Stimuli-responsive shell cross-linked micelles from amphiphilic four-arm star copolymers as potential nanocarriers for 'pH/redox-triggered' anticancer drug release

A novel amphiphilic four-arm star copolymer [poly(e-caprolactone)-b-poly(poly(ethylene glycol) methyl ether methacrylate-co-p-(2-methacryloxyethoxy) benzaldehyde)]4 [4-AS-PCL-P(PEGMA-co-MAEBA)] was designed and synthesized by a combination of ring-opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). Stimuli-responsive cross-linked micelles (SCMs) were prepared by crosslinking the shell structure of the self-assembled micelles from star copolymers. The SCMs could be de-cross-linked under low pH and redox conditions. After loading with the anticancer drug camptothecin (CPT), the SCMs displayed a good stability against extensive dilution and a slow sustained drug release at pH 7.4 with 15% in 24 h, while a fast release (54%) was observed at pH 5.0 and 10 mM DTT. Confocal microscopy studies and MTT assays revealed that the CPT-loaded SCMs showed a good uptake property and a high cytotoxicity against HepG2 tumor cells. The pH/redox dual stimuli-responsive cross-linked micelles are proposed to be a highly promising platform for the intracellular delivery of insoluble chemotherapeutics for cancer therapy.