Dual Stable Nanomedicines Prepared by Cisplatin-Crosslinked Camptothecin Prodrug Micelles for Effective Drug Delivery.

Abstract

A polymer micelle-based drug delivery system has faced many challenges due to the lack of stability especially after being diluted in blood, resulting in a premature release. Herein, we developed camptothecin (CPT)-conjugated prodrug (CPTP) micelles in which CPT was grafted to the poly(ethylene glycol)-poly(glutamic acid) block copolymer via a disulfide bond linker for a redox-triggered drug release. Then, the cisplatin (CDDP)-crosslinked CPT-prodrug micelles (CPTP/CDDP) with a hybrid complex as a stable structure were successfully established via the CDDP (Pt)-carboxyl (COOH) chelate interaction. The resulting dual CPTP/CDDP had an average hydrodynamic radius of about 50 nm with a narrow distribution, which was conducive to the promotion of solid tumor accumulation. Importantly, CPT chemical bonding to the polymer backbone obviously stabilizes the CPT-prodrug micelles and prolongs their circulation time. Moreover, both CPT and CDDP are clinically used antitumor drugs; CDDP not only behaves as an ancillary anticarcinogen but also serves as a crosslinker to restrain the untimely burst release of CPT and to achieve synergistic antitumor efficacy. In addition, the CPTP/CDDP also exhibited a sustained reduction responsive release of CPT accompanied by the dissociation of the CDDP-COOH complex. This design ingeniously solved the contradiction between the stability and release of polymer micelle-based nanomedicines. Both in vitro and in vivo tests demonstrated an amazing antineoplastic efficacy compared with free drugs (CPT or CDDP) and just their physical mixing, indicating great promise for cancer treatment.