Redox-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-lactic acid) for intracellular drug delivery

Redox-responsive micelles self-assembled from triblock copolymers of poly(l-lactic acid)-poly(ethylene glycol)-poly(l-lactic acid) (PLA-PEG-PLA) with double-disulfide linkage in the backbone were synthesized and characterized by proton nuclear magnetic resonance (¹H NMR) and size exclusion chromatography (SEC), in which both PEG (M_n = 1000, 2000 and 4000 g mol^-1) and PLA (M_n = 1600 g mol^-1) have different molecular weights respectively. The triblock copolymers PLA₃₀₀₀-PEG₂₀₀₀-PLA₃₀₀₀ and PLA₃₀₀₀-PEG₄₀₀₀-PLA₃₀₀₀ can self-assemble into flower-like micelles in aqueous media with average diameters 110 nm and 43 nm and lower critical micelle concentrations (CMC) 0.017 and 0.014 mg mL^-1 respectively compared with that of diblock copolymers. Moreover, in vitro drug release analyses indicated that reductive environment can result in triggered drug release profiles. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl- 2-H-tetrazolium bromide (MTT) assay in vitro showed no significant cytotoxicity as NIH 3T3 cells incubated in the micelles even when the concentrations up to 1000 μg/mL. Additionally fluorescence microscopy measurements and MTT assay demonstrated that the micelles exhibited a faster drug release and higher cellular proliferation inhibition due to the effect of intracellular reduction responsiveness compared with that of diblock copolymers. The above results suggest that the reduction-responsive, biodegradable and biocompatibility micelles could provide a platform to construct potential drug delivery systems for cancer therapy.