Chemoaffinity Agents For Capturing Prostate Cancer Cells

描述(由申请人提供)：紧密结合的小分子抑制剂对前列腺特异性膜抗原(PSMA)的抑制作用尚未完全用于细胞捕获和检测策略。我们的长期目标是开发一种新的高通量技术来捕获、成像和量化转移细胞，该技术利用细胞表面水解酶的紧密结合抑制物的效力和特定亲和力。这项R21应用的总体目标是证明可以使用PMSA的高亲和力不可逆抑制剂来捕获前列腺癌细胞进行检测和量化的概念。我们对这项拟议工作的中心假设是，PSMA的不可逆转小分子抑制剂通过可切割连接到固体载体上，可以选择性地捕获表达PSMA的前列腺癌细胞，以进行检测和定量。我们计划验证我们的中心假设，并通过追求以下具体目标来实现这一应用的总体目标：(1)开发基于PSMA高亲和力抑制剂结构框架的转移性前列腺癌细胞捕获平台；(2)开发基于PSMA高亲和力抑制剂的核心结构选择性标记前列腺癌细胞的纳米荧光探针。开展这项拟议研究的基本原理是，一旦我们证明与固体载体连接的高亲和力PSMA小分子抑制剂可以选择性地捕获PSMA表达的细胞，它将作为后续R01提案中开发转移性前列腺癌诊断生物传感技术的概念验证。这项工作的预期结果将是开发基于PSMA固定化抑制剂的捕获和释放平台，因为将开发亲和元件来捕获血液中的转移癌细胞。其次，用于检测和定量选择性捕获的前列腺癌细胞的新型纳米颗粒试剂将被开发用于荧光显微镜和流式细胞术的应用。这些结果的预期积极影响是，它将最终帮助临床医生对前列腺癌进行分期，开发个性化治疗方式，并监测治疗情况。这些成就是重要的，因为这项工作允许开发临床相关的细胞选择平台，用于检测和隔离转移性前列腺癌细胞。

DESCRIPTION (provided by applicant): The inhibition of prostate-specific membrane antigen (PSMA) by tight-binding small-molecule inhibitors has not been fully exploited for cell-capture and detection strategies. Our long-term goal is to develop a novel high-throughput technology to capture, image, and quantify metastatic cells that capitalizes on the potency and specific affinity of tight-binding inhibitors for cell-surface hydrolytic enzymes. The overall objective of this R21 application is to prove the concept that high-affinity irreversible inhibitors of PMSA can be employed to capture prostate cancer cells for detection and quantification. Our central hypothesis for the proposed work is that irreversible small-molecule inhibitors of PSMA tethered to a solid support through a cleavable linker can selectively capture prostate cancer cells that express PSMA for detection and quantification. We plan to test our central hypothesis and accomplish our overall objective of this application by pursuing the following specific aims: (1) develop a cell-capture platform for metastatic prostate cancer based on the structural framework of high-affinity inhibitors of PSMA and (2) develop a nanoparticle fluorescent probe to selectively label prostate cancer cells based on the core structure of high-affinity inhibitors of PSMA. The rationale for undertaking the proposed research is that, once we demonstrate that high-affinity small-molecule inhibitors of PSMA tethered to a solid support can selectively capture PSMA-expressing cells, it will serve as a proof-of-concept for the development of novel diagnostic biosensing technology for metastatic prostate cancer in a subsequent R01 proposal. The expected outcomes of this work will be the development of catch and release platforms based on immobilized inhibitors of PSMA as affinity elements will be developed to capture metastatic cancer cells from blood. Secondly, novel nanoparticle agents for detecting and quantifying selectively captured prostate cancer cells will be developed for fluorescence microscopy and flow cytometry applications. The expected positive impact of these results is that it will ultimately assist clinicians in staging prostate cancer, developing personalized therapy modalities, and monitoring treatment. These accomplishments are important, because this work allow for the development of clinically relevant cell-selecting platforms for the detection and sequestering of metastatic prostate cancer cells.