Within the next decade, it is likely that imaging of human pathology will expand from traditional anatomic descriptions of the presence and extent of disease, to include the depiction of cellular and molecular constituents and mechanisms of disease and their associated pathophysiologic consequences. This competitive renewal proposal is based on our recent development of a novel site targeted nanoparticle contrast agent that is broadly applicable for ultrasonic, magnetic resonance, and nuclear imaging of molecular epitopes. Unlike a blood pool agent, a site directed contrast agent is intended to specifically enhance a pathological tissue that would otherwise be difficult to distinguish from surrounding normal tissue. Our agent is a small (-200 nanometer diameter), nongaseous, lipid-encapsulated, perfluorocarbon emulsion will be administered i.v. in a one step approach based on conjugation of a specific binding ligand to the emulsion nanoparticle (e.g., monoclonal antibody fragment, aptamer, oligopeptide). This contrast agent is modeled after an FDA approved emulsion technology that is commercially available as a blood substitute. The inherent safety of this class of agents has been proven in extensive clinical studies already published in the literature. The unifying and long-range HYPOTHESIS of this work is that targeted molecular imaging with novel contrast agents can delineate selected molecular features of atherosclerotic lesions that are important to critical for early lesion growth and late lesion rupture, which might serve to better guide therapeutic decisions to prevent untoward clinical events such as myocardial infarction and stroke. Accordingly, we seek to produce a clinically testable contrast agent characterized by: I ) flexible targeting options depending on the binding ligand selected, 2) flexible imaging choices based on contrast mechanism best suited to the pathology in question, and 3) flexible opportunities for local delivery of therapeutic agents coupled directly with imaging of actual nanoparticle deposition to ensure site specificity. The SPECIFIC AINIS are: 1) to characterize nanoparticle binding and contrast enhancement effects for ultrasound imaging; 2) to characterize clinically important features of atherosclerosis with targeted ultrasound molecular imaging; and 3) to optimize nanoparticle formulation for clinical testing. The clinical impact of this technology is expected to encompass early noninvasive detection of pathologies such as atherosclerosis, convenient longitudinal outpatient evaluation, and site-targeted delivery of therapeutics as clinically indicated.
