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Abstract
Introduction Epithelial ovarian cancer (EOC) is a lethal gynecological malignancy. Primary treatment involves platinum (Pt)/taxane-based chemotherapy. However, chemoresistance emerges in most cases, alongside significant toxicity, leading to poor prognosis. Harnessing reactive oxygen species (ROS) induction leads to cancer cell death. This study aims to develop a potent Pt-based ROS inducer to overcome drug resistance in the treatment of EOC.
Methods We synthesized a novel Pt drug, comprising a poly(amino acid)-based polymer incorporating Pt-based nanoparticles (termed: carrier-Pt). We evaluated its ROS-inducing capacity on both parental and drug-resistant EOC in vitro and assessed its therapeutic efficacy in A2780 subcutaneous and intraperitoneal tumor models, along with toxicity profiling.
Results Carrier-Pt elevated intracellular ROS levels by 5-fold in human EOC A2780 cells within 30 minutes, contrasting with minimal effects from cisplatin, docetaxel, or doxorubicin. Carrier-Pt exhibited rapid cytotoxicity (within 30 minutes), outperforming cisplatin (24 hours). Remarkably, carrier-Pt selectively targeted EOC cells with 4-5 times lower IC50compared to non-cancerous Human Ovarian Surface Epithelial (hOSE) cells. It effectively eliminated cisplatin-resistant A2780-Cis and taxanes-/anthracyclines-resistant Hey-T30 cells. Carrier-Pt also surpassed cisplatin in inhibiting tumor growth in vivo, in both subcutaneous and intraperitoneal models, even in drug-resistant model. Furthermore, carrier-Pt maintained stable body weight in the models and had no hematotoxicity, hepatotoxicity, nephrotoxicity, or cardiac toxicity.
Conclusion/Implications The novel Pt nanotherapeutic, carrier-Pt, robustly triggers intracellular ROS, eradicating both parental and therapeutic-resistant EOC tumors in vivo, while maintaining a favorable toxicity profile. Carrier-Pt presents a promising option for EOC patients resistant to current chemotherapeutics.
