Reduction-responsive shell cross-linked micelles derived from amphiphilic triblock copolymer as anticancer drug delivery carrier

Abstract

Stimuli-responsive crosslinked micelles are attractive carriers for in vivo delivery of water-insoluble therapeutic drugs due to their excellent stability during the blood circulation and high therapeutic effect resulting from the intelligent break-up of the crosslinked structure triggered by intracellular conditions as well as the subsequent fast drug release. Herein, novel amphiphilic triblock copolymer poly(l-lactide)-b-poly(allyl glycidyl ether/propanedithiol)-b-poly(ethylene glycol) (PLLA-b-P(AGE-SH)-b-PEG) was designed and synthesized by combining two successive ring-opening polymerizations and subsequent “thio-ene” reaction. Due to their unique amphiphilic architecture, copolymer PLLA-b-P(AGE-SH)-b-PEG could self-assemble into core-shell micelles, and the stimuli-responsive crosslinked micelles (SCMs) were obtained by crosslinking the P(AGE-SH) segments in the micellar shell under redox condition. The SCMs exhibited good stability against extensive dilution and slow sustained drug release in a simulated normal physiologycal environment, but fast release in the presence of GSH. As revealed by the cytotoxicity assay, the micelles from the copolymer PLLA-b-P(AGE-SH)-b-PEG showed excellent biocompatibility against HEK293T cells. Due to these combined good properties, the stimuli-responsive crosslinked micelles from PLLA-b-P(AGE-SH)-b-PEG are proposed to be an ideal carrier for the in vivo delivery of water-insoluble therapeutics.