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，利用细胞表面水解酶紧密结合抑制剂的效力和特异性亲和力。本R21应用的总体目标是证明PMSA的高亲和力不可逆抑制剂可用于捕获前列腺癌细胞进行检测和定量的概念。我们提出的工作的中心假设是，不可逆的PSMA小分子抑制剂通过可切割的连接物连接到固体载体上，可以选择性地捕获表达PSMA的前列腺癌细胞进行检测和定量。我们计划通过以下具体目标来验证我们的中心假设并实现本应用的总体目标：(1)基于PSMA高亲和力抑制剂的结构框架开发转移性前列腺癌的细胞捕获平台；(2)基于PSMA高亲和力抑制剂的核心结构开发纳米颗粒荧光探针，选择性标记前列腺癌细胞。开展这项研究的基本原理是，一旦我们证明附着在固体载体上的高亲和力PSMA小分子抑制剂可以选择性地捕获表达PSMA的细胞，它将在随后的R01提案中作为开发转移性前列腺癌新型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固定化PSMA抑制剂作为亲和元件的捕获和释放平台，以捕获血液中的转移性癌细胞。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。预期这些结果的积极影响是，它将最终帮助临床医生分期前列腺癌，发展个性化的治疗方式，并监测治疗。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.