Nanoparticles for Molecular MRI of Atherosclerosis

用于动脉粥样硬化分子 MRI 的纳米颗粒

• 批准号: 8274740
• 负责人: Zahi A. Fayad
• 金额: $ 70.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-22 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274740
• 关键词: Address; Amphipathic Alpha Helix; Anatomy; Apolipoprotein A-I; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biocompatible; Biodistribution; Biological; Biological Process; Blood Circulation; Caliber; Cardiovascular Diseases; Cardiovascular system; Caring; Cell Adhesion Molecules; Cell Surface Receptors; Characteristics; Charge; Clinic; Clinical; Connective Tissue; Contrast Media; Detection; Diagnosis; Dose; Drug Kinetics; Engineering; Evaluation; Exhibits; Extracellular Matrix; Goals; High Density Lipoproteins; Image; Imaging Techniques; In Vitro; Individual; Inflammation; Kinetics; Label; Lead; Lesion; Ligands; Link; Lipids; Lipoproteins; Liposomes; Magnetic Resonance Imaging; Methods; Micelles; Modeling; Modification; Molecular; Molecular Diagnosis; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Oryctolagus cuniculus; Patients; Peptide antibodies; Peptides; Performance; Preparation; Prevalence; Process; Proteins; Renal clearance function; Reticuloendothelial System; Route; Staging; Stroke; Surface; Symptoms; Technology; Therapeutic Intervention; Translating; Validation; Work; abstracting; atherogenesis; base; chemical property; clinical application; design; extracellular; high risk; imaging modality; improved; in vivo; in vivo Model; intervention effect; iron oxide; macrophage; mimetics; molecular imaging; mortality; nanocarrier; nanoparticle; nanoprobe; novel; oxidized low density lipoprotein; pandemic disease; particle; physical property; programs; reconstitution; synthetic peptide; uptake

Abstract: It is well recognized that despite advances in cardiovascular care, the prevalence of atherosclerosis and its complications, myocardial infarction and stroke, remains the leading cause of morbidity and mortality worldwide. Current noninvasive methods to evaluate the status and assess the effects of therapeutic intervention rely mainly on anatomic and structural features of the lesion. New noninvasive molecular imaging techniques of atherosclerosis1 may enable a novel biologically based approach that exceeds anatomic and morphologic examination of the vessel wall. Current imaging modalities disclose minimal information about this key biological process. Thus, by characterizing the pathophysiological processes responsible for plaque progression and instability using non-invasive and reliable imaging approaches, it may be possible to early identify high-risk patients and to evaluate the effects of interventions, including emerging therapies. The central goal of this work is therefore the study of molecular imaging methods for the non-invasive evaluation of the biological activity associated with atherogenesis. We propose the use of versatile/modular (allowing facile interchange of MR imaging labels and ligands) and well-characterized high-density lipoprotein (HDL) imaging nanocarrier platforms for the targeted (known and newly discovered targets) study of the progression and regression of atherosclerotic plaques in vivo. These spherical HDL platforms will be programmed for single modality imaging (Gd-MR or iron oxide-MR) allowing assessment at possibly different levels of sensitivity (Aim 1). Based on in vivo efficacy imaging studies the lead candidate between the native and synthetic MR-HDL platforms will be selected for further study in the subsequent aims. In vitro and in vivo studies will be linked intimately with the nanocarriers design strategies and assembly work to achieve validation of the biological performance and mechanism of action elucidation of the HDL MR imaging platforms (Aim 2). Known and newly identified targets will be functionalized to achieve plaque specific selective targeting. We will demonstrate the in vivo efficacy of these targeted HDL MR-nanocarriers for the evaluation of plaque progression and regression in mouse and rabbit models of atherosclerosis (Aim 3).

抽象的： 众所周知，尽管心血管护理取得了进步，但心血管疾病的患病率 动脉粥样硬化及其并发症、心肌梗塞和中风仍然是 全世界发病率和死亡率的主要原因。目前的非侵入性方法 评价治疗干预的现状和效果主要依靠 病变的解剖和结构特征。新型无创分子成像 动脉粥样硬化技术1可能会带来一种新的基于生物学的方法 超出了血管壁的解剖学和形态学检查。当前成像 模式披露了有关这一关键生物过程的最少信息。因此，通过 表征导致斑块进展的病理生理过程和 使用非侵入性和可靠的成像方法来消除不稳定性，有可能 及早识别高危患者并评估干预措施的效果，包括 新兴疗法。因此，这项工作的中心目标是研究分子 用于非侵入性评估相关生物活性的成像方法 动脉粥样硬化。我们建议使用多功能/模块化（允许轻松互换 MR 成像标签和配体）和充分表征的高密度脂蛋白 (HDL) 针对目标（已知和新发现的目标）的成像纳米载体平台 研究体内动脉粥样硬化斑块的进展和消退。这些 球形 HDL 平台将被编程用于单模态成像（Gd-MR 或铁 氧化物-MR）允许在可能不同的灵敏度水平上进行评估（目标1）。基于 体内功效成像研究天然和合成之间的主要候选者 后续目标将选择MR-HDL平台进行进一步研究。体外和 体内研究将与纳米载体的设计策略密切相关 组装工作以实现生物性能和机制的验证 HDL MR 成像平台的作用阐明（目标 2）。已知和新发现的 目标将被功能化以实现斑块特异性选择性靶向。我们将 证明了这些靶向 HDL MR 纳米载体的体内功效 小鼠和兔模型中斑块进展和消退的评估 动脉粥样硬化（目标 3）。