A Polymeric Nanoparticle to Co-Deliver Mitochondria-Targeting Peptides and Pt(IV) Prodrug: Toward High Loading Efficiency and Combination Efficacy.

Abstract

Developing combination chemotherapy systems with high drug loading efficiency at predetermined drug ratios to achieve a synergistic effect is important for cancer therapy. Herein, a polymeric dual-drug nanoparticle composed of a Pt(IV) prodrug derived from oxaliplatin and a mitochondria-targeting cytotoxic peptide is constructed through emulsion interfacial polymerization, which processes high drug loading efficiency and high biocompatibility. The depolymerization of polymeric dual-drug nanoparticle and the activation of Pt prodrug can be effectively triggered by the acidic tumor environment extracellularly and the high levels of glutathione intracellularly in cancer cells, respectively. The utilization of mitochondria-targeting peptide can inhibit ATP-dependent processes including drug efflux and DNA damage repair. This leads to increased accumulation of Pt-drugs within cancer cells. Eventually, the polymeric dual-drug nanoparticle demonstrates appreciable antitumor effects on both cell line derived and patient derived xenograft lung cancer model. It is highly anticipated that the polymeric dual-or multi-drug systems can be applied for combination chemotherapy to achieve enhanced anticancer activity and reduced side effects.