As a systemic disease of the vessel wall, atherosclerosis occurs in carotid, coronary and peripheral arteries, and has contributes to significant morbidity and mortality in the adult population. Recent advances in basic sciences have established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, to the development of thrombosis. These new findings provide important links between risk factors and the mechanisms of atherosclerosis. Elevation in markers of inflammation predicts adverse outcomes in subjects with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the adhesion molecule ICAM-1, among others, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. While current molecular imaging systems such as PET/CT, MRI, and contrast-enhanced ultrasound imaging using microbubbles have been applied to cardiovascular atherosclerosis imaging with limited success, an imaging technique based on photoacoustics can be of exceptional value for inflammation detection. An ultrasound array transducer in combination with a commercial ultrasound imaging system can be used to record a photoacoustic signal. The identical beam forming technique for classical ultrasound imaging can be used except that the temporal compression of the sequences by a factor of two for the laser-induced case to fit the half acoustic traveling distance. This imaging system is perfectly fit both to the small animal experiments and clinical setting. The contrast of a photoacoustic image can be enhanced using external agents of high optical absorption selectively bound to a tissue of interest or specific cell type. Gold nanorods have an exceptional optical absorption and high selectivity of wavelength depending on their aspect ratio. Gold nanoparticles conjugated with an antibody have been used to enhance optical absorption (and photoacoustic signals) in targeted cancer tissue and provide high contrast for non-invasive cancer imaging. Conventional ultrasound scanner in combination with a laser will provide real-time high-sensitive and high-resolution photoacoustic imaging of gold nanoparticles bound to the specific vascular inflammatory biomarkers in vivo. The fundamental hypotheses of this proposal are: 1.Bio-conjugated gold nanorods can be used as selectively labeled contrast agent for photoacoustic molecular imaging (PMI) on inflammation;2.PMI using bio- conjugated gold nanorods can be used to non-invasively detect and monitor highly localized functional activity of the cardiovascular inflammation in rodents, and is readily translatable into a clinical diagnostic tool. Therefore, the two specific aims of this application are: 1. To develop bio-conjugated gold nanorods with high sensitivity and selectivity as inflammation biomarker-targeted contrast agent for PMI;2. To determine whether PMI is able to detect cardiovascular inflammation in vitro and in vivo.
Cardiovascular disease is the leading cause of death in the industrialized world, which results in about 1 million deaths in the US each year. Atherosclerotic plaques, most dangerous form of cardiovascular disease, often become unstable (vulnerable plaques) and rupture, releasing thrombogenic material to form blood clots totally blocking blood flow in the artery, causing the majority of heart attacks and strokes and hence are extremely important to clinicians. Recent findings in basic sciences provide important links between risk factors and the mechanisms of atherosclerosis by establishing a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, to the development of thrombosis. While current molecular imaging systems such as PET/CT, MRI, and contrast-enhanced ultrasound imaging using microbubbles have been applied to cardiovascular atherosclerosis imaging with limited success, an imaging technique based on photoacoustics can be of remarkable value for inflammation detection. A commercial ultrasound imaging system in combination with a laser system can be used to record a photoacoustic signal with exceptionally enhanced image contrast using gold nanorods (GNR) as external agents selectively bound to a tissue of interest or specific cell type, for example, inflamed cells. This imaging system is perfectly fit both to the small animal experiments and clinical setting. Gold nanoparticles (GNP) conjugated with an antibody have been used to enhance optical absorption (and photoacoustic signals) in targeted cancer tissue and provide high contrast for non-invasive cancer imaging. GNP display very good biocompatibility and systematic efforts to get approval have been in process such as GNP carriers for anticancer drugs. Conventional ultrasound scanner in combination with a laser will provide real-time high- sensitive and high-resolution photoacoustic imaging of Gold nanorods bound to the specific vascular inflammatory biomarkers. This method also can be rapidly translated into clinical practice since it is based upon novel processing of ultrasound data that can be obtained with commercially available scanners.
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