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

CRPC一流药物的靶向纳米给药系统：PK/PD评估和联合治疗

基本信息

批准号：
10676841
负责人：
Huan Xie
金额：
$ 17.05万
依托单位：
TEXAS SOUTHERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676841
关键词：
Address Adverse reactions Affinity African American African American population Agreement Androgen Antagonists Androgen Receptor Androgens Animal Model Antigen Targeting Area Award Binding Biological Availability CWR22Rv1 Caco-2 Cells Cancer Etiology Cancer Patient Cell Culture Techniques Cell model Cessation of life Characteristics Chemosensitization Clinical Data Clinical Research Clinical Trials Collaborations Combined Modality Therapy Communities Data Disease Dose Drug Delivery Systems Drug Receptors Drug Targeting Drug or chemical Tissue Distribution Environment Enzymes Evaluation FOLH1 gene Folic Acid Food Formulation Fostering Future Gene Expression Genetically Engineered Mouse Goals Hormones Incidence Institution Intestines Intravenous Investigational Drugs Investigational New Drug Application Legal patent Liposomes Magic Malignant neoplasm of prostate Marketing Mediating Medical Membrane Metabolism Minority Health Research Modeling Monitor Morphology New Drug Approvals Outcome Particle Size Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Polymers Primates Publications Race Rattus Reaction Receptor Signaling Recurrence Regimen Research Research Infrastructure Role Series Site Solid Statistical Data Interpretation Surface Tacrolimus Binding Proteins Techniques Texas Therapeutic Training United States Universities Xenograft Model Xenograft procedure absorption advanced prostate cancer antitumor effect castration resistant prostate cancer chemotherapy clinical application community engagement deprivation docetaxel drug candidate enzalutamide experimental study fighting first-in-human in vivo indexing intravenous administration lipid nanoparticle male men minority student mortality mouse model nanodrug new therapeutic target novel novel strategies novel therapeutics overexpression pharmacodynamic model pharmacokinetics and pharmacodynamics preclinical study prostate cancer cell prostate cancer cell line response standard care success synergism tacrolimus binding protein 4 targeted treatment therapeutic development tumor tumor growth tumor xenograft zeta potential

项目摘要

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.

项目概要前列腺癌 (PCa) 是美国男性癌症死亡的第二大原因，尽管最初对雄激素剥夺或抗雄激素反应良好，但在非洲裔美国男性中更为常见。服用雄激素药物后，肿瘤总是会复发并发展成致命的去势抵抗性前列腺癌（CRPC）。目前，CRPC的可用治疗方案，包括金标准化疗多西他赛，已经 52 kDa FK506 结合蛋白 (FKBP52) 是一种有前景的新型策略，但仅取得了有限的成功。 MJC13 和 GMC1 是两种特异性抑制 FKBP52- 的一流药物。德克萨斯大学埃尔帕索分校的 Cox 博士发现了 AR 信号传导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了在 CRPC 中观察到的令人兴奋的抗肿瘤功效。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）将 MJC13 和 GMC1 特异性递送至肿瘤部位，然后稳定释放药物以促进协同作用与多西紫杉醇联合治疗CRPC的效果。我们的目标是开发 MJC13 和 GMC1 的叶酸 (FA) 缀合 NDDS，用于特定肿瘤靶向、高疗效和低脱靶不良反应；进行全面的体内药代动力学和对 MJC13 和 GMC1 的最佳 NDDS 进行药效学评估以研究联合治疗；我们将使用 MJC13 和 GMC1 以及多西紫杉醇与市售抗 AR 药物恩杂鲁胺的比较。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进行这些实验是与托国立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，并将传播该项目的研究成果通过我们的社区参与核心 (CEC) 的支持，各个 TSU 社区将进一步增强。 RCMI 机构在生物医学和少数族裔健康研究领域的声誉成功执行。这项研究将为 CRPC 患者带来潜在的先进治疗。