Detection of plaque based macrophages with light

用光检测基于斑块的巨噬细胞

基本信息

批准号：
7930086
负责人：
MARC David FELDMAN
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7930086
关键词：
Aorta Arterial Fatty Streak Atherosclerosis Biological Biology Biomedical Engineering Blood Blood Chemical Analysis Blood Circulation Blood Vessels Cardiac Cardiac Catheterization Procedures Cardiovascular system Catheterization Cause of Death Cells Cerebrum Cessation of life Chemical Engineering Clinical Research Coin Collaborations Collection Colloids Contrast Media Coupled Data Detection Development Dextrans Dose Excretory function Flow Cytometry Fluorescence Future Goals Gold Growth Half-Life Hemoglobin Hepatic Histology Image Imaging Techniques Infiltration Intravenous Kidney Label Laboratories Lasers Lead Letters Light Lipids Liquid substance Liver Magnetic Resonance Angiography Matrix Metalloproteinases Mechanics Methodology Motion Myocardial Infarction Nanotechnology Optical Coherence Tomography Optics Organ Oryctolagus cuniculus Pathologic Pathway interactions Patients Peripheral Catheterization Peripheral Vascular Diseases Phase Photophobia Physicians Physiologic pulse Production Property Public Health Relaxation Research Resolution Risk Rupture Scientist Sensitivity and Specificity Shoulder Signal Transduction Smooth Muscle Myocytes Societies Specificity Stroke Surface System Techniques Time Tissues Toxic effect Translating Translations Ultrasonography Veterans abstracting acute coronary syndrome base cell type cellular imaging density design dextran eosinophil in vivo iron oxide light scattering macrophage member multidisciplinary nanometer nanoparticle nanorod nanoshell novel optical imaging particle patient population prevent programs receptor research study surface coating time use uptake

项目摘要

DESCRIPTION (provided by applicant): Project Summary/Abstract The pathologic features that predict atherosclerotic plaque rupture are large lipid collections, thinning of the fibrous cap, and infiltration of macrophages. Optical Coherence Tomography (OCT) has already been demonstrated to accurately image thin fibrous caps and large lipid cores. We now propose an approach which will detect macrophages in vulnerable plaque with OCT in patients at the time of catheterization. We demonstrate that by labeling plaque-based macrophages with intravenous gold nanoparticles we can detect the presence of macrophages for the first time using phase-sensitive OCT coupled with a stimulating laser. In this approach, optical nanoparticles engulfed by plaque-based macrophages are put into nanometer (nm) motion via thermal expansion and relaxation due to application of a pulsed laser, and this motion detected with a phase-sensitive OCT system. We have also developed novel optical nanoparticles for this approach which are excited by light maximally at a wavelength of 700-800 nm, to prevent laser interaction with competing plaque components such as hemoglobin, lipid, and arterial wall which maximally absorb light at 500-600 nm. Due to their multi-faceted surface, we have coined the term "nanorose" to describe these nanoparticles. To demonstrate cellular imaging of macrophages in intact plaque, we propose the following specific aims: Specific Aim # 1 - Specificity and sensitivity of nanoparticle (nanorose) uptake. 1.1 We will synthesize and fully characterize nanorose with controlled size, and gold and dextran amounts, to achieve strong NIR absorbance and specific cell (macrophage) uptake. 1.2 We will demonstrate specific uptake of nanorose by macrophages as opposed to endothelial and smooth muscle cells in culture via the use of flow cytometry. 1.3 We will inject nanorose iv into atherosclerotic rabbits, and perform detailed histology with fluorescence microcopy to determine both the minimal detectable dose and the specificity of nanorose uptake in plaque. Specific Aim # 2 - Ex vivo and in vivo OCT imaging of macrophages in rabbit atherosclerotic aortas with nanorose. 2.1 We will inject nanorose iv into atherosclerotic rabbits, perform OCT imaging of ex vivo aortic tissue, and compare these images with histology via RAM-11 identification of macrophages, and hyperspectral imaging of nanorose. 2.2 We will inject nanorose iv into atherosclerotic rabbits, repeat each of the histological experiments in section 2.1, but with in vivo OCT imaging. Specific Aim # 3 - Excretion and toxicity of nanorose. 3.1 We will characterize the excretion pathway of nanorose (hepatic vs. renal, organs of distribution, and blood half-life). 3.2 We will demonstrate in rabbits the absence of organ toxicity via blood chemistry for evidence of hepatic and renal damage, eosinophil production, and post-mortem examination. These studies will also be performed in collaboration with the Nanotechnology Characterization Laboratory (see letter of support). PUBLIC HEALTH RELEVANCE: Project Narrative Development of a combined contrast agent - light based approach to identify vulnerable plaques will have a significant impact on the public health. Inasmuch as atherosclerosis remains the leading cause of death in Western society, application of the proposed technique that can image plaques at risk for rupture can reduce the number of deaths from heart attack, stroke and peripheral vascular disease. Successful completion of the proposed research will provide a basis for expanded clinical studies to validate the proposed methodology in a large patient population.

描述（由申请人提供）：项目摘要/摘要预测动脉粥样硬化斑块破裂的病理特征是大脂质收集，纤维帽的变薄和巨噬细胞的浸润。光学相干断层扫描（OCT）已被证明可以准确地对纤维帽和大脂质核心进行成像。现在，我们提出了一种方法，该方法将在导管插入时在患者中检测出易受攻击的斑块中的巨噬细胞。我们证明，通过将基于斑块的巨噬细胞用静脉注射金纳米颗粒标记，我们可以使用相敏感的OCT与刺激激光偶联时首次检测到巨噬细胞的存在。在这种方法中，由于使用脉冲激光器的应用，通过热膨胀和松弛，将被斑块的巨噬细胞吞没的光学纳米颗粒被放入纳米表运动（NM）运动中，并通过相位敏感的OCT系统检测到这种运动。我们还为这种方法开发了新型的光学纳米颗粒，该方法在700-800 nm的波长下最大程度地激发了光线，以防止激光与竞争斑块成分（如血红蛋白，脂质和动脉壁）的相互作用，这些斑块成分在500-600 nm处最大吸收光。由于它们的多面表面，我们创造了“纳米糖”一词来描述这些纳米颗粒。为了证明完整斑块中巨噬细胞的细胞成像，我们提出了以下特定目的：特定目的＃1-纳米颗粒（纳米糖）摄取的特异性和灵敏度。 1.1我们将合成并充分表征具有控制尺寸以及金和葡萄糖量的纳米糖，以实现强大的NIR吸光度和特定细胞（巨噬细胞）的摄取。 1.2我们将通过使用流式细胞仪来证明巨噬细胞对巨噬细胞对纳米糖的特定摄取，而不是培养中的内皮和平滑肌细胞。 1.3我们将纳米糖IV注入动脉粥样硬化兔，并用荧光微拷贝进行详细的组织学，以确定可检测的最小剂量和斑块中纳米糖摄取的特异性。特定的目标＃2-兔动脉粥样硬化主动脉中巨噬细胞中巨噬细胞的体内和体内OCT成像。 2.1我们将向动脉粥样硬化的兔子注射纳米糖IV，对离体主动脉组织进行OCT成像，并通过RAM-11鉴定巨噬细胞和纳米糖的高光谱成像将这些图像与组织学进行比较。 2.2我们将向动脉粥样硬化的兔子注入纳米糖IV，重复第2.1节中的每个组织学实验，但具有体内OCT成像。特定目的＃3-纳米糖的排泄和毒性。 3.1我们将表征纳米糖的排泄途径（肝与肾脏，分布器官和血液半衰期）。 3.2我们将通过血液化学表明兔子缺乏器官毒性，以证明肝和肾脏损伤，嗜酸性粒细胞的产生和验尸检查。这些研究还将与纳米技术特征实验室合作进行（请参阅支持信）。公共卫生相关性：组合对比代理的项目叙事发展 - 基于轻的方法来识别脆弱的斑块将对公共卫生产生重大影响。由于动脉粥样硬化仍然是西方社会死亡的主要原因，因此提出的技术可以对有破裂风险的斑块进行成像的应用可以减少心脏病发作，中风和周围血管疾病的死亡人数。拟议研究的成功完成将为扩展的临床研究提供基础，以验证大型患者人群中提出的方法。