Nanoparticles for Molecular MRI of Athersclerosis

用于动脉粥样硬化分子 MRI 的纳米颗粒

• 批准号: 8679194
• 负责人: Zahi A. Fayad
• 金额: $ 7.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679194
• 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; 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

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).

众所周知，尽管心血管护理取得了进步，但动脉粥样硬化及其并发症、心肌梗塞和中风的患病率仍然是全世界发病和死亡的主要原因。目前评估状态和评估治疗干预效果的无创方法主要依赖于病变的解剖和结构特征。动脉粥样硬化的新无创分子成像技术可能会带来一种新的基于生物学的方法，超越血管壁的解剖和形态学检查。目前的成像方式揭示了有关这一关键生物过程的最少信息。因此，通过使用非侵入性和可靠的成像方法表征斑块进展和不稳定性的病理生理过程，有可能早期识别高危患者并评估干预措施（包括新兴疗法）的效果。因此，这项工作的中心目标是研究分子成像方法，以非侵入性评估与动脉粥样硬化相关的生物活性。我们建议使用多功能/模块化（允许 MR 成像标签和配体轻松互换）和特征良好的高密度脂蛋白（HDL）成像纳米载体平台来进行靶向（已知和新发现的靶标）进展和回归研究体内动脉粥样硬化斑块。这些球形 HDL 平台将针对单模态成像（Gd-MR 或氧化铁-MR）进行编程，允许以可能不同的灵敏度水平进行评估（目标 1）。根据体内功效成像研究，将选择天然和合成 MR-HDL 平台之间的主要候选者进行后续目标的进一步研究。体外和体内研究将与纳米载体设计策略和组装工作密切相关，以验证 HDL MR 成像平台的生物学性能和作用机制（目标 2）。已知和新确定的靶标将被功能化以实现斑块特异性选择性靶向。我们将展示这些靶向 HDL MR 纳米载体的体内功效，用于评估小鼠和兔子动脉粥样硬化模型中的斑块进展和消退（目标 3）。