3-in-1 Nanotherapeutic Strategies for Ovarian Cancer

Abstract

Among gynecological cancers, ovarian cancer causes the most fatalities. Currently, cisplatin is a potent chemotherapy used for treatment. However, cisplatin efficacy remains limited due to chemotherapy resistance. DNA repair and altered metabolism are two resistance mechanisms that prevent effective cytotoxicity. Olaparib and metformin have improved cisplatin sensitivity by targeting these two mechanisms, respectively. Although previous studies have demonstrated that cisplatin combined with either olaparib or metformin have shown stronger efficacy than a single drug alone, non-selective distribution causes systemic toxicity, thus preventing full benefit. In this context, cancer nanotechnology has several advantages, including targeted drug delivery. Therefore, we hypothesized that the combination of cisplatin, olaparib, and metformin encapsulated into a single nanoparticle (NP) will improve overall survival in ovarian cancer compared to free drugs in combination. We first developed cisplatin and metformin conjugates for increased encapsulation into polymeric NPs. The synergistic ratio between cisplatin, olaparib, and metformin was identified using CompuSyn and Synergy Finder software. Self-assembly PLGA-PEG NPs were synthesized, encapsulating the cisplatin polymers, olaparib, and metformin derivatives. Final NP formulations were selected based on the most optimal values in terms of size, morphology, polydispersity index, surface charge, and encapsulation efficiency. Preliminary evidence using flow cytometry and western blot analysis demonstrated the individual drug efficacy in the triple combination NP following endosomal escape in SKOV-3 cells. Initial NP cytotoxicity studies were conducted using low cisplatin concentrations given the synergistic combination with olaparib and metformin. Taken together, the results provide insight into novel nanotherapeutic strategies for improving ovarian cancer treatment.