A foremost problem in ovarian cancer therapy is that conventional platinum-based metallodrugs promote cancer relapse via enriching cancer stem cells (CSCs). In this study, we present the first platinum-based anticancer agent that can target and eliminate ovarian CSCs. Oxidative phosphorylation in mitochondria has been recognized as the preferred energy production process in ovarian CSCs, and therefore, we synthesized cationic lipophilic Pt(IV) prodrugs to target mitochondria toward eradicating ovarian CSCs. Biological studies were completed to confirm the prodrug’s effect on ovarian CSCs compared to cisplatin. To examine drug efficacy, cytotoxicity profiles were evaluated by MTT assay across a variety of cancerous and noncancerous cell lines. Mitochondrial platinum uptake was measured, and fluorescent imaging was completed to confirm mitochondrial localization of a Pt(IV) prodrug labelled with rhodamine. Flow cytometric analysis was utilized to assess mitochondrial damage by production of superoxide and loss of mitochondrial membrane potential using MitoSOX and MitoStatus TMRE, respectively. Upon confirming mitochondrial damage, CSC populations were treated with Pt(IV) prodrug and evaluated by tumor sphere formation and flow cytometric analysis of CSC biomarkers, CD44, CD117, and CD133, showing the ability of the prodrug to eradicate CSCs. Lastly, <i>in vivo</i> efficacy was measured using a SKOV3 xenograft model. Treatment with the prodrug showed lowered systemic toxicity and increased drug efficacy when compared to cisplatin by measuring tumor volume and body weight. By successfully eliminating CSCs, these prodrugs serve as an effective method to eliminate ovarian CSCs in a selective manner. Treatment with these platinum-based anticancer agents could have future potential in eliminating chemoresistance and relapse in ovarian cancer.

Development of new platinum-based anticancer agents targeting ovarian cancer stem cells

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.