Chemoaffinity Agents For Capturing Prostate Cancer Cells

用于捕获前列腺癌细胞的化学亲和剂

基本信息

批准号：
7666023
负责人：
Clifford Berkman
金额：
$ 16.26万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7666023
关键词：
Address Affinity Antibodies Attention Avidin Be++ element Beryllium Binding Biological Assay Biological Markers Biosensing Techniques Biotin Blood Blood specimen Cancer Detection Cell Culture Techniques Cell Line Cell Surface Receptors Cell surface Cells Chemicals Chemistry Cleaved cell Core Facility Detection Development Disease Disseminated Malignant Neoplasm Dyes Elements Endothelium Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Flow Cytometry Fluorescence Microscopy Fluorescent Probes Glutamate Carboxypeptidase II Goals Image Incubated LNCaP Label Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Methodology Microscope Modality Modeling Molecular Monitor Outcome PC3 cell line Patients Polyethylene Glycols Prostatic Quantum Dots Reagent Reporter Research Risk Scheme Site Slide Solid Staging Streptavidin Structure Structure of base of prostate Technology Testing Therapeutic Therapeutic Agents Translating Universities Washington Work anticancer research base cancer cell cancer imaging clinically relevant cost experience high throughput technology in vivo inhibitor/antagonist innovation magnetic beads member nanoparticle neovasculature novel novel diagnostics pyrrolidin-3-yl-methanesulfonic acid research study scaffold small molecule success targeted delivery technology development

项目摘要

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.

描述（由申请人提供）：紧密结合小分子抑制剂对前列腺特异性膜抗原（PSMA）的抑制尚未充分用于细胞捕获和检测策略。我们的长期目标是开发一种新型高通量技术来捕获、成像和量化转移细胞，该技术利用细胞表面水解酶紧密结合抑制剂的效力和特异性亲和力。该 R21 应用的总体目标是证明 PMSA 高亲和力不可逆抑制剂可用于捕获前列腺癌细胞以进行检测和定量的概念。我们对拟议工作的中心假设是，通过可裂解接头连接到固体支持物上的 PSMA 不可逆小分子抑制剂可以选择性捕获表达 PSMA 的前列腺癌细胞以进行检测和定量。我们计划通过追求以下具体目标来测试我们的中心假设并实现我们该应用的总体目标：（1）基于 PSMA 高亲和力抑制剂的结构框架开发用于转移性前列腺癌的细胞捕获平台和（2 ）基于 PSMA 高亲和力抑制剂的核心结构，开发了一种纳米颗粒荧光探针，可选择性标记前列腺癌细胞。进行拟议研究的理由是，一旦我们证明与固体支持物相连的 PSMA 高亲和力小分子抑制剂可以选择性捕获表达 PSMA 的细胞，它将作为开发随后的 R01 提案中提出了用于转移性前列腺癌的新型诊断生物传感技术。这项工作的预期成果将是开发基于 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性癌细胞。其次，将开发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，用于荧光显微镜和流式细胞术应用。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和监测治疗。这些成就很重要，因为这项工作可以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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chemoaffinity capture of pre-targeted prostate cancer cells with magnetic beads.

DOI：
10.1002/pros.22508
发表时间：
2012-10-01
期刊：
PROSTATE
影响因子：
2.8
作者：
Wu, Lisa Y.;Liu, Tiancheng;Hopkins, Mark R.;Davis, William C.;Berkman, Clifford E.
通讯作者：
Berkman, Clifford E.

A targeted low molecular weight near-infrared fluorescent probe for prostate cancer.

DOI：
10.1016/j.bmcl.2010.09.057
发表时间：
2010-12-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Liu, Tiancheng;Wu, Lisa Y.;Hopkins, Mark R.;Choi, Joseph K.;Berkman, Clifford E.
通讯作者：
Berkman, Clifford E.

Biochemical characterization of prostate-specific membrane antigen from canine prostate carcinoma cells.

DOI：
10.1002/pros.22727
发表时间：
2014-05
期刊：
PROSTATE
影响因子：
2.8
作者：
Wu, Lisa Y.;Johnson, Jacqueline M.;Simmons, Jessica K.;Mendes, Desiree E.;Geruntho, Jonathan J.;Liu, Tiancheng;Dirksen, Wessel P.;Rosol, Thomas J.;Davis, William C.;Berkman, Clifford E.
通讯作者：
Berkman, Clifford E.

Spacer length effects on in vitro imaging and surface accessibility of fluorescent inhibitors of prostate specific membrane antigen.

间隔区长度对前列腺特异性膜抗原荧光抑制剂的体外成像和表面可及性的影响。

DOI：
10.1016/j.bmcl.2011.09.115
发表时间：
2011-12-01
期刊：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
影响因子：
2.7
作者：
Liu, Tiancheng;Nedrow-Byers, Jessie R.;Hopkins, Mark R.;Berkman, Clifford E.
通讯作者：
Berkman, Clifford E.