Cardiovascular Inflammation Function Imaging by Photoacoustics using Gold Nanorod

描述（由申请人提供）：动脉粥样硬化是一种血管壁的全身性疾病，发生于颈动脉、冠状动脉和外周动脉，是成年人群中发病率和死亡率较高的疾病。基础科学的最新进展已经确立了炎症在动脉粥样硬化的所有阶段（从开始到进展，最终到血栓形成）中的基本作用。这些新发现提供了危险因素与动脉粥样硬化机制之间的重要联系。炎症标志物升高预测急性冠状动脉综合征患者的不良结局，独立于心肌损伤。此外，粘附分子ICAM-1水平所显示的低级别慢性炎症，以及其他因素，可以预测动脉粥样硬化并发症的风险，从而增加了传统危险因素提供的预后信息。虽然目前的分子成像系统，如PET/CT、MRI和使用微泡的对比增强超声成像已经应用于心血管动脉粥样硬化成像，但成功率有限，但基于光声的成像技术在炎症检测方面具有特殊价值。超声阵列换能器与商用超声成像系统相结合，可用于记录光声信号。除了在激光诱导的情况下将序列的时间压缩两倍以适应半声传播距离外，可以使用经典超声成像的相同波束形成技术。该成像系统非常适合小动物实验和临床环境。光声图像的对比度可以使用高光学吸收的外部试剂选择性地结合到感兴趣的组织或特定的细胞类型来增强。金纳米棒具有优异的光吸收和高波长选择性，这取决于它们的长宽比。与抗体结合的金纳米颗粒已被用于增强靶向癌症组织的光吸收（和光声信号），并为非侵入性癌症成像提供高对比度。传统的超声扫描仪与激光相结合，将提供与体内特定血管炎症生物标志物结合的金纳米颗粒的实时高灵敏度和高分辨率光声成像。这一建议的基本假设是：1。生物共轭金纳米棒可作为选择性标记造影剂用于炎症的光声分子成像（PMI）；2.使用生物共轭金纳米棒的PMI可用于无创检测和监测啮齿动物心血管炎症的高度局部功能活动，并且易于转化为临床诊断工具。因此，这个应用程序的两个具体目标是：1。开发具有高灵敏度和选择性的生物偶联金纳米棒作为炎症生物标志物靶向造影剂；2. 目的：确定PMI在体外和体内是否能够检测心血管炎症。公共卫生相关性：心血管疾病是工业化国家的主要死亡原因，在美国每年导致约100万人死亡。动脉粥样硬化斑块是心血管疾病最危险的一种形式，它经常变得不稳定（易损斑块）和破裂，释放血栓形成物质形成血栓，完全阻断动脉中的血液流动，导致大多数心脏病发作和中风，因此对临床医生非常重要。最近的基础科学研究发现，炎症在动脉粥样硬化的所有阶段（从开始到进展，最终到血栓形成）中发挥了重要作用，从而提供了危险因素与动脉粥样硬化机制之间的重要联系。虽然目前的分子成像系统，如PET/CT、MRI和使用微泡的对比增强超声成像已经应用于心血管动脉粥样硬化成像，但成功率有限，但基于光声的成像技术在炎症检测方面具有显著的价值。结合激光系统的商用超声成像系统可用于记录光声信号，并具有特别增强的图像对比度，使用金纳米棒（GNR）作为外部介质选择性地结合到感兴趣的组织或特定细胞类型（例如，发炎细胞）。该成像系统非常适合小动物实验和临床环境。与抗体偶联的金纳米颗粒（GNP）已被用于增强靶向癌症组织的光吸收（和光声信号），并为非侵入性癌症成像提供高对比度。国产GNP具有很好的生物相容性，并且正在进行系统的努力，以获得诸如抗癌药物的国产GNP载体的批准。传统的超声扫描仪结合激光将提供与特定血管炎症生物标志物结合的金纳米棒的实时高灵敏度和高分辨率光声成像。这种方法也可以迅速转化为临床实践，因为它是基于超声数据的新处理，可以用市售扫描仪获得。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.