Nanoparticles for Molecular MRI of Athersclerosis

众所周知，尽管心血管护理取得了进展，但动脉粥样硬化及其并发症、心肌梗死和中风的患病率仍然是全球发病率和死亡率的主要原因。目前的无创性方法来评估状态和评估治疗干预的效果主要依赖于病变的解剖和结构特征。动脉粥样硬化的新的无创分子成像技术1可以使一种新的生物学为基础的方法，超过了血管壁的解剖和形态学检查。目前的成像方式揭示了关于这一关键生物过程的最小信息。因此，通过使用非侵入性和可靠的成像方法表征导致斑块进展和不稳定的病理生理过程，可以早期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成像方法，用于非侵入性评价与动脉粥样硬化形成相关的生物活性。我们建议使用多功能/模块化（允许MR成像标记和配体的轻松互换）和充分表征的高密度脂蛋白（HDL）成像纳米载体平台，用于体内动脉粥样硬化斑块进展和消退的靶向（已知和新发现的靶点）研究。这些球形HDL平台将被编程用于单模态成像（Gd-MR或氧化铁-MR），允许在可能不同的灵敏度水平下进行评估（目标1）。基于体内有效性成像研究，将选择天然和合成MR-HDL平台之间的主要候选物，用于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（目的2）。已知和新鉴定的靶标将被功能化以实现斑块特异性选择性靶向。我们将证明这些靶向HDL MR纳米载体在评价小鼠和兔动脉粥样硬化模型中斑块进展和消退的体内功效（目的3）。

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).