Targeted Nano-drug-delivery-systems of Frist-in-class Drugs for CRPC: PK/PD Evaluation and Combination Therapy

项目摘要 前列腺癌（PCa）是美国男性癌症死亡的第二大原因， 多见于非裔美国男性尽管雄激素剥夺或抗- 雄激素药物，肿瘤总是复发，并发展成致命的去势抵抗性前列腺癌（CRPC）。 目前，CRPC的可用治疗选择，包括金标准化疗多西他赛， 只取得了有限的成功。52 kDa FK 506结合蛋白（FKBP 52）是一种有前途的新的治疗策略。 有针对性的治疗发展。MJC 13和GMC 1，两种一流的药物，特异性抑制FKBP 52- 德克萨斯大学埃尔帕索分校的考克斯博士已经发现了AR信号的介导增强作用， 由德克萨斯南方大学的谢博士进一步开发。在CRPC中观察到的令人兴奋的抗肿瘤疗效 异种移植动物模型鼓励我们进一步开发新型靶向纳米药物递送系统（NDDS） 特异性地将MJC 13和GMC 1递送到肿瘤部位，然后稳定地释放药物以促进协同作用。 多西他赛治疗CRPC疗效观察 我们的目标是开发叶酸（FA）缀合的MJC 13和GMC 1的NDDS，用于特异性肿瘤靶向， 有效性和低脱靶不良反应;进行全面的体内药代动力学和 对MJC 13和GMC 1的最佳NDDS进行药效学评价;研究联合治疗 MJC 13和GMC 1和多西他赛与市售抗AR药物enzalutamide相比的差异。我们将使用 各种技术、大鼠、肿瘤异种移植小鼠模型和基因工程小鼠模型来进行 这些实验是与大津和其他机构的专家合作进行的。 该项目将寻求CBMHR行政核心的支持和评估，将大量利用 研究基础设施核心进行研究，并将传播本项目的研究成果， 通过我们的社区参与核心（CEC）的支持，支持各种大津TSU社区。将进一步提升 RCMI机构在生物医学和少数民族健康研究领域的声望。的成功执行 这项研究将为CRPC患者带来潜在的先进治疗。

PROJECT SUMMARY Prostate cancer (PCa) is the second leading cause of cancer death in the United States among men and it is more common in African American males. Despite initial good responses to androgen deprivation or anti- androgen drugs, tumors invariably recur and develop into lethal castration resistant prostate cancer (CRPC). Currently, the available therapeutic options for CRPC, including the gold standard chemotherapy docetaxel, have only met with limited success. The 52 kDa FK506 binding protein (FKBP52) is a promising strategy for novel targeted therapeutic development. MJC13 and GMC1, two first-in-class drugs that specifically inhibit FKBP52- mediated potentiation of AR signaling, have been discovered by Dr. Cox at University of Texas at El Paso and further developed by Dr. Xie at Texas Southern University. The exciting anti-tumor efficacy observed in CRPC xenograft animal models encourage us to further develop novel targeted nano-drug delivery systems (NDDS) that specifically deliver MJC13 and GMC1 to the tumor site then steadily release the drug to facilitate synergistic effect with docetaxel to treat CRPC. Our aims are to develop folic acid (FA)-conjugated NDDS of MJC13 and GMC1 for specific tumor targeting, high efficacy and low off-target adverse reactions; to perform comprehensive in vivo pharmacokinetic and pharmacodynamic evaluations on the optimal NDDS of MJC13 and GMC1; to investigate combination therapy of MJC13 and GMC1 and docetaxel in comparison to the marketed anti-AR drug enzalutamide. We will use various techniques, rats, tumor xenograft mouse models and genetically engineered mouse models to conduct those experiments in collaboration with experts at TSU and other institutions. This project will seek support and evaluation from the CBMHR Administrative Core, will heavily utilize the Research Infrastructure Core to perform studies, and will disseminate the research findings from this project with various TSU communities via support from our Community Engagement Core (CEC). It will further enhance RCMI institutions’ prestige in the areas of biomedical and minority health research. The successful execution of this research will result potential advanced treatment for CRPC patients.