Preparation and evaluation of reduction-responsive micelles based on disulfide-linked chondroitin sulfate A-tocopherol succinate for controlled antitumour drug release

Objectives The study was to construct reduction-responsive chondroitin sulfate A (CSA)-conjugated TOS (CST) micelles with disulfide bond linkage, which was used for controlled doxorubicin (DOX) release and improved drug efficacy in vivo. Methods CST and non-responsive CSA-conjugated TOS (CAT) were synthesized, and the chemical structure was confirmed by Fourier transform infrared (FTIR) spectroscopy, proton nuclear magnetic resonance (H-1 NMR) spectroscopy, fluorescence spectrophotometer and dynamic light scattering. Antitumour drug DOX was physically encapsulated into CST and CSA by dialysis method. Cell uptake of DOX-based formulations was investigated by confocal laser scanning microscopy. In vitro cytotoxicity was studied in A549 and AGS cells. Furthermore, antitumour activity was evaluated in A549-bearing mice. Key findings CST and CAT can form self-assembled micelles, and have low value of critical micelle concentration. Notably, DOX-containing CST (D-CST) micelles demonstrated reduction-triggered drug release in glutathione-containing media. Further, reduction-responsive uptake of D-CST was observed in A549 cells. In addition, D-CST induced stronger cytotoxicity (P < 0.05) than DOX-loaded CAT (D-CAT) against A549 and AGS cells. Moreover, D-CST exhibited significantly stronger antitumour activity in A549-bearing nude mice than doxorubicin hydrochloride and D-CAT. Conclusions The reduction-responsive CST micelles enhanced the DOX effect at tumour site and controlled drug release.

Automated summary

The reduction-responsive CST micelles can enhance the efficacy of DOX at the tumor site and control drug release. These micelles can form self-assembled micelles, with DOX-containing CST micelles showing reduction-triggered drug release in the presence of reducing agents. Furthermore, D-CST exhibited stronger cytotoxicity against A549 and AGS cells.