Verteporfin-loaded supramolecular micelles for enhanced cisplatin-based chemotherapy via autophagy inhibition.

Abstract

Cisplatin (CDDP) is one of the most successful chemotherapeutic agents for cancer therapy. However, CDDP can activate pro-survival autophagy, which inhibits the therapeutic efficacy of CDDP. Herein, autophagy inhibitor verteporfin (VTPF) is integrated into CDDP-conjugated micelles to address this issue. The CDDP-conjugated micelles are prepared by host-guest interaction of zwitterionic poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(methacryloyloxy)ethyl adamantane-1-carboxylate) (P(MPC-co-MAd)) and CDDP conjugated β-cyclodextrin (CD-CDDP). VTPF is then physically encapsulated into the supramolecular micelles by hydrophobic interaction. Due to the zwitterionic corona of the supramolecular micelles, the micelles are stable in different media. CDDP and VTPF could be released in a reductive environment. CDDP-activated autophagy could be inhibited by VTPF, which is fully characterized by western blot, fluorescence imaging, and transmission electron microscopy (TEM). Moreover, the outstanding therapeutic efficacy of CDDP and VTPF co-loaded micelles is validated both in vitro and in vivo. This research not only provides a new strategy to fabricate CDDP delivery systems by supramolecular self-assembly, but also presents an innovative way to enhance cisplatin-based chemotherapy via autophagy inhibition.