Nano-cocktail overcomes multidrug-resistance for ovarian cancer therapy

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 DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most common cause of cancer-related deaths in women and results in more deaths than any other cancer of the female reproductive system. The primary reasons for the high death rate of ovarian cancer are multidrug-resistance and the metastatic nature of cancer stem cells (CSCs). Since conventional anticancer drugs cannot kill drug resistant cells and eliminate CSCs, a novel effective treatment for ovarian cancer is urgently needed. The objective of this research is to develop a dual targeted nano-cocktail (DTNC) for safe and effective ovarian cancer therapy. We hypothesize that: (a) the low density combination of two targeting moieties can minimize the non-specific targeting effect while ensuring that the drug carrier will be exclusively localized in the tumor tissue and taken up by cancer cells through hetero-multivalent binding; (b) the drug combination of different anticancer mechanisms will exhibit synergistic effects and eradicate ovarian tumor. Our project has three specific aims. In Aim 1, we will explore drug combinations for optimal cancer cell proliferation inhibitory effect. Aim 2 will examine the dual-ligand targeting effect on the biodistribution of DTNC and investigate its pharmacokinetic properties. Aim 3 will evaluate the tumor growth inhibitory effect of DTNC in both subcutaneous xenograft and orthotopic intraperitoneal tumor mouse models and examine its systemic toxicity. Over the course of this 3-year project, undergraduate, graduate, and Doctor of Pharmacy students will participate in the project in various levels, from hands-on skills with state-of-arts equipment to creative thinking. Undergraduate students will be recruited from the highly selective Honors College and Biomedical Engineering program of the University of South Carolina, as well as Morris College, a Historically Black, coeducational college. Therefore, the development of DTNC will provide clinicians with a more effective tool in fighting against ovarian cancer as well as offer precious biomedical research training opportunities for students, especially underrepresented minority students.