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：
10271287
负责人：
Huan Xie
金额：
$ 22.41万
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/10271287
关键词：
Address Adverse reactions Affinity African American 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 Gold Hormones Incidence Institution Intestines Intravenous Investigational Drugs Investigational New Drug Application Legal patent Liposomes Magic Malignant neoplasm of prostate Mediating Medical Membrane Metabolism Modeling Monitor Morphology Nanoconjugate New Drug Approvals Outcome Particle Size Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Polymers Primates Publications Race Rattus Reaction Receptor Signaling 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 base castration resistant prostate cancer chemotherapy clinical application community engagement deprivation docetaxel drug candidate experimental study fight against fighting first-in-human in vivo indexing lipid nanoparticle male men minority health minority student mortality mouse model nanodrug new therapeutic target novel novel strategies novel therapeutics overexpression pharmacodynamic model pharmacokinetic 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

Address Adverse reactions Affinity African American 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 Gold Hormones Incidence Institution Intestines Intravenous Investigational Drugs Investigational New Drug Application Legal patent Liposomes Magic Malignant neoplasm of prostate Mediating Medical Membrane Metabolism Modeling Monitor Morphology Nanoconjugate New Drug Approvals Outcome Particle Size Pathway interactions Patients Perfusion Pharmaceutical Preparations Pharmacologic Substance Polymers Primates Publications Race Rattus Reaction Receptor Signaling 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 base castration resistant prostate cancer chemotherapy clinical application community engagement deprivation docetaxel drug candidate experimental study fight against fighting first-in-human in vivo indexing lipid nanoparticle male men minority health minority student mortality mouse model nanodrug new therapeutic target novel novel strategies novel therapeutics overexpression pharmacodynamic model pharmacokinetic 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

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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.

项目摘要前列腺癌（PCA）是美国男性癌症死亡的第二大原因，这是在非洲裔美国男性中更常见。尽管最初对雄激素剥夺或抗 - 雄激素药物，肿瘤总是会复发并发展为致命的cast割前列腺癌（CRPC）。目前，CRPC的可用治疗选择，包括金标准化学疗法多西他赛，具有只有有限的成功。 52 kDa FK506结合蛋白（FKBP52）是新颖的有前途的策略有针对性的治疗发展。 MJC13和GMC1，两种一流的药物，专门抑制FKBP52- Cox博士在德克萨斯大学El Paso和由德克萨斯州南部大学的Xie博士进一步开发。 CRPC中观察到的令人兴奋的抗肿瘤效率异种移植动物模型鼓励我们进一步开发新的靶向纳米药物输送系统（NDDS）专门将MJC13和GMC1传递到肿瘤部位，然后稳步释放该药物以促进协同作用多西他赛的效果以治疗CRPC。我们的目的是开发MJC13和GMC1的叶酸（FA）偶联的NDD，用于特定的肿瘤靶向效率和低目标不良反应；进行全面的体内药代动力学和对MJC13和GMC1的最佳NDD的药物学评估；调查组合疗法与销售的抗AR药物Enzalutamide相比，MJC13和GMC1和多西他赛的摄入量。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进行这些实验与TSU和其他机构的专家合作。该项目将寻求CBMHR行政核心的支持和评估，将大力利用研究基础设施核心进行研究，并将通过该项目传播该项目的研究结果通过我们社区参与核心（CEC）的支持，各种TSU社区。它将进一步增强 RCMI机构在生物医学和少数民族健康研究领域的声望。成功执行这项研究将导致CRPC患者的潜在晚期治疗。