Imaging tumor associated fibroblast activation protein

肿瘤相关成纤维细胞激活蛋白成像

• 批准号: 7281787
• 负责人: CHING-HSUAN TUNG
• 金额: $ 37.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7281787
• 关键词: aminopeptidase; athymic mouse; bioimaging /biomedical imaging; chemical synthesis; colon neoplasms; enzyme activity; enzyme induction /repression; fibroblasts; fluorescent dye /probe; ionophores; molecular /cellular imaging; molecular probes; neoplasm /cancer diagnosis; neoplasm /cancer transplantation; peptidyl dipeptidase; technology /technique development

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop a novel fibroblast activation protein (FAP) sensing near infrared fluorescence reporter for early tumor detection and tumor classification. FAP is a cell surface antigen of reactive tumor stromal fibroblasts founded in more than 90% of epithelial carcinomas, but it is absent from epithelial carcinoma cells, normal fibroblasts, and other normal human tissue. Supporting tumor stromal fibroblasts are generally localized close to tumor vasculature, which is essential for early tumor development and growth. Thus it has been chosen as a target for monoclonal antibody based tumor therapy. FAP is not only a membrane protein but also a dipeptidyl peptidase. An imaging probe to report enzymatic activity and location of FAP could be extremely useful for early tumor detection. In this application we will develop a small molecular probe with ultra-sensitivity based on a unique class of fluorogenic chromophore that has significant changes in emission at different chemical states. Specifically, the probes emit no fluorescence in their initial intact state but become brightly fluorescent after specific proteolytic reaction. The newly developed low molecular weight, well defined fluorogenic probes are expected to have several advantages for imaging: a) fast tissue distribution allowing earlier imaging after injection, b) fast clearance allowing repeated imaging, and c) high likelihood of developing key candidates into clinically useful agents. The choice of FAP is based on its importance in tumor growth, invasion, and other processes in oncogenesis. Together with recent developments in fluorescence imaging technologies, this research is expected to ultimately result in clinical imaging agents with specificity for targeted enzymes. We believe that the developed approach can be used as a platform to design a broad spectrum of activatable molecular probes to image other amino peptidases in vivo.

描述（由申请人提供）： 这项研究的长期目标是开发一种新型的成纤维细胞激活蛋白（FAP）接近红外荧光报告基因，用于早期肿瘤检测和肿瘤分类。 FAP是在超过90％的上皮癌中成立的反应性肿瘤基质成纤维细胞的细胞表面抗原，但上皮癌细胞，正常成纤维细胞和其他正常人体组织不存在。支撑肿瘤基质成纤维细胞通常位于接近肿瘤脉管系统的附近，这对于早期肿瘤发育和生长至关重要。因此，它被选为基于单克隆抗体的肿瘤疗法的靶标。 FAP不仅是膜蛋白，而且是二肽基肽酶。报告酶活性和FAP位置的成像探针对于早期肿瘤检测可能非常有用。在此应用中，我们将根据独特的荧光发色团产生一个具有超敏率的小分子探针，该探针在不同的化学状态下具有显着变化。具体而言，探针在其初始完整状态下没有发出荧光，但是在特定的蛋白水解反应后变成明亮的荧光。新开发的低分子量，定义明确的荧光探针预计将具有成像的几个优点：a）快速组织分布允许注射后较早的成像，b）快速清除允许重复成像，c）高可能将关键候选者开发到临床上有用的药物中。 FAP的选择是基于其在肿瘤生长，侵袭和其他过程中的重要性。随着荧光成像技术的最新发展，这项研究有望最终导致具有针对性酶特异性的临床成像剂。我们认为，开发的方法可以用作平台设计一系列可激活的分子探针，以在体内成像其他氨基肽酶。