Molecular Imaging of Angiogenesis by MRI

MRI 血管生成的分子成像

• 批准号: 7174670
• 负责人: Gregory M Lanza
• 金额: $ 22.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174670
• 关键词: Animal Model; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Blood flow; Caliber; Cell Adhesion; Cholesterol; Chronic Disease; Clinical; Complex; Condition; Contrast Media; Coronary Arteriosclerosis; Coupled; Detection; Development; Diabetes Mellitus; Diet; Diffuse; Disease; Early Diagnosis; Encapsulated; Epitopes; Exercise Tolerance; Fluorocarbons; Gadolinium; Gadolinium DTPA; Gadopentetate Dimeglumine; Hyperlipidemia; Hypertension; Hypoxia; Image; Image Analysis; Imaging Techniques; Injury; Integrin alphaVbeta3; Integrins; Ischemia; Lead; Ligand Binding; Ligation; Limb structure; Lipids; Magnetic Resonance Imaging; Medical; Methods; Modeling; Molecular; Molecular Profiling; Monitor; Noise; Obstruction; Outcome; Pain; Patients; Peripheral Vascular Diseases; Process; Range; Research; Research Personnel; Rest; Signal Transduction; Site; Therapeutic; Tissues; Ultrasonography; Vascular Endothelial Cell; Vascular Permeabilities; Weight; angiogenesis; atherogenesis; clinically relevant; density; feeding; femoral artery; mathematical model; migration; molecular imaging; nanometer; nanoparticle; neovascularization; novel; programs; response

DESCRIPTION (provided by applicant): Currently, there is no optimal medical therapy for peripheral vascular disease (PVD). A noninvasive method for detecting angiogenesis would provide invaluable information for managing PVD patients as well as for detecting response to angiogenic therapies. Cell adhesion integrins regulate angiogenesis by controlling the migration and invasion of vascular endothelial cells. In particular, the alpha(v)beta(3) integrin is ideally suited for detection of angiogenesis because only very low levels are expressed in normal vessels, expression quickly increases upon ischemia and it is expressed at higher density than other integrins. We have developed a novel, site-targeted, paramagnetic nanoparticle contrast agent for magnetic resonance imaging of molecular epitopes. The agent is a small (approximately 250 nm diameter), lipid-encapsulated, perfluorocarbon nanoparticle covalently coupled to an alpha(v)beta(3) specific antagonist. One key advantage of molecular imaging with this unique nanoparticle is the unusually large paramagnetic payload (approximately 90,000 Gd-DTPA complexes per nanoparticle) for high T1-weighted relaxivity. This provides a higher detection sensitivity and a better signal-to-noise ratio than previously achieved. The central hypothesis of this research is that alpha(v)beta(3)-targeted paramagnetic nanoparticles will allow sensitive detection of the early molecular signatures of angiogenesis. Accordingly, we have developed the following specific aims: 1) Develop and validate the following animal models of PVD to mimic a wide range of clinical conditions: femoral artery ligation, high-cholesterol diet, pro-angiogenic therapy and anti-angiogenic pharmacological manipulation. 2) Optimize molecular imaging techniques by quantifying gadolinium bound to angiogenic vasculature, modeling MRI signals, evaluating the sensitivity of different imaging sequences to gadolinium and developing automated unbiased image analysis programs. 3) Utilize alpha(v)beta(3)-targeted nanoparticles to demonstrate molecular imaging of angiogenesis in animal models developed in Aim 1. Apply mathematical models of tissue compartmentalization to determine the contributions of target binding and vascular permeability to MRI signal enhancement.

描述(由申请人提供)： 目前，外周血管疾病(PVD)尚无理想的药物治疗方法。一种检测血管生成的非侵入性方法将为PVD患者的治疗以及检测血管生成治疗的反应提供宝贵的信息。细胞黏附整合素通过控制血管内皮细胞的迁移和侵袭来调节血管生成。特别是，α(V)β(3)整合素非常适合于血管生成的检测，因为在正常血管中只有很低的水平表达，缺血时表达迅速增加，而且它的表达密度比其他整合素高。 我们开发了一种新型的、定点定位的顺磁性纳米颗粒造影剂，用于分子表位的磁共振成像。该制剂是一种小的(直径约250 nm)、脂质包裹的全氟碳纳米颗粒，与α(V)β(3)特异性拮抗剂共价偶联。使用这种独特的纳米颗粒进行分子成像的一个关键优势是具有异常大的顺磁有效载荷(每个纳米颗粒大约有90,000个Gd-DTPA复合体)，具有很高的T1加权弛豫度。这提供了比以前实现的更高的检测灵敏度和更好的信噪比。 这项研究的中心假设是，以α(V)、β(3)为靶标的顺磁纳米颗粒将允许敏感地检测血管生成的早期分子特征。因此，我们制定了以下具体目标： 1)建立和验证以下PVD动物模型，以模拟多种临床情况：股动脉结扎、高胆固醇饮食、促血管生成治疗和抗血管生成药物操作。 2)通过量化与血管新生血管结合的Gd、对MRI信号建模、评估不同成像序列对Gd的敏感性以及开发自动化的无偏图像分析程序来优化分子成像技术。 3)利用α(V)β(3)靶向纳米粒子在Aim 1中建立的动物模型中展示血管生成的分子成像。应用组织区划的数学模型来确定靶点结合和血管通透性对MRI信号增强的贡献。