Development of a RNA-Guided Drug Delivery System

Abstract

By Jacob Stump, Biochemistry; David Smithrud, University of Cincinnati; Guerni Paolo, University of Cincinnati

Advisor: Pheruza Tarapore

Abstract: Prostate cancer (PCa) is the second leading cause of cancer deaths among American men. One in 9 men will be diagnosed with PCa and one in 41 men will die from it. When caught early, PCa can be treated with androgen-deprivation therapy (ADT). However, most PCa's eventually progress to being hormone/castration-resistant PCa (CRPC) and are thus unaffected by ADT. Diethylstilbestrol (DES), an agonist of the estrogen receptors was used for treatment of CRPC. Although effective in this role, the dosage size required often lead to cardiovascular issues, hence limiting its usage. We hypothesize that by specifically delivering DES to CRPC cells, we can negate the off-target toxicity and thus lower the dose of DES used for treatments. In this project, we utilize click chemistry to develop a conjugate between DES and a small RNA molecule called an aptamer. This aptamer binds specifically and tightly to prostate specific membrane antigen (PSMA), a protein overexpressed on CRPC tumors. DES-aptPSMA chimeras bind to CRPC cells rather than other cells that don't express PSMA. To determine the efficacy of the conjugate, CRPC cells were treated with increasing concentrations of either DES or DES-aptamer. We used the MTS assay, which links color change to the number of living cells. By comparing the rate of cell death at different doses between the DES with and without the conjugate, we determine the IC50 of the DES-aptPSMA and DES. Future experiments will determine the efficacy of this conjugate to decrease tumor size in animal models.