Reduction-responsive Crosslinked Micellar Nanoassemblies for Tumor-targeted Drug Delivery

Purpose The purpose of the study was to devise and evaluate crosslinked nanoassemblies to achieve enhanced drug delivery to tumors. Methods A novel copolymer comprised of polyethylene glycol 5000 (PEG(114)), Vitamin E (VE) and thioctic acid (TA) with a molar ratio of PEG114:VE:TA at 1:4:4 was synthesized. The resulting PEG(114)-VE4-TA(4) copolymer self-assembled into micelles, which formed polydisulfide crosslinks catalyzed by dithiothreitol. Employing paclitaxel as a model drug, the crosslinked PEG(114)-VE4-TA(4) micelles were characterized for the physicochemical and biological properties. The pharmacokinetics and anticancer efficacy of paclitaxel-loaded crosslinked PEG(114)-VE4-TA(4) micelles were assessed in a human ovarian cancer xenograft murine model. Results The crosslinked PEG(114)-VE4-TA(4) micelles demonstrated markedly improved thermodynamic and kinetic stability. The disulfide crosslinks were responsive to the intracellular level of glutathione, which caused rapid disassembly of the micelles and accelerated drug release. Intravenous administration of paclitaxel-loaded crosslinked PEG(114)-VE4-TA(4) micelles yielded approximately 3-fold and 5-fold higher plasma concentration than the non-crosslinked micelles and Taxol (R), respectively, leading to increased drug accumulation in the tumor. Importantly, paclitaxel-loaded crosslinked micelles exerted superior tumor growth repression compared to the non-crosslinked counterparts and Taxol (R). Conclusions These results suggest that the crosslinked PEG(114)-VE4-TA(4) nanocarrier system is a promising platform for the delivery of hydrophobic anticancer agents.