Targeted Prodrug Chemotherapy for Prostate Cancer

DESCRIPTION (provided by applicant): The ultimate goal of this SBIR proposal is to develop the novel pharmaceutical prodrug: DOX-PSASP-BBN- RGD as a molecular targeting chemotherapeutic agent for the treatment for prostate cancer. Prostate cancer is the most common cancer for men worldwide. Currently, early stage prostate cancer is treated with surgery, external beam radiation or radioactive seed implants. Hormonal therapy, chemotherapy and radiation are used for the treatment of advanced disease. However, no effective treatment is available for androgen independent (AI) prostate cancers. Conventional chemotherapy is often associated with substantial toxicity, which limits its use in prostate cancer treatment. Consequently, the therapy of late-stage prostate cancer remains a challenge, and new treatment approaches are needed. Therefore, to overcome those limitations in the treatment of prostate cancer, we developed a strategy intended to selectively kill prostate cancer cells using traditional cytotoxic chemotherapeutics. We hypothesize here that a targeted chemotherapeutic prodrug derived from a BBN-RGD heterodimer can selectively and effectively deliver the cytotoxic agent with a PSA Specific Peptide(PSASP) linker to prostate cancer cells, upon cleavage of the linker, the cytotoxic agent can then be released and kill the cancer cells specifically. Thus, the new prodrug is expected to have high targeting specificity for prostate cancer thus resulting in better efficacy and lower general toxicity compared with conventional chemotherapy. The first six month phase I of this proposal will focus on developing and synthesizing the prodrugs and in vitro characterization for their receptor binding affinity, hydrophilicity and cytotoxicity. The second phase of the proposal will focus on the pharmacokinetics and pharmacodynamics of DOX-PSASP- BBN-RGD prodrugs. We will carry out clinical monitoring systems using molecular imaging for treatment efficient study. We will obtain GMP quality DOX-PSASP-BBN-RGD conjugate. We will generate and compile sufficient data and reports for preclinical safety assessment of DOX-PSASP-BBN-RGD. The innovation in this proposal is developing a novel strategy which provides exciting promise to develop efficient targeted chemotherapy products that can be applied to various types of cancers. PUBLIC HEALTH RELEVANCE: We will develop the novel prodrugs: DOX-PSASP-BBN-RGD for the targeted chemotherapy of prostate cancer. The new prodrugs have a highly potent cytotoxic agent, a heterodimer of two peptides specific for prostate cancer receptors and different cleavable linkers for targeted chemotherapy of prostate cancers. Because the prodrugs targets preferentially to specific receptors on cancer cells, we anticipated that the new prodrugs will have better efficacy and reduced peripheral toxicity. The same strategy should also be applicable to other cancer therapeutics.