Calcium Phosphate-cured Nanocluster of Poly(L-glutamic acid)-Cisplatin and Arsenic Trioxide for Synergistic Chemotherapy of Peritoneal Metastasis of Ovarian Cancer

Cisplatin (CDDP), as a traditional first-line chemotherapeutic drug, has been broadly used for the treatment of numerous solid cancers in the clinic. However, the treatment efficacy of CDDP is limited by a variety of issues, including enhanced efflux, increased detoxification capability, and improved ability of DNA damage repair of cancer cells. For example, the high level of intracellular glutathione (GSH) significantly decreases the cytotoxicity of CDDP through the formation of stable GS-Pt complex, which can be rapidly extracted from the tumor cells through an adenosine triphosphate-dependent glutathione S-conjugate export pump (GS-X pump). Therefore, the antitumor efficacy of CDDP can be upregulated by inhibiting the synthesis of GSH with drugs, directly depleting GSH with organic or inorganic nanoparticles, or neutralizing GSH through upregulating the level of reactive oxygens species (ROS) in the cells. Herein, the intracellular acidity-sensitive nanocluster (NCPGN-Pt+As) was developed to improve the antitumor efficacy, which was fabricated by the calcium phosphate (Ca-3(PO4)(2))-curing of CDDP-loaded poly(L-glutamic acid) nanoparticle (PGN-Pt) and arsenic trioxide (ATO). The optimal mass ratio of CDDP and ATO in NCPGN-Pt+As was determined to be 2:1 by the coefficient of drug interaction (CDI) between CDDP and ATO. NCPGN-Pt+As exhibited a nanosphere structure with a diameter of 129.8 nm. NCPGN-Pt+As showed prolonged blood circulation, evidenced by the increased half-life (t(1/2 beta)) and the area under the drug concentration-time curve (AUC(0-t)). Moreover, NCPGN-Pt+As demonstrated the reduced accumulation in the normal tissues and improved accumulation in the tumor. The intratumoral accumulations of CDDP and ATO were 5.7 and 3.9 times higher than those of the free CDDP+ATO group, respectively, which should be attributed to the enhanced permeability and retention effect. Upon entering the endosome, NCPGN-Pt+As decomposed and released PGN-Pt and ATO under the acidic conditions. CDDP was sustainedly released from PGN-Pt in the cells and maintained effective concentration. CDDP and ATO synergistically upregulated the level of intracellular ROS, which could kill tumor cells or enhance the efficacy of CDDP and synergistically inhibit peritoneal metastasis of ovarian cancer. At the same time, NCPGN-Pt+As was proved safe by the remained body weights of mice during the treatment period and normal levels of the liver- and kidney-related parameters after all treatments relative to free CDDP+ATO. Given its excellent efficacy and safety, this platform provided a uniquely effective strategy for the design of CDDP nanomedicines.