Nano-assembly of ursolic acid with platinum prodrug overcomes multiple deactivation pathways in platinum-resistant ovarian cancer

Abstract

As the most common cause of gynecological cancer-related deaths worldwide, ovarian cancer requires novel therapy strategies. Pt(II)-Based antitumor drugs (e.g. cisplatin) are one of the most successful and frequently used drugs in ovarian cancer chemotherapy at present. However, drug resistance and severe side effects are the major problems in cancer treatment. Herein, the design of a reduction responsive platinum(IV) (Pt(IV))/ursolic acid (UA)/polyethylene glycol (PEG) dual prodrug amphiphile (Pt(IV)–UA–PEG) to treat cisplatin-resistant ovarian cancer is reported for the first time. Pt(IV)–UA–PEG could self-assemble into nanoparticles (Pt(IV)–UA NPs) with a fixed and precise Pt/UA ratio, and a constantly high content of drugs. Pt(IV)–UA NPs could be efficiently taken up by cisplatin-resistant ovarian cancer cells and release the drug in intracellular reductive and acidic environments. In vitro studies show that the released UA and cisplatin have different anticancer mechanisms, and their synergistic effects overcome the detoxification and anti-apoptotic mechanisms of cancer cells. Furthermore, the in vivo results indicate that Pt(IV)–UA NPs have a prolonged blood circulation time, enhanced tumor accumulation, and significantly improved antitumor efficacy in A2780/DDP tumor-bearing mice, without causing any side effects. In summary, our results demonstrate that the development of the stimuli-responsive dual prodrug amphiphile nano-assembly provides a new strategy to overcome drug resistance.