Molecular imaging of novel PARP inhibitor nanomedicine delivery

新型 PARP 抑制剂纳米药物递送的分子成像

基本信息

批准号：
10682472
负责人：
Rahul Aggarwal
金额：
$ 58.93万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-12 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682472
关键词：
Address Animal Model Biodistribution Biological Markers CT26 Cancer Model Cancer Patient Cell Line Clinical Companions Coupling DNA Damage DU145 Data Detection Development Disease Drug Combinations Drug Delivery Systems Effectiveness Extravasation FDA approved Future Goals High Pressure Liquid Chromatography Human Image Imaging Device Institutional Review Boards Investigational Drugs LAPC4 Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Mediating Metastatic Prostate Cancer Methods Modeling Mutation Neoplasm Metastasis Normal tissue morphology Outcome PC3 cell line Parents Patient Care Patient Selection Patients Permeability Pharmaceutical Preparations Phenotype Physicians Pilot Projects Play Poly(ADP-ribose) Polymerase Inhibitor Polymers Porosity Positron-Emission Tomography Pre-Clinical Model Prostate Adenocarcinoma Prostate Cancer therapy Prostatic Neoplasms Radiation Radioactivity Radioisotopes Radiolabeled Role Safety Site Solid Neoplasm Testing Therapeutic Toxic effect Tracer Transgenic Organisms Translations Vertebral column Visualization Zirconium arm castration resistant prostate cancer clinical translation cohort companion diagnostics efficacy testing experience experimental study feasibility testing image-guided drug delivery imaging agent imaging scientist improved inclusion criteria lymphatic drainage men molecular imaging mutant nanomaterials nanomedicine nanoparticle novel novel therapeutics particle patient derived xenograft model pre-clinical prostate cancer model response testing uptake translational study treatment response tumor uptake

项目摘要

PROJECT SUMMARY The goal of this proposal is to develop novel PARP inhibitor nanomedicine and a companion PET biomarker for treatment of prostate cancer. Despite recent advances, metastatic castration resistant prostate cancer remains a lethal, incurable disease with poor outcomes. Recently, PARP inhibitors have demonstrated great promise in this disease in patients bearing enabling mutations. We have developed a novel nanomedicine, star-PEG-TLZ4, with a cleavable linker which enhances delivery of talazoparib, a PARP inhibitor, to tumors while reducing potential toxicity. We have also developed a cognate molecular imaging tool, [89Zr]DFO-star-PEG-TLZ3, which enables imaging of the delivery of this nanomedicine. In this proposal, we develop [89Zr]DFO-star-PEG-TLZ3 and star-PEG-TLZ4 as novel imaging agent and drug combination in prostate cancer. The central hypothesis of this proposal is that the star-PEG backbone will enable enhanced delivery of PARP inhibitors and the imaging agent to prostate cancer, both in animal models as well as in a pilot translational study. In order to test this hypothesis, we have assembled an experienced team of chemists, imaging scientists, physicists, and physicians to evaluate this method in preclinical models and to perform initial feasibility testing in men with metastatic prostate cancer. In specific aim 1, we test the biodistribution of [89Zr]DFO-star-PEG-TLZ3 in prostate cancer preclinical models including patient derived xenografts. In specific aim 2, we test if [89Zr]DFO- star-PEG-TLZ3 can serve as a companion biomarker of star-PEG-TLZ4 mediated talazoparib delivery, and test the efficacy of star-PEG-TLZ4 in prostate cancer models bearing enabling mutations. In specific aim 3, we perform a translational study in men with prostate cancer, to determine the feasibility of star-PEG mediated drug delivery and imaging in men with that disease. These experiments will help aid the development and implementation of star-PEG mediated PARPi delivery, thereby improving patient care for men with prostate cancer.

项目概要该提案的目标是开发新型 PARP 抑制剂纳米药物和配套 PET 生物标志物治疗前列腺癌。尽管最近取得了进展，转移性去势抵抗性前列腺癌仍然存在一种致命的、无法治愈的疾病，结果不佳。最近，PARP抑制剂在以下领域显示出巨大的前景：这种疾病发生在携带有利突变的患者中。我们开发了一种新型纳米药物star-PEG-TLZ4，具有可裂解的接头，可增强 PARP 抑制剂他拉佐帕尼 (talazoparib) 向肿瘤的递送，同时减少潜在的毒性。我们还开发了同源分子成像工具 [89Zr]DFO-star-PEG-TLZ3，能够对这种纳米药物的输送进行成像。在本提案中，我们开发了 [89Zr]DFO-star-PEG-TLZ3 和 star-PEG-TLZ4作为前列腺癌的新型显像剂和药物组合。中心假设为该提案认为，星形 PEG 主链将能够增强 PARP 抑制剂的递送，并且前列腺癌显像剂，无论是在动物模型还是在试点转化研究中。为了验证这一假设，我们组建了一支经验丰富的团队，其中包括化学家、成像科学家、物理学家和医生在临床前模型中评估这种方法，并在患有转移性前列腺癌的男性。在具体目标 1 中，我们测试了 [89Zr]DFO-star-PEG-TLZ3 在前列腺癌临床前模型，包括患者来源的异种移植物。在具体目标 2 中，我们测试是否 [89Zr]DFO- 星形 PEG-TLZ3 可以作为星形 PEG-TLZ4 介导的他拉佐帕尼递送的伴随生物标志物，并进行测试 star-PEG-TLZ4 在具有突变的前列腺癌模型中的功效。在具体目标 3 中，我们对患有前列腺癌的男性进行转化研究，以确定星型 PEG 介导药物的可行性患有这种疾病的男性的分娩和成像。这些实验将有助于帮助开发和实施星型 PEG 介导的 PARPi 递送，从而改善前列腺男性患者的护理癌症。