Taxanes (e.g. docetaxel) have been used to as standard treatments for androgen-independent prostate cancer. However, many patients relapse due to the development of multiple drug resistance (MDR), which results in poor prognosis. To address this challenge, we propose to develop a polymeric nanomedicine which has integrated multiple innovations in drug discovery, cancer therapy and nanotechnology-based drug delivery. First, we will use a novel microtubule inhibitor, 4-substituted methoxybenzoyl-aryl-thiazole-100 (SMART), to overcome MDR in prostate cancers. Second, multifunctional polymer-drug conjugate (PDC) micelles will be utilized to targeted deliver SMART into prostate cancers. The unique design of PDC micelles enables prostate cancer specific drug delivery through both enhanced permeability and retention (EPR) effects and active tumor targeting via tumor targeting peptides. The central hypothesis is that tumor targeting pH-responsive polymer- drug conjugate (PDC) micelles can enhance the delivery of SMART drugs into prostate cancer cells and effectively treat MDR prostate cancers by inducing cell cycle arrest and apoptosis. The following specific aims will be investigated: (1) Synthesize pH-responsive Polymer-drug Conjugate Micelles for the Delivery of SMART;(2) Prepare Targeting Peptide Decorated PDC micelles for Prostate Cancer Targeting;(3) Evaluate Anticancer Effects of SMART PDC micelles with MDR Prostate Cancer cells.
Prostate cancer is the second most common cancer affecting males in the USA. African American males, in particular, have the highest incidence for prostate cancer and are more likely to die of the disease than those of other ethnic populations in the United States. Despite a variety of current treatments, many patients relapse and develop resistant cancers. This research project will develop new polymeric nanomedicines to treat refractory prostate cancers, which, in the long term, can benefit late stage prostate cancer patients.