Molecular imaging of novel PARP inhibitor nanomedicine delivery

项目总结 该方案的目标是开发新型的PARP抑制剂纳米药物和与之配套的PET生物标记物 前列腺癌的治疗。尽管最近取得了进展，但转移性去势抵抗前列腺癌仍然存在 一种致命的、无法治愈的疾病，结果很差。最近，PARP抑制剂在治疗中显示出巨大的前景 这种疾病的患者携带使能突变。我们开发了一种新型纳米药物，STAR-PEG-TLZ4， 使用可切割的连接体，可增强PARP抑制剂他拉唑巴利对肿瘤的输送，同时减少 潜在的毒性。我们还开发了一种同源分子成像工具[89Zr]DFO-STAR-PEG-TLZ3，它 能够对这种纳米药物的输送进行成像。在本方案中，我们开发了[89Zr]DFO-STAR-PEGTLZ3和 Star-PEG-TLZ4作为前列腺癌新型显像剂及其药物组合的研究的中心假说 这项提议是，STAR-PEG主干将能够增强PARP抑制剂和 前列腺癌的显像剂，在动物模型和先导性翻译研究中都是如此。 为了验证这一假设，我们组建了一支经验丰富的化学家、成像科学家、 物理学家和内科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。在特定的目标1中，我们测试了[89Zr]DFO-STAR-PEGTLZ3在体内的生物分布 前列腺癌临床前模型，包括患者来源的异种移植。在特定的目标2中，我们测试了[89Zr]DFO- StAR-PEG-TLZ3可作为StAR-PEG-TLZ4介导的他唑普利给药的伴生物标志物 STAR-PEG-TLZ4对携带使能突变的前列腺癌模型的疗效。在具体目标3中，我们 在患有前列腺癌的男性患者中进行翻译研究，以确定星形聚乙二醇介导物的可行性 对患有这种疾病的男性进行分娩和成像。这些实验将有助于开发和 实施STAR-PEG介导的PARPI传递，从而改善对前列腺癌患者的护理 癌症。

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.