Enzymatic synthesis of poly(ω-pentadecalactone-co-butylene-co-3,3′-dithiodipropionate) copolyesters and self-assembly of the PEGylated copolymer micelles as redox-responsive nanocarriers for doxorubicin delivery

Abstract

Biodegradable copolyesters bearing disulfide functional groups in the main chain have been successfully synthesized by lipase-catalyzed copolymerization of lactone with disulfide-containing diester and diol. When poly(ethylene glycol) methyl ether (MeO-PEG-OH) was added as a chain terminating agent, the corresponding amphiphilic PEG-polyester block copolymers were formed. NMR analyses of the synthesized poly(ω-pentadecalactone-co-butylene-co-3,3′-dithiodipropionate) (PPBD) and PEG-PPBD copolymers indicate that the repeat unit distributions in PPBD chains or PPBD segments of PEG-PPBD chains are nearly statistically random. These new functional polyesters possess low toxicity and their hydrophobicity can be systematically adjusted by varying the lactone content in the polymers. In aqueous medium, the amphiphilic PEG-PPBD block copolymers self-assembled readily to form nanosized micelles that are capable of serving as efficient redox-responsive nanocarriers for anticancer drug delivery. The addition of D,L-dithiothreitol (DTT) reductant into the medium caused substantial swelling of the PEG-PPBD micelles and effectively triggered a fast drug release from the doxorubicin (DOX)-loaded micelles. Consistently, an in vitro cytotoxicity study revealed that the efficacy of DOX-loaded PEG-PPBD micelles against HepG2 cancer cells is enhanced by intracellular glutathione (GSH) after the internalization of the micelles by the cells.