriaens E, Bender J, De Geest BG, Hoogenboom R. Partial hydrolysis of poly(2-ethyl-2-oxazoline) and potential implications for biomedical applications? Macromol Biosci. 2012;12(8):1114–23.CrossRefGoogle Scholar
  144. 144.
    Konradi R, Pidhatika B, Muhlebach A, Textor M. Poly-2-methyl-2-oxazoline: a peptide-like polymer for protein-repellent surfaces. Langmuir. 2008;24(3):613–6.CrossRefGoogle Scholar
  145. 145.
    Pidhatika B, ller J, Vogel V, Konradi R. Nonfouling surface coatings based on poly(2-methyl-2-oxazoline). CHIMIA Int J Chem. 2008;62(4):264–9.CrossRefGoogle Scholar
  146. 146.
    Pidhatika B, Möller J, Benetti EM, Konradi R, Rakhmatullina E, Mühlebach A, et al. The role of the interplay between polymer architecture and bacterial surface properties on the microbial adhesion to polyoxazoline-based ultrathin films. Biomaterials. 2010;31(36):9462–72.CrossRefGoogle Scholar
  147. 147.
    Chang B-J, Prucker O, Groh E, Wallrath A, Dahm M, Rühe J. Surface-attached polymer monolayers for the control of endothelial cell adhesion. Colloid Surf A. 2002;198–200:519–26.CrossRefGoogle Scholar
  148. 148.
    Murata H, Chang BJ, Prucker O, Dahm M, Rühe J. Polymeric coatings for biomedical devices. Surf Sci. 2004;570(1–2):111–8.CrossRefGoogle Scholar
  149. 149.
    Wang H, Li L, Tong Q, Yan M. Evaluation of photochemically immobilized poly(2-ethyl-2-oxazoline) thin films as protein-resistant surfaces. ACS Appl Mater Interfaces. 2011;3(9):3463–71.CrossRefGoogle Scholar
  150. 150.
    Jordan R, Ulman A. Surface initiated living cationic polymerization of 2-oxazolines. J Am Chem Soc. 1998;120(2):243–7.CrossRefGoogle Scholar
  151. 151.
    Zhang N, Steenackers M, Luxenhofer R, Jordan R. Bottle-brush brushes: cylindrical molecular brushes of poly(2-oxazoline) on glassy carbon. Macromolecules. 2009;42(14):5345–51.CrossRefGoogle Scholar
  152. 152.
    Zhang N, Pompe T, Amin I, Luxenhofer R, Werner C, Jordan R. Tailored poly(2-oxazoline) polymer brushes to control protein adsorption and cell adhesion. Macromol Biosci. 2012;12(7):926–36.CrossRefGoogle Scholar
  153. 153.
    Zhang N, Luxenhofer R, Jordan R. Thermoresponsive poly(2-oxazoline) molecular brushes by living ionic polymerization: kinetic investigations of pendant chain grafting and cloud point modulation by backbone and side chain length variation. Macromol Chem Phys. 2012;213(9):973–81.CrossRefGoogle Scholar
  154. 154.
    Charnley M, Textor M, Acikgoz C. Designed polymer structures with antifouling–antimicrobial properties. React Funct Polym. 2011;71(3):329–34.CrossRefGoogle Scholar
  155. 155.
    Siedenbiedel F, Tiller JC. Antimicrobial polymers in solution and on surfaces: overview and functional principles. Polymers. 2012;4(1):46–71.CrossRefGoogle Scholar
  156. 156.
    Fik CP, Krumm C, Muennig C, Baur TI, Salz U, Bock T, et al. Impact of functional satellite groups on the antimicrobial activity and hemocompatibility of telechelic poly(2-methyloxazoline)s. Biomacromolecules. 2011;13(1):165–72.CrossRefGoogle Scholar
  157. 157.
    Waschinski CJ, Herdes V, Schueler F, Tiller JC. Influence of satellite groups on telechelic antimicrobial functions of polyoxazolines. Macromol Biosci. 2005;5(2):149–56.CrossRefGoogle Scholar
  158. 158.
    Waschinski CJ, Zimmermann J, Salz U, Hutzler R, Sadowski G, Tiller JC. Design of contact-active antimicrobial acrylate-based materials using biocidal macromers. Adv Mater. 2008;20(1):104–8.CrossRefGoogle Scholar
  159. 159.
    Bieser AM, Thomann Y, Tiller JC. Contact-active antimicrobial and potentially self-polishing coatings based on cellulose. Macromol Biosci. 2011;11(1):111–21.CrossRefGoogle Scholar
  160. 160.
    Phadtare S, Vinod VP, Mukhopadhyay K, Kumar A, Rao M, Chaudhari RV, et al. Immobilization and biocatalytic activity of fungal protease on gold nanoparticle-loaded zeolite microspheres. Biotechnol Bioeng. 2004;85(6):629–37.CrossRefGoogle Scholar
  161. 161.
    Tokarev I, Tokareva I, Gopishetty V, Katz E, Minko S. Specific biochemical-to-optical signal transduction by responsive thin hydrogel films loaded with noble metal nanoparticles. Adv Mater. 2010;22(12):1412–6.CrossRefGoogle Scholar
  162. 162.
    Agrawal M, Rueda JC, Uhlmann P, Müller M, Simon F, Stamm M. Facile approach to grafting of poly(2-oxazoline) brushes on macroscopic surfaces and applications thereof. ACS Appl Mater Interfaces. 2012;4(3):1357–64.CrossRefGoogle Scholar
  163. 163.
    Claeys B, Vervaeck A, Vervaet C, Remon JP, Hoogenboom R, De Geest BG. Poly(2-ethyl-2-oxazoline) as matrix excipient for drug formulation by hot melt extrusion and injection molding. Macromol Rapid Commun. 2012;33(19):1701–7.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Supramolecular Chemistry Group, Department of Organic ChemistryGhent UniversityGhentBelgium

Personalised recommendations