Development of Novel Metal-Based Supramolecular Therapeutics for Ovarian Cancer - PROJECT SUMMARY
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.
