Folate-conjugated crosslinked biodegradable micelles for receptor-mediated delivery of paclitaxel

Abstract

The poor stability of micellar drug delivery systems in vivo due to large volume dilution and interactions with blood pool often leads to premature drug release with low targetability and therapeutic efficacy. Here, we designed folate-conjugated interfacially crosslinked biodegradable micelles consisting of poly(ethylene glycol)-b-poly(acryloyl carbonate)-b-poly(D,L-lactide) (PEG-PAC-PLA) and folate-PEG-PLA (FA-PEG-PLA) block copolymers for receptor-mediated delivery of paclitaxel (PTX) into KB cells. Micelles with varying amounts of folate ligands were prepared at 0–20 wt.% of FA-PEG-PLA. The resulting micelles, either with or without PTX loading, were readily crosslinked by UV irradiation. The crosslinked micelles had much smaller sizes and better stability as compared to the non-crosslinked controls. Notably, these micelles achieved high drug loading efficiencies of 70–88% at an initial PTX loading content of 10 wt.%. The in vitro release studies revealed that crosslinked micelles exhibited significantly inhibited PTX release at low micelle concentrations. MTT assays in KB cells showed that the crosslinked micelles were non-toxic while the toxicity of PTX-loaded micelles, either crosslinked or non-crosslinked, increased with increasing folate contents. Remarkably, at 12 h incubation time folate-decorated PTX-loaded crosslinked micelles composed of 20 wt.% of FA-PEG-PLA displayed markedly higher toxicity to KB cells than free PTX (33% versus 50% cell viability), which is most likely due to their much more efficient cellular uptake through FA receptor-mediated endocytosis. Flow cytometry studies showed that folate-decorated FITC-labeled crosslinked micelles were much more efficiently taken up by KB cells than controls without folate ligands. These results indicate that ligand-conjugated interfacially crosslinked PEG-PLA micelles have great potential in targeted cancer therapy.