Solid tumor growth in-vivo beyond 1-2 mm in diameter is associated with angiogenesis (the formation of new blood vessels), and overexpression of the alphavbeta3 integrin facilitates angiogenesis. This integrin, which acts as a """"""""grappling hook"""""""" to mediate adhesion of angiogenic cells in developing vasculature, is highly expressed on metastatic tumors and endothelial cells during neovascularization. In addition, the expression of alphavbeta3has been shown to correlate with tumor grade. These properties make the alphavbeta3 integrin an ideal target for imaging strategies that seek to identify neoplasms. With recent advances in molecular science, the opportunity arises to design """"""""smart"""""""" contrast agents, which would allow enhanced detection of cancer, thrombus, or inflammatory response. These novel targeted contrast agents are unique because they are minimally-invasive, and specific for a selected adhesion mechanism. The combined tools and experience of the University of California, Davis, and ImaRx Therapeutics provide a unique opportunity to develop targeted contrast agents for the detection of tumors using ultrasound. Ultrasound contrast agents, which are encapsulated microbubbles, have demonstrated effectiveness in cardiology and radiology applications. ImaRx has designed an FDA-approved ultrasound contrast agent consisting of a phospholipid-shell encapsulating a perfluorocarbon gas core. This agent can be targeted to the alphavbeta3 integrin with a high avidity and selectivity by incorporating a cyclic peptide ligand containing the Arg-Gly-Asp sequence, also known as RGD, into the microbubble shell. The Principal Investigator and collaborators have completed extensive studies of adhesion receptor funtion, tumor cell biology, the manufacture of ultrasound contrast agents and bioconjugates, and physical and acoustical analysis of ultrasound contrast agents, and therefore present an ideal research group for the proposed studies. We propose to design and optimize an RGD-targeted ultrasound contrast agent for tumor detection by characterizing adhesion efficiency as a function of cyclic peptide conformation and determining optimal acoustic parameters for detection of the agent. Cone-plate viscometry in conjunction with Fluorescence-Activated Cell Sorting and parallel-plate flow chamber analysis will be used to determine adhesion avidity between the targeted contrast agent and tumor cells expressing alphavbeta3. Optical and acoustical studies of targeted contrast agents during insonation using ultra-high speed video analysis and acoustic backscatter measurements will be used to determine the echo signature and optimal imaging parameters for targeted contrast agents. Finally, the effect of contrast agent localization due to acoustic radiation force will be studied on targeting efficiency.
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