Isoliquiritigenin-Loaded Platinum(IV) Prodrug Micelles Induce Sustained Endoplasmic Reticulum Stress for Promoting Cisplatin Chemosensitivity in Ovarian Cancer

Platinum-based chemotherapy is the cornerstone of ovarian cancer (OC) treatment. However, decrease of cellular concentration of the drug, glutathione (GSH)-mediated drug inactivation, and severe toxic side effects contribute to its clinical chemotherapy failure. Cisplatin has the ability to induce endoplasmic reticulum stress (ERS) production in OC, and sustained ERS can potentiate the cytotoxic effects of chemotherapy. Herein, platinum(IV) prodrug nanoparticles (IPD NPs) are prepared as nanocarriers of isoliquiritigenin (ISL, traditional Chinese medicine) with redox-responsive degradation properties and synergistic ERS amplification for enhanced OC treatment. Notably, IPD NPs contain docosahexaenoic acid (DHA) which enhanced cellular uptake as well as generated reactive oxygen species (ROS), thereby breaking redox homeostasis and further augmenting the effect of ERS. This current strategy of sustained ERS amplification for enhanced cisplatin-based chemotherapy overcomes the low cellular uptake, GSH-mediated drug detoxification, avoids the dose-dependent nephrotoxicity of cisplatin, and is promising for OC treatment.