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.
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