Our goal in this R15 proposal is to engineer novel photoactivatable Pt(IV) metallodrugs for ovarian cancer therapy. Platinum-based metallodrugs are widely used in ovarian cancer treatment, but they have major drawbacks, including high systematic toxicity and enrichment of cancer stem cells (CSCs) that lead to chemoresistance and tumor recurrence. This R15 proposal aim to present a new approach toward overcoming such drawbacks by inventing novel photoactivatable amphiphilic Pt(IV) prodrugs (AMPLs). The central hypothesis is that the NIR-activatable, CD36 targetable AMPLs can eliminate ovarian CSCs in a safe, effective manner. This hypothesis is based on our preliminary data. At first, we discovered that AMPLs bearing a C16 hydrocarbon tail can harness CD36-depedent cell entry and mitochondrial damage to target and kill ovarian cancer cells. Secondly, we reported that the cationic AMPLs are able to eliminate ovarian CSCs via inducing mitochondrial damage. Thirdly, we engineered liposomal supramolecular nanoparticles of AMPLs that can stably circulate in blood in vivo. Finally, we have found that photoinduced electron transfer empowers rapid activation of AMPLs via conjugation with fluorophores. To test our central hypothesis, we hereby present a three-year research project composed of two specific aims.
In Aim 1, we wish to engineer and evaluate NIR-activatable AMPLs, and the hypothesis is that conjugation of AMPLs with NIR dyes enables photoactivation by NIR irradiation towards elimination of ovarian CSCs.
In Aim 2, we will validate the CD36-depedent drug accumulation and efficacy of AMPLs, and our hypothesis is that AMPLs harness CD36 to facilitate their drug accumulation to eradicate ovarian tumors. At the completion of the these specific aims, we anticipate to make two significant contributions to the field of bioinorganic chemistry and ovarian cancer therapy: First, we will deliver new knowledge about engaging photoinduced electron transfer to achieve NIR-activation of Pt(IV) prodrugs toward eliminating ovarian CSCs; Second, we will create NIR-responsive CD36-targetable platinum-based metallodrugs with high specificity and efficacy. The educational goal of this R15 proposal is to enhance undergraduate student biomedical research at Kent State University (KSU). Based on the different background of the two PIs, including bioinorganic chemistry and cancer biology, we seek to establish a multidisciplinary research program to train six undergraduate students at KSU every year.
FDA-approved platinum-based anticancer agents (cisplatin and carboplatin) are widely used in clinics for the treatment of ovarian cancer in the US and worldwide. Cancer patients using these platinum agents often develop drug resistance and are then deemed incurable. This research project aims to resolve this problem by engineering novel photoactivatable Pt(IV) metallodrugs.