PH-responsive Hydrogels Based On Short Peptides Assembly For The Controlled Release Of Insulin

Peptide and protein therapeutics are appealing and acceptable options for the treatment of various diseases,such as diabetes and rheumatoid arthritis,owing to their high efficacy and selectivity.However,being biomolecules,peptide and protein drugs are usually susceptible to proteolytic degradation,elimination by the immune system or physical-chemical denaturing.Especially,oral administration of peptide and protein drugs has been a long-lasting challenge due to the possible destabilization of drugs by the high proteolytic activity and ultralow pH in stomach.To address the above-mentioned problems,a number of efforts have been devoted to the development of drug delivery systems for protecting the bioactivity and controlled release of peptide and protein drugs.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 amount of insulin(or BSA)was released in the artificial gastric fluid(AGF),while quicker release of insulin(or BSA)occurred 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 cultured cells were viable 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.