The unifying and long-range HYPOTHESIS of this project is that imaging with novel ultrasound contrast agents can delineate selected molecular epitopes associated with angiogenesis, inflammation, and metastasis in tumors at very early stages in the process of tumor expansion (the """"""""angiogenic switch"""""""") with the use of ligand-targeted, perfluorocarbon nanoparticle emulsion contrast agents. Targeting ligands such as vascular integrin alphavbeta3 or asfa and transmembrane glycoproteins such as """"""""tissue factor"""""""" are present in early stages of angiogenic neo-vasculature that are required for tumor growth and metastases. Other epitopes such as fibrin serve as the provisional matrix of tumors and permit implantation. We have developed a liquid-perfluorocarbon nanoparticle contrast agent that serves as a targeting platform for a variety of pathologies. We propose to employ this platform to define the expression of selected molecular epitopes by conjugation of either monoclonal Ab or small molecule peptidomimetics to the nanoparticle for use as targeting ligands: Because ultrasound technology is clinically ubiquitous throughout the world, and is a comparatively cheap, portable, and straightforward imaging modality available at most medical centers, it offers an opportunity to implement clinical molecular imaging with global penetration and relevance to broad-based disease segments. Accordingly, we will define the role of targeted nanoparticles for characterizing cancer with both clinical and research (high frequency) ultrasound imagers. We will demonstrate the application of drug-carrying nanoparticles for local delivery of antiangiogenic agents that can be monitored with ultrasound imaging as a surrogate endpoint for drug delivery and efficacy. We also will develop approaches to enhance drug deposition and therapeutic efficacy from drug-carrying nanoparticles with the use of noncavitating focused ultrasound applied with commercially available imagers that also may improve diagnostic accuracy for detecting binding of targeted drug-carrying nanoparticles. We also will develop and implement new combined thermal and imaging probes (""""""""TIPS"""""""") together with ultrasound scientists at Philips Medical Systems for flexible and tunable thermal activation of certain types of nanoparticles that are more easily visualized with novel """"""""thermal flash imaging"""""""" techniques, and for focused phase conversion of targeted liquid perfluorocarbon nanoparticles for therapeutics. Finally, we will evaluate these methods and compositions in preclinical safety testing in anticipation of filing IND and 51 OK applications on new nanoparticulate agents, methods, and hardware.
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