Journal of Polymer Research

, 26:278 | Cite as

pH-responsive hydrogels based on the self-assembly of short polypeptides for controlled release of peptide and protein drugs

  • Xue Bao
  • Xinghui Si
  • Xiaoya Ding
  • Lijie DuanEmail author
  • Chunsheng XiaoEmail author


In this study, a pH-responsive hydrogel consisting of a 4-arm poly(ethylene glycol)-block-poly(L-glutamic acid) (4a-PEG-PLG) copolymer was developed and used for the controlled release of peptide and protein drugs. It was found that the mechanical properties and degradation processes of the hydrogels could be tuned by changing the polymer concentrations. In vitro drug release results revealed that the release of insulin (or BSA) from hydrogel was highly dependent on the pH, i.e., less than 20% of insulin (or BSA) was released in the artificial gastric fluid (AGF) at 72 h, while close to 100% of insulin (or BSA) was released in the artificial intestinal fluid (AIF). It was because that the deprotonation of carboxyl groups in PLG block caused the disassembly, and even disintegration of the hydrogel in AGF, thereby resulting in accelerated drug release. Circular dichroism spectra showed that the bioactivities of insulin and BSA released from hydrogels were obviously unchanged compared to those of native insulin and BSA, respectively. Mouse fibroblast L929 cells were cultured on the surface of hydrogels and the viabilities of cultured cells were above 90% after incubation for 24 h, indicating that the hydrogels had good cytocompatibilities. Moreover, in vivo degradation evaluation disclosed that the formed hydrogels will completely degrade after 8 days, and the H&E staining study demonstrated the excellent biocompatibility of the as-prepared hydrogels. Therefore, the biocompatible and biodegradable 4a-PEG-PLG hydrogel may serve as a promising platform for pH-responsive drug delivery.

Graphical abstract



Poly(L-glutamic acid) Hydrogel pH-responsiveness Insulin Self-assembly 



This work was financially supported by the National Natural Science Foundation of China (51520105004 and 51833010) and the Youth Innovation Promotion Association of CAS (2017266).

Supplementary material

10965_2019_1953_MOESM1_ESM.docx (275 kb)
ESM 1 (DOCX 274 kb)


  1. 1.
    Ferreira NN, Ferreira LMB, Cardoso VMO, Boni FI, Souza ALR, Gremiao MPD (2018) Recent advances in smart hydrogels for biomedical applications: from self-assembly to functional approaches. Eur Polym J 99:117–133Google Scholar
  2. 2.
    Park K, Kwon IC, Park K (2011) Oral protein delivery: current status and future prospect. React Funct Polym 71:280–287Google Scholar
  3. 3.
    Vermonden T, Censi R, Hennink WE (2012) Hydrogels for Protein Delivery. Chem Rev 112:2853–2888PubMedGoogle Scholar
  4. 4.
    Pelegri-O’Day EM, Lin EW, Maynard HD (2014) Therapeutic protein–polymer conjugates: advancing beyond PEGylation. J Am Chem Soc 136:14323–14332PubMedGoogle Scholar
  5. 5.
    Renukuntla J, Vadlapudi AD, Patel A, Boddu SHS, Mitra AK (2013) Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 447:75–93PubMedPubMedCentralGoogle Scholar
  6. 6.
    Pisal DS, Kosloski MP, Balu-Iyer SV (2010) Delivery of therapeutic proteins. J Pharm Sci 99:2557–2575PubMedPubMedCentralGoogle Scholar
  7. 7.
    Yu M, Wu J, Shi J, Farokhzad OC (2016) Nanotechnology for protein delivery: overview and perspectives. J Control Release 240:24–37PubMedGoogle Scholar
  8. 8.
    Ali I (2011) Nano anti-cancer drugs: pros and cons and future perspectives. Curr Cancer Drug Tar 11:131–134Google Scholar
  9. 9.
    Ali I, Lone MN, Suhail M, Mukhtar SD, Asnin L (2016) Advances in Nanocarriers for anticancer drugs delivery. Curr Med Chem 23:2159–2187PubMedGoogle Scholar
  10. 10.
    Caló E, Khutoryanskiy VV (2015) Biomedical applications of hydrogels: a review of patents and commercial products. Eur Polym J 65:252–267Google Scholar
  11. 11.
    Gyles DA, Castro LD, Silva JOC, Ribeiro-Costa RM (2017) A review of the designs and prominent biomedical advances of natural and synthetic hydrogel formulations. Eur Polym J 88:373–392Google Scholar
  12. 12.
    Jeong KH, Park D, Lee YC (2017) Polymer-based hydrogel scaffolds for skin tissue engineering applications: a mini-review. J Polym Res 24:112Google Scholar
  13. 13.
    Buwalda SJ, Vermonden T, Hennink WE (2017) Hydrogels for therapeutic delivery: current developments and future directions. Biomacromolecules 18:316–330PubMedGoogle Scholar
  14. 14.
    Li J, Mooney DJ (2016) Designing hydrogels for controlled drug delivery. Nat Rev Mater 1:16071PubMedPubMedCentralGoogle Scholar
  15. 15.
    Nguyen QV, Huynh DP, Park JH, Lee DS (2015) Injectable polymeric hydrogels for the delivery of therapeutic agents: a review. Eur Polym J 72:602–619Google Scholar
  16. 16.
    Alarcón CH, Pennadam S, Alexander C (2005) Stimuli responsive polymers for biomedical applications. Chem Soc Rev 34:276–285Google Scholar
  17. 17.
    Chaturvedi K, Ganguly K, Nadagouda MN, Aminabhavi TM (2013) Polymeric hydrogels for oral insulin delivery. J Control Release 165:129–138PubMedGoogle Scholar
  18. 18.
    Ding X, Wang Y, Li G, Xiao C, Chen X (2019) Iminoboronate Ester cross-linked hydrogels with injectable, self-healing and multi-responsive properties. Acta Polym Sin 50:505–515Google Scholar
  19. 19.
    Buwalda SJ, Boere KWM, Dijkstra PJ, Feijen J, Vermonden T, Hennink WE (2014) Hydrogels in a historical perspective: from simple networks to smart materials. J Control Release 190:254–273PubMedGoogle Scholar
  20. 20.
    Shafagh N, Sabzi M, Afshari MJ (2018) Development of pH-sensitive and antibacterial gelatin/citric acid/ag nanocomposite hydrogels with potential for biomedical applications. J Polym Res 25:259Google Scholar
  21. 21.
    Fan X, Wang T, Miao W (2018) The preparation of pH-sensitive hydrogel based on host-guest and electrostatic interactions and its drug release studies in vitro. J Polym Res 25:215Google Scholar
  22. 22.
    Peppas NA, Wood KM, Blanchette JO (2004) Hydrogels for oral delivery of therapeutic proteins. Expert Opin Biol Th 4:881–887Google Scholar
  23. 23.
    Lowman AM, Morishita M, Kajita M, Nagai T, Peppas NA (1999) Oral delivery of insulin using pH-responsive complexation gels. J Pharm Sci 88:933–937PubMedGoogle Scholar
  24. 24.
    Torres-Lugo M, Peppas NA (1999) Molecular design and in vitro studies of novel pH-sensitive hydrogels for the Oral delivery of calcitonin. Macromolecules 32:6646–6651Google Scholar
  25. 25.
    Nakamura K, Murray RJ, Joseph JI, Peppas NA, Morishita M, Lowman AM (2004) Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology on insulin delivery characteristics. J Control Release 95:589–599PubMedGoogle Scholar
  26. 26.
    Zhao C, Zhuang X, He P, Xiao C, He C, Sun J, Chen X, Jing X (2009) Synthesis of biodegradable thermo- and pH-responsive hydrogels for controlled dru g release. Polymer 50:4308–4316Google Scholar
  27. 27.
    Zhang Z, Chen L, Zhao C, Bai Y, Deng M, Shan H, Zhuang X, Chen X, Jing X (2011) Thermo- and pH-responsive HPC-g-AA/AA hydrogels for controlled drug delivery applications. Polymer 52:676–682Google Scholar
  28. 28.
    Zhao C, He P, Xiao C, Gao X, Zhuang X, Chen X (2012) Photo-cross-linked biodegradable thermo- and pH-responsive hydrogels for controlled drug release. J Appl Polym Sci 123(5):2923–2932Google Scholar
  29. 29.
    Yang N, Wang Y, Zhang Q, Chen L, Zhao Y (2017) γ-Polyglutamic acid mediated crosslinking PNIPAAm-based thermo/pH-responsive hydrogels for controlled drug release. Polym Degrad Stabil 144:53–61Google Scholar
  30. 30.
    Wang Y, Yang N, Wang D, He Y, Chen L, Zhao Y (2018) Poly (MAH-β-cyclodextrin-co-NIPAAm) hydrogels with drug hosting and thermo/pH-sensitive for controlled drug release. Polym Degrad and Stabil 147:123–131Google Scholar
  31. 31.
    Yu L, Ding J (2008) Injectable hydrogels as unique biomedical materials. Chem Soc Rev 37:1473–1481PubMedGoogle Scholar
  32. 32.
    Dong R, Pang Y, Su Y, Zhu X (2015) Supramolecular hydrogels: synthesis, properties and their biomedical applications. Biomater Sci 3:937–954PubMedGoogle Scholar
  33. 33.
    Chung HJ, Park TG (2009) Self-assembled and nanostructured hydrogels for drug delivery and tissue engineering. Nano Today 4:429–437Google Scholar
  34. 34.
    Yang JA, Yeom J, Hwang BW, Hoffman AS, Hahn SK (2014) In situ-forming injectable hydrogels for regenerative medicine. Prog Polym Sci 39:1973–1986Google Scholar
  35. 35.
    Kopeček J, Yang J (2012) Smart self-assembled hybrid hydrogel biomaterials. Angew Chem Int Edit 51:7396–7417Google Scholar
  36. 36.
    Radvar E, Azevedo HS (2019) Supramolecular peptide/polymer hybrid hydrogels for biomedical applications. Macrom Biosci 19:1800221Google Scholar
  37. 37.
    Clarke DE, Pashuck ET, Bertazzo S, Weaver JV, Stevens MM (2017) Self-healing, self-assembled β-sheet peptide–poly (γ-glutamic acid) hybrid hydrogels. J Am Chem Soc 139:7250–7255PubMedPubMedCentralGoogle Scholar
  38. 38.
    Gačanin J, Hedrich J, Sieste S, Glaßer G, Lieberwirth I, Schilling C, Fischer S, Barth H, Knöll B, Synatschke CV, Weil T (2019) Autonomous ultrafast self-healing hydrogels by pH-responsive functional nanofiber Gelators as cell matrices. Adv Mater 31:1805044Google Scholar
  39. 39.
    Xiao C, Zhao C, He P, Tang Z, Chen X, Jing X (2010) Facile synthesis of Glycopolypeptides by combination of ring-opening polymerization of an alkyne-substituted N-carboxyanhydride and click "glycosylation". Macromol Rapid Comm 31:991–997Google Scholar
  40. 40.
    Ding J, Shi F, Xiao C, Lin L, Chen L, He C, Zhuang X, Chen X (2011) One-step preparation of reduction-responsive poly(ethylene glycol)-poly(amino acid)s nanogels as efficient intracellular drug delivery platforms. Polym Chem 2:2857–2864Google Scholar
  41. 41.
    Liu L, Zhang Y, Yu S, Yang Z, He C, Chen X (2018) Dual stimuli-responsive nanoparticle-incorporated hydrogels as an Oral insulin carrier for intestine-targeted delivery and enhanced Paracellular permeation. Acs Biomater Sci Eng 4:2889–2902Google Scholar
  42. 42.
    Patel M, Lee HJ, Park S, Kim Y, Jeong B (2018) Injectable thermogel for 3D culture of stem cells. Biomaterials 159:91–107PubMedGoogle Scholar
  43. 43.
    Xiao C, Cheng Y, Zhang Y, Ding J, He C, Zhuang X, Chen X (2014) Side chain impacts on pH- and thermo-responsiveness of tertiary amine functionalized polypeptides. J Polym Sci Polym Chem 52:671–679Google Scholar
  44. 44.
    Donten ML, Hamm P (2013) pH-jump induced α-helix folding of poly-L-glutamic acid. Chem Phys 422:124–130Google Scholar
  45. 45.
    Lou J, Stowers R, Nam S, Xia Y, Chaudhuri O (2018) Stress relaxing hyaluronic acid-collagen hydrogels promote cell spreading, fiber remodeling, and focal adhesion formation in 3D cell culture. Biomaterials 154:213–222PubMedGoogle Scholar
  46. 46.
    Wollenberg AL, O'Shea TM, Kim JH, Czechanski A, Reinholdt LG, Sofroniew MV, Deming TJ (2018) Injectable polypeptide hydrogels via methionine modification for neural stem cell delivery. Biomaterials 178:527–545PubMedPubMedCentralGoogle Scholar
  47. 47.
    Ding X, Li G, Xiao C, Chen X (2019) Enhancing the stability of hydrogels by doubling the Schiff Base linkages. Macromol Chem Phys 220:1800484Google Scholar

Copyright information

© The Polymer Society, Taipei 2019

Authors and Affiliations

  1. 1.School of Chemistry and Life ScienceChangchun University of TechnologyChangchunChina
  2. 2.Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchunChina
  3. 3.University of Chinese Academy of SciencesBeijingChina
  4. 4.Jilin Biomedical Polymers Engineering LaboratoryChangchunChina

Personalised recommendations