Skip to main content
SpringerLink
Log in

Temperature/pH Responsive Hydrogels Based on Poly(ethylene glycol) and Functionalized Poly(e-caprolactone) Block Copolymers for Controlled Delivery of Macromolecules

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To assess the potential of triblock copolymers based on poly(ethylene glycol) (PEG) and functionalized poly(ε-caprolactone) as temperature/pH responsive gels for controlled delivery of macromolecules.

Methods

Poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone)-PEG-poly(α-carboxylate-co-α-benzylcarboxylate-ε-caprolactone) (PCBCL-PEG-PCBCL) was synthesized through ring opening polymerization of α-benzyl carboxylate-ε-caprolactone by PEG, followed by 30% debenzylation of the lateral blocks. The effect of Tris buffer and pH on the sol–gel transition temperature of PCBCL-PEG-PCBCL was assessed. The temperature/pH responsive release of tetramethylrhodamine-dextran (TMR-D) (10 and 40 kDa) from PCBCL-PEG-PCBCL was investigated.

Results

Replacement of water with Tris buffer reduced PCBCL-PEG-PCBCL sol–gel transition temperature. Thermo-reversible hydrogels were only formed at pHs ≥ 5.0, but PCBCL-PEG-PCBCL transition temperature was not affected by pH above pH 5.0. In contrast to Pluronic F127 that released 100% of TMR-D within 2 h, PCBCL-PEG-PCBCL hydrogel controlled TMR-D release efficiently at pH = 7.4 and 37°C (~27 and 11% TMRD 10 and 40 kDa release within 150 h, respectively). At 50°C or pH = 9.0, TMR-D release was increased slightly, while at room temperature or pH = 5.0, no control over TMR-D release was observed by PCBCL-PEG-PCBCL hydrogel.

Conclusion

PCBCL-PEG-PCBCL hydrogel provides depot release of macromolecules at physiological conditions. This release can be triggered through changes in the temperature or pH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

ARCI:

Alberta Research Chemicals Inc

BCL:

α-Benzylcarboxylate ε-caprolactone

CGC:

Critical gelation concentration

CGT:

Critical gelation temperature

DMA:

Dynamic mechanical analysis

DSC:

Differential scanning calorimetry

G′:

Storage modulus

G″:

Loss modulus

h:

Hour

HCl:

Hydrochloric acid

MDSC:

Modulated differential scanning calorimetry

min:

Minute

mL:

Milliliter

mM:

Mili mole

MW:

Molecular weight

NaOH:

Sodium hydroxide

NMR:

Nuclear magnetic resonance

OSM:

Oligosulfamethazine

OSM–PCLA–PEG– PCLA–OSM:

Oligosulfamethazine–poly(lactide-co-caprolactone)–PEG–poly(lactide-co-caprolactone)–oligosulfa-methazine

Pa:

Pascal

PBCL:

Poly(α-benzylcarboxylate ε-caprolactone)

PBCL-b-PEG-b-PBCL:

Poly(α-benzyl carboxylate-ε-caprolactone)-block-polyethylene glycol-block-poly(α-benzyl carboxylate-ε-caprolactone)

PCBCL:

Poly(α-benzyl carboxylate-co-α-carboxyl-ε-caprolactone)

PCL:

Poly(ε-caprolactone)

Pd/C:

Palladium, 10% on activated charcoal

PEG:

Poly(ethylene glycol)

ppm:

Part per million

rad/s:

Radian per second

TEM:

Transmission electron microspcopy

W/W:

Weight per weight

References

  1. Crompton KE, Goud JD, Bellamkonda RV, Gengenbach TR, Finkelstein DI, Horne MK, et al. Polylysine-functionalised thermoresponsive chitosan hydrogel for neural tissue engineering. Biomaterials. 2007;28(3):441–9.

    Article  CAS  PubMed  Google Scholar 

  2. Tan H, Ramirez CM, Miljkovic N, Li H, Rubin JP, Marra KG. Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. Biomaterials. 2009;30(36):6844–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Stile RA, Healy KE. Thermo-responsive peptide-modified hydrogels for tissue regeneration. Biomacromolecules. 2001;2(1):185–94.

    Article  CAS  PubMed  Google Scholar 

  4. Gant RM, Abraham AA, Hou Y, Cummins BM, Grunlan MA, Cote GL. Design of a self-cleaning thermoresponsive nanocomposite hydrogel membrane for implantable biosensors. Acta Biomater. 2010;6(8):2903–10.

    Article  CAS  PubMed  Google Scholar 

  5. Fujimoto KL, Ma Z, Nelson DM, Hashizume R, Guan J, Tobita K, et al. Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium. Biomaterials. 2009;30(26):4357–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Moon HJ, Ko DY, Park MH, Joo MK, Jeong B. Temperature-responsive compounds as in situ gelling biomedical materials. Chem Soc Rev. 2012;41(14):4860–83.

    Article  CAS  PubMed  Google Scholar 

  7. Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm. 2000;50(1):27–46.

    Article  CAS  PubMed  Google Scholar 

  8. Van Tomme SR, Storm G, Hennink WE. In situ gelling hydrogels for pharmaceutical and biomedical applications. Int J Pharm. 2008;355(1–2):1–18.

    Article  PubMed  Google Scholar 

  9. Yin H, Gong C, Shi S, Liu X, Wei Y, Qian Z. Toxicity evaluation of biodegradable and thermosensitive PEG-PCL-PEG hydrogel as a potential in situ sustained ophthalmic drug delivery system. J Biomed Mater Res B Appl Biomater. 2010;92(1):129–37.

    Article  PubMed  Google Scholar 

  10. Gong C, Shi S, Dong P, Kan B, Gou M, Wang X, et al. Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel. Int J Pharm. 2009;365(1–2):89–99.

    Article  CAS  PubMed  Google Scholar 

  11. Vermonden T, Censi R, Hennink WE. Hydrogels for protein delivery. Chem Rev. 2012;112(5):2853–88.

    Article  CAS  PubMed  Google Scholar 

  12. Ni PY, Fan M, Qian ZY, Luo JC, Gong CY, Fu SZ, et al. Synthesis and characterization of injectable, thermosensitive, and biocompatible acellular bone matrix/poly(ethylene glycol)-poly (epsilon-caprolactone)-poly(ethylene glycol) hydrogel composite. J Biomed Mater Res A. 2012;100A(1):171–9.

    Article  CAS  Google Scholar 

  13. Jiang ZQ, Deng XM, Hao JY. Novel thermogelling poly(epsilon-caprolactone-co-lactide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-lactide) aqueous solutions. Chin Chem Lett. 2007;18(6):747–9.

    Article  CAS  Google Scholar 

  14. Mahmud A, Xiong X-B, Lavasanifar A. Novel self-associating poly (ethylene oxide)-b lock-poly (ε-caprolactone) block copolymers with functional side groups on the polyester block for drug delivery. Macromolecules. 2006;39(26):9419–28.

    Article  CAS  Google Scholar 

  15. Nikouei NS, Lavasanifar A. Characterization of the thermo- and pH-responsive assembly of triblock copolymers based on poly(ethylene glycol) and functionalized poly(epsilon-caprolactone). Acta Biomater. 2011;7(10):3708–18.

    Article  Google Scholar 

  16. Nikouei NS, Vakili MR, Bahniuk MS, Unsworth L, Akbari A, Wu J, et al. Thermoreversible hydrogels based on triblock copolymers of poly(ethylene glycol) and carboxyl functionalized poly(ε-caprolactone): the effect of carboxyl group substitution on the transition temperature and biocompatibility in plasma. Acta Biomater. 2015;12:81–92.

    Article  CAS  Google Scholar 

  17. Huynh CT, Nguyen MK, Lee DS. Injectable block copolymer hydrogels: achievements and future challenges for biomedical applications. Macromolecules. 2011;44(17):6629–36.

    Article  CAS  Google Scholar 

  18. Shim WS, Yoo JS, Bae YH, Lee DS. Novel injectable pH and temperature sensitive block copolymer hydrogel. Biomacromolecules. 2005;6(6):2930–4.

    Article  CAS  PubMed  Google Scholar 

  19. Yin X, Hoffman AS, Stayton PS. Poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers that respond sharply to temperature and pH. Biomacromolecules. 2006;7(5):1381–5.

    Article  CAS  PubMed  Google Scholar 

  20. Garbern JC, Hoffman AS, Stayton PS. Injectable pH- and temperature-responsive poly(N-isopropylacrylamide-co-propylacrylic acid) copolymers for delivery of angiogenic growth factors. Biomacromolecules. 2010;11(7):1833–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Bae SJ, Suh JM, Sohn YS, Bae YH, Kim SW, Jeong B. Thermogelling poly (caprolactone-b-ethylene glycol-b-caprolactone) aqueous solutions. Macromolecules. 2005;38(12):5260–5.

    Article  CAS  Google Scholar 

  22. Wang QQ, Li L, Jiang SP. Effects of a PPO-PEO-PPO triblock copolymer on micellization and gelation of a PEO-PPO-PEO triblock copolymer in aqueous solution. Langmuir. 2005;21(20):9068–75.

    Article  CAS  PubMed  Google Scholar 

  23. Lee DS, Shim MS, Kim SW, Lee H, Park I, Chang TY. Novel thermoreversible gelation of biodegradable PLGA-block-PEO-block-PLGA triblock copolymers in aqueous solution. Macromol Rapid Commun. 2001;22(8):587–92.

    Article  CAS  Google Scholar 

  24. Safaei Nikouei N, University of Alberta. Faculty of Pharmacy and Pharmaceutical Sciences. Development of novel stimuli-responsive drug delivery systems.

  25. Cheng YL, He CL, Ding JX, Xiao CS, Zhuang XL, Chen XS. Thermosensitive hydrogels based on polypeptides for localized and sustained delivery of anticancer drugs. Biomaterials. 2013;34(38):10338–47.

    Article  CAS  PubMed  Google Scholar 

  26. Takeuchi Y, Tsujimoto T, Uyama H. Thermogelation of amphiphilic poly(asparagine) derivatives. Polym Adv Technol. 2011;22(5):620–6.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank Dr. Ali Akbari and Dr. Jianping Wu for providing rheometer equipment for this study. The study was supported by funds from the Natural Science and Engineering Research Council of Canada (NSERC).

Author information

Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada

    Nazila Safaei Nikouei, Nasim Ghasemi & Afsaneh Lavasanifar

  2. Department of Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta, T6G 2V4, Canada

    Afsaneh Lavasanifar

  3. 2-142F Faculty of Pharmacy and Pharmaceutical Sciences, Katz Group/Rexall Centre for Pharmacy & Health Research, University of Alberta, Edmonton, Alberta, T6G 2E1, Canada

    Afsaneh Lavasanifar

Authors
  1. Nazila Safaei Nikouei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nasim Ghasemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Afsaneh Lavasanifar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Afsaneh Lavasanifar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nikouei, N.S., Ghasemi, N. & Lavasanifar, A. Temperature/pH Responsive Hydrogels Based on Poly(ethylene glycol) and Functionalized Poly(e-caprolactone) Block Copolymers for Controlled Delivery of Macromolecules. Pharm Res 33, 358–366 (2016). https://doi.org/10.1007/s11095-015-1794-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-015-1794-z

KEY WORDS

Search

Navigation