A high-density lipoprotein-based theranostic nanoparticle platform for atherosclerosis

描述(申请人提供)：动脉粥样硬化性冠状动脉疾病是全世界主要的死亡原因。急性动脉粥样硬化事件是由斑块成分的变化引起的，最终导致斑块破裂或侵蚀。促进这种所谓的“斑块脆弱性”的两个主要事件是巨噬细胞炎症和细胞凋亡。在心血管疾病中，高密度脂蛋白(HDL)是一种由脂质和载脂蛋白-I(apoA-I)组成的自组装纳米颗粒(NP)，通常被称为“好胆固醇”，已知具有保护作用。因此，开发有针对性的纳米技术，对凋亡的巨噬细胞进行非侵入性成像，以检测脆弱的斑块，并开始利用高密度脂蛋白的血管保护作用进行预防性治疗，可以降低冠心病的发病率和死亡率。首席研究员的实验室最近开发了一种完全合成但可生物降解的高密度脂蛋白，模仿NP。随着这一成功，我们假设开发一种新的诊断和治疗方案，使用针对巨噬细胞的NP，使用高密度脂蛋白和载脂蛋白A-I成分，线粒体膜电位(Δψm)的崩溃作为巨噬细胞凋亡的指标，并包含用于磁共振成像的纳米对比剂氧化铁(IO)晶体，可以提供一种极好的基于诊断的动脉粥样硬化替代治疗方法。这一假说是建立在巨噬细胞能够吸收过量胆固醇的事实基础上的，众所周知，将胆固醇输送到线粒体是肝脏胆固醇降解的限速步骤。因此，靶向于高密度脂蛋白的线粒体模拟NP将能够将过量的胆固醇从胞浆携带到巨噬细胞的线粒体中，在维持细胞内脂质平衡方面发挥重要作用。为了构建这个NP平台并展示其潜力，我们定义了以下特定目标：(1)构建并体外优化靶向高密度脂蛋白和Δψm的巨噬细胞和高密度脂蛋白m，用于斑块检测和预防治疗；(2)高密度脂蛋白模拟纳米粒在小鼠体内的安全性和毒性以及在动脉粥样硬化小鼠中的联合成像和治疗；(3)在尤卡坦小型猪动脉粥样硬化模型中的联合成像和治疗。尽管动脉粥样硬化性心血管疾病导致的死亡和残疾超过了所有癌症的总和，但目前还没有针对无症状动脉粥样硬化的全国性筛查指南，也没有政府或医疗保健赞助的动脉粥样硬化筛查报销。如果成功，这项拟议的研究可以用来为动脉粥样硬化检测呈阳性的所有个体提供有针对性的治疗。

DESCRIPTION (provided by applicant): Atherosclerotic coronary artery disease is a major cause of death all over the world. Acute atherosclerotic events are caused by changes in plaque composition that eventually lead to plaque rupture or erosion. Two major events that promote this so-called "plaque vulnerability" are macrophage inflammation and apoptosis. In cardiovascular diseases, high-density lipoprotein (HDL), a self-assembled nanoparticle (NP) of lipids and apolipoprotein-I (apoA-I) popularly termed as "good cholesterol," is known to have a protective role. Therefore, development of targeted nanotechnologies for noninvasive imaging of apoptotic macrophages for vulnerable plaque detection and the initiation of preventative therapies that exploit the vascular protective effects of HDL could reduce the morbidity and mortality of coronary heart diseases. The Principal Investigator's laboratory recently developed a completely synthetic yet biodegradable HDL mimicking NP. With this success, we hypothesized that development of a new diagnosis and therapeutic options using a macrophage targeted NP that uses HDL and apoA-I components, collapse of mitochondrial membrane potential (Δψm) as an indicator of macrophage apoptosis, and contains nanoscale contrast agents iron oxide (IO) crystals for magnetic resonance imaging can provide an excellent alternative diagnosis-based treatment approach of atherosclerosis. This hypothesis was constructed based on the fact that macrophages are capable of taking up excess cholesterol, and it is well known that delivery of cholesterol to the mitochondria is the rate- limiting step fo cholesterol degradation in the liver. Therefore, a mitochondria targeted HDL mimicking NP will be able to carry excess cholesterol from cytosol to the mitochondria of macrophages to play an important role in the maintenance of intracellular lipid homeostasis. To construct this NP platform and to demonstrate its potential, we have defined the following Specific Aims: (1) Construction and in vitro optimization of a macrophage and Δψm targeted HDL mimicking NP containing IO for plaque detection and preventive therapy; (2) Safety and toxicities of HDL mimicking NPs in mice and combined imaging and therapy in atherosclerotic mice; (3) Combined imaging and therapy in atherosclerotic Yucatan mini swine model. Although atherosclerotic cardiovascular disease accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic atherosclerosis, and there is no government or healthcare sponsored reimbursement for atherosclerosis screening. If successful, this proposed research could be used to provide targeted therapies to all individuals with a positive test for atherosclerosis.