Shear-responsive injectable supramolecular hydrogel releasing doxorubicin loaded micelles with pH-sensitivity for local tumor chemotherapy

In this study, glycol chitosan-Pluronic F127 conjugate (GC-PF127), produced by an amidation reaction between terminal-carboxylated PF127 and glycol chitosan (GC), was used to prepare doxorubicin (DOX)-loaded micelles. The DOX/GC-PF127 micelles produced at optimal conditions had sizes of about 150 nm and pH-sensitive surface charges. DOX/GC-PF127 hydrogel formed after addition of alpha-cyclodextrin into DOX/GC-PF127 micelle solution. The hydrogel had good shear-responsive, injectable and rapid recovery properties. In vitro release experiment confirmed that the hydrogel could sustainedly release DOX/GCPF127 micelles via the dissociation of the hydrogel. After peritumoral injection into H22 tumor-bearing mice, the hydrogel could greatly increase DOX accumulation in tumor tissue and synchronously avoid DOX accumulation in normal tissues including heart. At similar total DOX dose administrated, the tumors of free DOX treatment group grew slowly after thrice intravenous injections, the tumors of the micelle group did not grow after twice intravenous injections, and the tumors of the hydrogel group disappeared almost after once peritumoral injection. This study demonstrates that injectable DOX/GC-PF127 hydrogel, which can sustainedly release DOX-loaded micelles with tumor-targeting function, is a promising system for local tumor chemotherapy. (C) 2017 Elsevier B.V. All rights reserved.