Oxidation-specific nanoparticles for imaging atherosclerosis

描述（由申请人提供）：本申请旨在生成基于磁共振的新型纳米颗粒，以对发炎动脉粥样硬化病变中存在的氧化特异性表位进行成像。现在已达成强烈共识，即对氧化特异性表位的先天性和适应性免疫反应会导致介导动脉粥样硬化和心血管事件的促炎症反应。大量的实验和临床数据，包括最近使用氧化特异性生物标志物预测死亡、心肌梗塞和中风的流行病学研究，支持氧化是动脉粥样硬化病变进展和不稳定的关键表现。其中一些氧化特异性表位，例如氧化磷脂和丙二醛-赖氨酸表位，已在我们的实验室中得到了很好的表征，并且已经产生了特异性鼠和全人抗体来检测血管壁中的它们。氧化特异性表位存在于人类动脉粥样硬化病变中，并且在病理学定义的易损斑块中特别丰富。我们的拨款提案将重点开发存在于种系中的氧化特异性“天然”抗体 人类的，作为独特和特异性的探针来成像动脉粥样硬化病变中的氧化特异性表位。这种方法主要针对动脉粥样硬化病变核心中凋亡和坏死巨噬细胞、氧化脂质和修饰/氧化基底蛋白上存在的细胞外氧化特异性表位。此外，作为更广泛的模仿的一部分，利用动脉粥样硬化形成中的先天免疫系统，特别是巨噬细胞清道夫受体的知识，我们开发了脂肽或模拟表位，模拟与巨噬细胞清道夫受体 CD36 和 SRA 特异性结合的氧化特异性表位。作为这些更基础研究的转化方面，我们将开发这些脂肽和模拟表位作为分子成像探针，针对活化巨噬细胞上存在的巨噬细胞清道夫受体。所有 3 种方法的开发可能使我们能够确定最佳成像方法，以区分细胞外氧化特异性表位与巨噬细胞清道夫受体的成像，并允许比较以确定一种或另一种或组合是否会产生最佳成像能力。这将回答关于这些方法中哪一种最有希望转化为临床领域的重要基本问题。检测和量化人类氧化特异性表位的能力将允许检测高风险斑块，并提供在各种治疗干预后进行监测的工具。

DESCRIPTION (provided by applicant): This application intends to generate novel magnetic resonance based nanoparticles to image oxidation-specific epitopes present in inflamed atherosclerotic lesions. There is now strong consensus that innate and adaptive immune responses to oxidation-specific epitopes lead to pro- inflammatory responses that mediate atherosclerosis and cardiovascular events. A wealth of experimental and clinical data, including recent epidemiological studies with oxidation-specific biomarkers predicting death, myocardial infarction and stroke, supports oxidation as a key manifestation of both the progression and destabilization of atherosclerotic lesions. Several of these oxidation-specific epitopes, such as oxidized phospholipids and malondialdehyde-lysine epitopes, have been well characterized in our laboratory and specific murine and fully human antibodies have been generated to detect them in the vessel wall. Oxidation-specific epitopes are present in human atherosclerotic lesions, and are particularly enriched in pathologically defined vulnerable plaques. Our grant proposal will focus on developing oxidation-specific "natural" antibodies, present in the germ line of humans, as unique and specific probes to image oxidation specific epitopes in atherosclerotic lesions. This approach would predominantly target extracellular oxidation-specific epitopes present on apoptotic and necrotic macrophages, oxidized lipids and, modified/oxidized basement proteins in the atherosclerotic lesion core. In addition, as part of a broader imitative t harness the knowledge of the innate immune system, and specifically macrophage scavenger receptors, in atherogenesis, we have developed lipopeptides or mimotopes modeling oxidation specific epitopes that bind specifically to macrophage scavenger receptors CD36 and SRA. As a translational aspect of these more basic investigations, we will develop these lipopeptides and mimotopes as molecular imaging probes targeting macrophage scavenger receptors present on activated macrophages. Development of all 3 approaches may allow us to determine optimal imaging approaches to differentiate imaging of extracellular oxidation-specific epitopes versus macrophage scavenger receptors, and allow comparisons to determine if one or the other or a combination results in optimal imaging capability. This will answer important fundamental questions about which of these approaches may be most promising to translate to the clinical arena. The ability to detect and quantify oxidation-specific epitopes in humans will allow detection of high risk plaques and provide the tools to allow surveillance following a variety of therapeutic interventions.