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.
| Wickline, Samuel A; Neubauer, Anne M; Winter, Patrick M et al. (2007) Molecular imaging and therapy of atherosclerosis with targeted nanoparticles. J Magn Reson Imaging 25:667-80 |
| Winter, Patrick M; Cai, Kejia; Caruthers, Shelton D et al. (2007) Emerging nanomedicine opportunities with perfluorocarbon nanoparticles. Expert Rev Med Devices 4:137-45 |
| Caruthers, Shelton D; Neubauer, Anne M; Hockett, Frank D et al. (2006) In vitro demonstration using 19F magnetic resonance to augment molecular imaging with paramagnetic perfluorocarbon nanoparticles at 1.5 Tesla. Invest Radiol 41:305-12 |
| Lanza, Gregory; Winter, Patrick; Cyrus, Tillmann et al. (2006) Nanomedicine opportunities in cardiology. Ann N Y Acad Sci 1080:451-65 |
| Cyrus, Tillmann; Abendschein, Dana R; Caruthers, Shelton D et al. (2006) MR three-dimensional molecular imaging of intramural biomarkers with targeted nanoparticles. J Cardiovasc Magn Reson 8:535-41 |
| Winter, Patrick M; Cai, Kejia; Chen, Junjie et al. (2006) Targeted PARACEST nanoparticle contrast agent for the detection of fibrin. Magn Reson Med 56:1384-8 |
| Hughes, Michael S; Marsh, Jon N; Zhang, Hyuing et al. (2006) Characterization of digital waveforms using thermodynamic analogs: detection of contrast-targeted tissue in vivo. IEEE Trans Ultrason Ferroelectr Freq Control 53:1609-16 |
| Soman, Neelesh R; Marsh, Jon N; Hughes, Michael S et al. (2006) Acoustic activation of targeted liquid perfluorocarbon nanoparticles does not compromise endothelial integrity. IEEE Trans Nanobioscience 5:69-75 |
| Hughes, Michael S; Marsh, Jon N; Hall, Christopher S et al. (2005) Acoustic characterization in whole blood and plasma of site-targeted nanoparticle ultrasound contrast agent for molecular imaging. J Acoust Soc Am 117:964-72 |
| Morawski, Anne M; Winter, Patrick M; Yu, Xin et al. (2004) Quantitative ""magnetic resonance immunohistochemistry"" with ligand-targeted (19)F nanoparticles. Magn Reson Med 52:1255-62 |
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