Targeted Prodrug Chemotherapy for Prostate Cancer

描述（由申请人提供）：本SBIR申请的最终目标是开发新型药物前药：DOX-PSASP-BBN- RGD作为治疗前列腺癌的分子靶向化疗药物。前列腺癌是全世界男性最常见的癌症。目前，早期前列腺癌的治疗方法是手术、外部束辐射或放射性粒子植入。激素疗法、化学疗法和放射疗法用于晚期疾病的治疗。然而，对于雄激素非依赖性（AI）前列腺癌，目前尚无有效的治疗方法。传统的化疗通常具有很大的毒性，这限制了它在前列腺癌治疗中的应用。因此，晚期前列腺癌的治疗仍然是一个挑战，需要新的治疗方法。因此，为了克服前列腺癌治疗中的这些局限性，我们开发了一种策略，旨在使用传统的细胞毒性化疗选择性地杀死前列腺癌细胞。我们在此假设，从BBN-RGD异源二聚体衍生的靶向化疗前药可以选择性和有效地将带有PSA特异性肽（PSASP）连接体的细胞毒性药物递送到前列腺癌细胞，在连接体切割后，细胞毒性药物可以被释放并特异性杀死癌细胞。因此，与传统化疗相比，新的前药有望对前列腺癌具有较高的靶向特异性，从而获得更好的疗效和更低的总毒性。前6个月的I期将集中于开发和合成前体药物，并对其受体结合亲和力、亲水性和细胞毒性进行体外表征。该提案的第二阶段将侧重于DOX-PSASP- BBN-RGD前药的药代动力学和药效学。开展分子影像学临床监测系统的临床疗效研究。我们将获得GMP质量的DOX-PSASP-BBN-RGD偶联物。我们将为dox - pasp - bbn - rgd的临床前安全性评估生成和汇编足够的数据和报告。这项提案的创新之处在于开发一种新的策略，为开发有效的靶向化疗产品提供了令人兴奋的前景，这种化疗产品可以应用于各种类型的癌症。公共卫生相关性：我们将开发用于前列腺癌靶向化疗的新型前药：DOX-PSASP-BBN-RGD。新的前药具有一种高效的细胞毒性药物，一种由两种前列腺癌受体特异性肽组成的异源二聚体，以及用于前列腺癌靶向化疗的不同可切割连接物。由于前药优先靶向癌细胞上的特定受体，我们预计新的前药将具有更好的疗效和降低外周毒性。同样的策略也应该适用于其他癌症疗法。

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.