Reduction-triggered release of paclitaxel from in situ formed biodegradable core-cross-linked micelles

Paclitaxel-loaded reduction-responsive core-crosslinked micelles were prepared in situ in aqueous media via"click" chemistry. An amphiphilic block copolymer with multiple pendant azide groups was first synthesized through the controlled ring-opening copolymerization of ε-caprolactone (CL) and 5,5-dibromomethyl trimethylene carbonate (DBTC) in the presence of methoxy poly(ethylene glycol) (mPEG) as a macroinitiator, followed by azidation. This amphiphilic block copolymer could self-assemble into micelles and paclitaxel (PTX) could be encapsulated into the micellar core to form PTX-loaded micelles, which were core-crosslinked in situ by propargyl dithiopropionate via"click" chemistry, to develop a reduction-responsive polymeric drug delivery system. The in vitro release studies revealed the minimized release of PTX under physiological conditions, whereas a burst release of PTX was observed in response to reductive conditions. The core-crosslinked micelles displayed efficient cell-uptake and reduction-responsive drug release due to the nanoscale diameter and splitting of disulfide bonds under a reductive environment, which was confirmed by confocal laser scanning microscopy using Nile red as a fluorescent probe. This kind of polymeric nano-carrier with excellent biocompatibility and quick reduction-response opens a new avenue to intracellular anticancer drug delivery.