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Synthesis of poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) conjugates by a new modular strategy

  • Umut Ugur Ozkose
  • Ozgur Yilmaz
  • Onur AlpturkEmail author
Original Paper
  • 23 Downloads

Abstract

Amphiphilic block copolymers where hydrophobicity and hydrophilicity coincide are essential building blocks for many supramolecular systems. By this time, polyethylene glycol (PEG) has been a conventional choice to constitute hydrophilicity; however, it suffers from certain drawbacks, severely limiting its use in these compounds. To date, one potential modality to overcome this complication is to utilize poly(2-ethyl-2-oxazoline) (PEtOx) instead, given that this also-hydrophilic polymer is very comparable to PEG, in many ways. In this regard, amphiphilic block copolymers harboring PEtOx and synthetic approaches to access these polymeric materials have been documented in the literature. Within this scope, we crafted a modular approach for the synthesis of poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) to govern its molecular structure. Herein, we extend this work and report a novel poly(2-ethyl-2-oxazoline)-b-poly(ε-caprolactone) derivative with electrophilic moiety on terminal position. We believe that this novel design could lead up to expeditious synthesis of block copolymer-biomolecule conjugates, which are of paramount significance for many applications.

Graphic abstract

Keywords

Amphiphilic block copolymer Copper-catalyzed azide-alkyne cycloaddition click chemistry Conjugation of biological functionalities Poly(ε-caprolactone) Polyoxazoline 

Notes

Acknowledgements

The authors would like to thank Turkish Scientific and Technological Council (TUBITAK-213M725) for financial supports.

References

  1. 1.
    Nishiyama N, Bae Y, Miyata K, Fukushima S, Kataoka K (2005) Smart polymeric micelles for gene and drug delivery. Drug Discov Today Technol 2(1):21–26.  https://doi.org/10.1016/j.ddtec.2005.05.007 CrossRefPubMedGoogle Scholar
  2. 2.
    Jain JP, Ayen WY, Kumar N (2011) Self assembling polymers as polymersomes for drug delivery. Curr Pharm Des 17:65–79.  https://doi.org/10.2174/138161211795049822 CrossRefPubMedGoogle Scholar
  3. 3.
    Klaikherd A, Nagamani C, Thayumanavan S (2009) Multi-stimuli sensitive amphiphilic block copolymer assemblies. J Am Chem Soc 131(13):4830–4838.  https://doi.org/10.1021/ja809475a CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Förster S, Plantenberg T (2002) From self-organizing polymers to nanohybrid and biomaterials. Angew Chem Int Ed 41:689–714.  https://doi.org/10.1002/1521-3773(20020301)41:5%3c688:AID-ANIE688%3e3.0.CO;2-3 CrossRefGoogle Scholar
  5. 5.
    Jeong B, Bae YH, Kim SW (1999) Thermoreversible gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions. Macromolecules 32:7064–7069.  https://doi.org/10.1021/ma9908999 CrossRefGoogle Scholar
  6. 6.
    Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliver Rev 54:459–476.  https://doi.org/10.1016/S0169-409X(02)00022-4 CrossRefGoogle Scholar
  7. 7.
    Harris JM, Chess RB (2003) Effect of PEGylation on pharmaceuticals. Nat Rev Drug Discov 2:214–221.  https://doi.org/10.1038/nrd1033 CrossRefPubMedGoogle Scholar
  8. 8.
    Caliceti P, Veronese FM (2003) Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 55:1261–1277.  https://doi.org/10.1016/S0169-409X(03)00108-X CrossRefPubMedGoogle Scholar
  9. 9.
    Veronese FM, Pasut G (2005) PEGylation, successful approach to drug delivery. Drug Discov Today 10:1451–1458.  https://doi.org/10.1016/S1359-6446(05)03575-0 CrossRefPubMedGoogle Scholar
  10. 10.
    Milla P, Dosio F, Cattel L (2012) PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery. Curr Drug Metab 13:105–119.  https://doi.org/10.2174/138920012798356934 CrossRefPubMedGoogle Scholar
  11. 11.
    Duan J, Liu C, Liang X, Li X, Chen Y, Chen Z, Wang X, Kong D, Li Y, Yang J (2018) Protein delivery nanosystem of six-arm copolymer poly(ε-caprolactone)–poly(ethylene glycol) for long-term sustained release. Int J Nanomed 13:2743–2754.  https://doi.org/10.2147/IJN.S161006 CrossRefGoogle Scholar
  12. 12.
    Xiao RZ, Zeng ZW, Zhou GL, Wang JJ, Li FZ, Wang AM (2010) Recent advances in PEG–PLA block copolymer nanoparticles. Int J Nanomed 5:1057–1065.  https://doi.org/10.2147/IJN.S14912 CrossRefGoogle Scholar
  13. 13.
    Wang J, Li S, Han Y, Guan J, Chung S, Wang C, Li D (2018) Poly(ethylene glycol)–polylactide micelles for cancer therapy. Front Pharmacol 9:202.  https://doi.org/10.3389/fphar.2018.00202 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kutikov AB, Song J (2015) Biodegradable PEG-based amphiphilic block copolymers for tissue engineering applications. ACS Biomater Sci Eng 1(7):463–480.  https://doi.org/10.1021/acsbiomaterials.5b00122 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liu G-Y, Chen C-J, Ji J (2012) Biocompatible and biodegradable polymersomes as delivery vehicles in biomedical applications. Soft Matter 8:8811–8821.  https://doi.org/10.1039/C2SM25721A CrossRefGoogle Scholar
  16. 16.
    Veronese FM, Mero A, Pasut G (2009) Protein PEGylation, basic science and biological applications. PEGylated protein drugs: basic science and clinical applications. In: Veronese FM (ed) Milestones in drug therapy. Basel, Birkhäuser, pp 11–31.  https://doi.org/10.1007/978-3-7643-8679-5_2 CrossRefGoogle Scholar
  17. 17.
    Ulbricht J, Jordan R, Luxenhofer R (2014) On the biodegradability of polyethylene glycol, polypeptoids and poly(2-oxazoline)s. Biomaterials 35:4848–4861.  https://doi.org/10.1016/j.biomaterials.2014.02.029 CrossRefPubMedGoogle Scholar
  18. 18.
    Viegas TX, Bentley MD, Harris JM, Fang Z, Yoon K, Dizman B, Weimer R, Mero A, Pasut G, Veronese FM (2011) Polyoxazoline: chemistry, properties, and applications in drug delivery. Bioconj Chem 22:976–986.  https://doi.org/10.1021/bc200049d CrossRefGoogle Scholar
  19. 19.
    Tao L, Liu J, Davis TP (2009) Branched polymer-protein conjugates made from mid-chain-functional P(HPMA). Biomacromolecules 12:2847–2851.  https://doi.org/10.1021/bm900678r CrossRefGoogle Scholar
  20. 20.
    Jain S, Hreczuk-Hirst DH, McCormack B, Mital M, Epenetos A, Laing P, Gregoriadis G (2003) Polysialylated insulin: synthesis, characterization and biological activity in vivo. Biochim Biophys Acta 1622:42–49.  https://doi.org/10.1016/S0304-4165(03)00116-8 CrossRefPubMedGoogle Scholar
  21. 21.
    Veronese FM, Sartore L, Caliceti P, Schiavon O, Ranucci E, Ferruti P (1990) Low molecular weight end-functionalized poly(N-vinylpyrrolidinone) for the modification of polypeptide amino groups. J Bioact Compat Polym 5:167–178.  https://doi.org/10.1177/088391159400900404 CrossRefGoogle Scholar
  22. 22.
    Hoogenboom R (2007) Poly(2-oxazoline)s: alive and kicking. Macromol Chem Phys 208(1):18–25.  https://doi.org/10.1002/macp.200600558 CrossRefGoogle Scholar
  23. 23.
    Zalipsky S, Hansen CB, Oaks JM, Allen TM (1996) Evaluation of blood clearance rates and biodistribution of poly(2-oxazoline)-grafted liposomes. J Pharm Sci 85:133–137.  https://doi.org/10.1021/js9504043 CrossRefPubMedGoogle Scholar
  24. 24.
    Lee SC, Chang YK, Yoon JS, Kim CH, Kwon IC, Kim YH, Jeong SY (1999) Synthesis and micellar characterization of amphiphilic diblock copolymers based on poly(2-ethyl-2-oxazoline) and aliphatic polyesters. Macromolecules 32:1847–1852.  https://doi.org/10.1021/ma981664k CrossRefGoogle Scholar
  25. 25.
    Wiesbrock F, Hoogenboom R, Leenen MAM, Meier MAR, Schubert US (2005) Investigation of the living cationic ring-opening polymerization of 2-methyl-, 2-ethyl-, 2-nonyl-, and 2-phenyl-2-oxazoline in a single-mode microwave reactor. Macromolecules 38:5025–5034.  https://doi.org/10.1021/ma0474170 CrossRefGoogle Scholar
  26. 26.
    Hoogenboom R, Wiesbrock F, Huang H, Leenen MAM, Thijs HML, Van Nispen SFGM, Van der Loop M, Fustin CA, Jonas AM, Gohy JF, Schubert US (2006) Microwave-assisted cationic ring-opening polymerisation of 2-oxazolines: a powerful method for the synthesis of amphiphilic triblock copolymers. Macromolecules 39:4719–4725.  https://doi.org/10.1021/ma060952a CrossRefGoogle Scholar
  27. 27.
    Adams N, Schubert US (2007) Poly(2-oxazolines) in biological and biomedical application contexts. Adv Drug Deliv Rev 59:1504–1520.  https://doi.org/10.1016/j.addr.2007.08.018 CrossRefPubMedGoogle Scholar
  28. 28.
    Mero A, Pasut G, Dalla VL, Fijten MW, Schubert US, Hoogenboom R, Veronese FM (2008) Synthesis and characterization of poly(2-ethyl 2-oxazoline)-conjugates with proteins and drugs: suitable alternatives to peg-conjugates. J Control Release 2:87–95.  https://doi.org/10.1016/j.jconrel.2007.10.010 CrossRefGoogle Scholar
  29. 29.
    Hoogenboom R (2009) Poly(2-oxazoline)s: a polymer class with numerous potential applications. Angew Chem Int Ed 48(43):7978–7994.  https://doi.org/10.1002/anie.200901607 CrossRefGoogle Scholar
  30. 30.
    Sedlacek O, Monnery BD, Filippov SK, Hoogenboom R, Hruby M (2012) Poly(2-Oxazoline)s: are they more advantageous for biomedical applications than other polymers? Macromol Rapid Commun 33(19):1648–1662.  https://doi.org/10.1002/marc.201200453 CrossRefPubMedGoogle Scholar
  31. 31.
    Kobayashi S (2012) Polymerization of oxazolines. In: Matyjaszewski K, Möller M (eds) Polymer science: a comprehensive reference, vol 4. Elsevier, Amsterdam, pp 397–426.  https://doi.org/10.1016/B978-0-444-53349-4.00110-2 CrossRefGoogle Scholar
  32. 32.
    Hoogenboom R (2009) Polyethers and polyoxazolines. In: Dubois P, Coulembier O, Raquez J-M (eds) Handbook of ring-opening polymerization. Wiley, Weinheim, pp 141–164.  https://doi.org/10.1002/9783527628407.ch6 CrossRefGoogle Scholar
  33. 33.
    Luxenhofer R, Han Y, Schulz A, Tong J, He Z, Kabanov AV, Jordan R (2012) Poly(2-oxazoline)s as polymer therapeutics. Macromol Rapid Commun 33:1613–1631.  https://doi.org/10.1002/marc.201200354 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Isaacman MJ, Theogarajan L (2013) Poly(oxazoline) block copolymers for biomedical applications. Tailored Polym Archit Pharm Biomed Appl 1135:53–68.  https://doi.org/10.1021/bk-2013-1135.ch005 CrossRefGoogle Scholar
  35. 35.
    Gulyuz S, Ozkose UU, Kocak P, Telci D, Yilmaz O, Tasdelen MA (2018) In-vitro cytotoxic activities of poly(2-ethyl-2-oxazoline)-based amphiphilic block copolymers prepared by CuAAC click chemistry. Express Polym Lett 12(2):146–158.  https://doi.org/10.3144/expresspolymlett.2018.13 CrossRefGoogle Scholar
  36. 36.
    Zhang Y, He H, Gao C (2008) Clickable macroinitiator strategy to build amphiphilic polymer brushes on carbon nanotubes. Macromolecules 41:9581–9594.  https://doi.org/10.1021/ma801696z CrossRefGoogle Scholar
  37. 37.
    Cai T, Li M, Neoh KG, Kang ET (2013) Surface-functionalizable membranes of polycaprolactone-click-hyperbranched polyglycerol copolymers from combined atom transfer radical polymerization, ring-opening polymerization and click chemistry. J Mater Chem B 1:1304–1315.  https://doi.org/10.1039/C2TB00273F CrossRefGoogle Scholar
  38. 38.
  39. 39.
    Britto PJ, Knipling L, Wolff J (2002) the local electrostatic environment determines cysteine reactivity of tubulin. J Biol Chem 277:29018–29027.  https://doi.org/10.1074/jbc.M204263200 CrossRefPubMedGoogle Scholar
  40. 40.
    Gurd FRN (1967) Carboxymethylation. Methods Enzymol 11:532–541.  https://doi.org/10.1016/S0076-6879(67)11064-1 CrossRefGoogle Scholar
  41. 41.
    Stark GR, Stein WH, Moore S (1961) Relationships between the conformation of ribonuclease and its reactivity toward iodoacetate. J Biol Chem 236:436–442Google Scholar
  42. 42.
    Kolb HC, Sharpless KB (2003) The growing impact of click chemistry on drug discovery. Drug Discov Today 8(24):1128–1137.  https://doi.org/10.1016/S1359-6446(03)02933-7 CrossRefPubMedGoogle Scholar
  43. 43.
    Pressly ED, Amir RJ, Hawker CJ (2011) Rapid synthesis of block and cyclic copolymers via click chemistry in the presence of copper nanoparticles. J Polym Sci A Polym Chem 49(3):814–819.  https://doi.org/10.1002/pola.24504 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lutz JF, Zarafshani Z (2008) Efficient construction of therapeutics, bioconjugates, biomaterials and bioactive surfaces using azide-alkyne “click” chemistry. Adv Drug Deliv Rev 60:958–970.  https://doi.org/10.1016/j.addr.2008.02.004 CrossRefPubMedGoogle Scholar
  45. 45.
    Guis C, Cheradame H (2000) Synthesis of polymers containing pseudohalide groups by cationic polymerization 15. Study of the functionalizing living cationic polymerization of 2-methyl-2-oxazoline in the presence of trimethylsilylazide. Eur Polym J 36:2581–2590.  https://doi.org/10.1016/S0014-3057(00)00071-9 CrossRefGoogle Scholar
  46. 46.
    Hoogenboom R, Fijten MWM, Meier MAR, Schubert US (2003) Living cationic polymerizations utilizing an automated synthesizer: high-throughput synthesis of polyoxazolines. Macromol Rapid Commun 24:92–97.  https://doi.org/10.1002/marc.200390003 CrossRefGoogle Scholar
  47. 47.
    Park JS, Akiyama Y, Winnik FM, Kataoka K (2004) Versatile synthesis of end-functionalized thermosensitive poly(2-isopropyl-2-oxazolines). Macromolecules 37:6786–6792.  https://doi.org/10.1021/ma049677n CrossRefGoogle Scholar
  48. 48.
    Aoi K, Okada M (1996) Polymerization of oxazolines. Prog Polym Sci 21:151–208.  https://doi.org/10.1016/0079-6700(95)00020-8 CrossRefGoogle Scholar
  49. 49.
    Hoogenboom R, Fijten MWM, Schubert US (2004) Parallel kinetic investigation of 2-oxazoline polymerizations with different initiators as basis for designed copolymer synthesis. J Polym Sci A Polym Chem 42:1830–1840.  https://doi.org/10.1002/pola.20024 CrossRefGoogle Scholar
  50. 50.
    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM (1999) Polymeric systems for controlled drug release. Chem Rev 99:3181–3198.  https://doi.org/10.1021/cr940351u CrossRefPubMedGoogle Scholar
  51. 51.
    Jeong B, Bae YH, Lee DS, Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery systems. Nature 388:860–862.  https://doi.org/10.1038/42218 CrossRefPubMedGoogle Scholar
  52. 52.
    Kowalski A, Duda A, Pencaek S (2000) Mechanism of cyclic ester polymerization initiated with tin (II) octoate. 2. Macromolecules fitted with tin(II) alkoxide species observed directly in MALDI-TOF spectra. Macromolecules 33:689–695.  https://doi.org/10.1021/ma9906940 CrossRefGoogle Scholar
  53. 53.
    Alvaradejo GG, Glassner M, Hoogenboom R, Delaittre G (2018) Maleimide end-functionalized poly(2-oxazoline)s by the functional initiator route: synthesis and (bio)conjugation. RSC Adv 8:9471–9479.  https://doi.org/10.1039/C8RA00948A CrossRefGoogle Scholar
  54. 54.
    Bontempo D, Heredia KL, Fish BA, Maynard HD (2004) Cysteine-reactive polymers synthesized by atom transfer radical polymerization for conjugation to proteins. J Am Chem Soc 126:15372–15373.  https://doi.org/10.1021/ja045063m CrossRefPubMedGoogle Scholar
  55. 55.
    Mathews AS, Ahmed S, Shahin M, Lavasanifar A, Kaur K (2013) Peptide modified polymeric micelles specific for breast cancer cells. Bioconj Chem 24:560–570.  https://doi.org/10.1021/bc3004364 CrossRefGoogle Scholar
  56. 56.
    Etayash H, Jiang K, Azmi S, Thundat T, Kaur K (2015) Real-time detection of breast cancer cells using peptide functionalized microcantilever arrays. Sci Rep 5(13967):1–13.  https://doi.org/10.1038/srep13967 CrossRefGoogle Scholar
  57. 57.
    Lewandowski B, de Bo G, Ward JW, Papmeyer M, Kuschel S, Aldegunde MJ, Gramlich PME, Heckmann D, Goldup SM, D’Souza DM, Fernandes AE, Leigh DA (2013) Sequence-specific peptide synthesis by an artificial small-molecule machine. Science 339(6116):189–193.  https://doi.org/10.1126/science.1229753 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of Science and LettersIstanbul Technical UniversityMaslak, IstanbulTurkey
  2. 2.Materials Institute, Marmara Research CenterTUBITAKGebze, KocaeliTurkey
  3. 3.Department of Chemistry, Faculty of Science and LettersPiri Reis UniversityTuzla, IstanbulTurkey

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