Tissue-Specific Optical Imaging Agents and Methods

Washington University, Saint Louis MO

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Abstract

Accurate and rapid detection of tumors results in good patient prognosis. An important step towards achieving this goal begins with the early diagnosis of cancer by molecular imaging of aberrant genes of proteins in tumors. Although nuclear methods are conventionally used for molecular imaging of pathologic conditions, the emerging field of optical imaging provides distinctly new diagnostic capabilities while complementing established imaging modalities. Optical imaging in the near infrared wavelengths can be used to evaluate superficial lesions, endoscope-accessible deep organs, surgical exposed tissues and deep tissues within several centimeters from the skin. We propose to develop novel optical imaging agents that will enhance tumor visualization in vivo based on the hypothesis that small peptide-based receptor-specific optical imaging agents will selectively and rapidly accumulate in the target receptor-positive tumors relative to surrounding normal tissues, and the resultant fluorescence intensity in vivo will correlate with the relative expression of the targeted receptor proteins in tumor cell membranes. To test this hypothesis and to accelerate the applications of optical imaging agents in translational research and eventually in clinical settings, we will target somatostatin receptor subtype 2 (STR2) that has been shown to be clinically valuable by nuclear methods. Accordingly, we will design and synthesize novel tumor-specific optical molecular probes that are useful for imaging a variety of tumors and other human diseases. The methods of molecular modeling and 2D NMR will be used to optimize the selectivity and binding affinity of the molecules for STR2. We will evaluate the receptor binding affinity, cytotoxicity, receptor-mediated internalization, and subcellular distribution of the probes to select promising candidates for in vivo studies. The biodistribution and planar optical imaging of tumor xenografts will be performed by optical methods to determine the specificity and sensitivity of STR2-mediated optical imaging of pathologic conditions. The optical images will be validated by histology. We anticipate identifying at least one optical molecular probe for translational research. Results of this study will provide a technology platform for developing other disease-specific optical molecular probes. Products of this study will also be made available to other investigators interested in molecular-probe- mediated optical imaging and related medical/pharmaceutical applications.