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

基于高密度脂蛋白的动脉粥样硬化治疗诊断纳米颗粒平台

基本信息

批准号：
8903508
负责人：
Shanta Dhar
金额：
$ 36.43万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-07-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8903508
关键词：
Accounting Acute Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Apolipoprotein E Apolipoproteins Apoptosis Apoptotic Arterial Fatty Streak Arteries Atherogenic Diet Atherosclerosis Binding Biodistribution Biological Biological Assay Blood Vessels Cardiology Cardiovascular Diseases Cause of Death Cells Cessation of life Characteristics Cholesterol Combined Modality Therapy Contrast Media Coronary Arteriosclerosis Coronary heart disease Cytosol Detection Development Diagnosis Disadvantaged Disease Drug Kinetics Emigrations Engineering Event Family suidae Flow Cytometry Foam Cells Generations Glycolates Government Guidelines Health Healthcare High Density Lipoproteins Homeostasis Human Hybrids Image In Vitro Individual Inflammation Inflammatory Infusion procedures Knock-out Laboratories Lead Lipids Lipoprotein (a)Liver Magnetic Resonance Imaging Maintenance Malignant Neoplasms Mannose Measures Membrane Potentials Mitochondria Modality Modeling Molecular Morbidity - disease rate Mus Nanotechnology Necrosis Patients Peptides Peritoneal Macrophages Phase Phospholipids Play Polyethylene Glycols Polymers Preventive Principal Investigator Process Property Recombinants Research Research Personnel Resort Role Rupture Safety Serum Staging Surface System Techniques Technology Testing Therapeutic Therapeutic Studies Thick Thrombosis Thrombus Toxic effect Treatment Efficacy Universities Variant Vascular Diseases base cardiovascular disorder therapy cholesteryl oleate cytokine disability engineering design high risk image guided therapy improved in vivo iron oxide lipid metabolism macrophage medical schools mimetics mitochondrial membrane monolayer mortality mouse model multidisciplinary nanocrystal nanoparticle nanoscale protective effect reconstitution reverse cholesterol transport scale up screening success theranostics therapy development uptake

项目摘要

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.

描述（由申请人提供）：动脉粥样硬化性冠状动脉疾病是全世界的主要死亡原因。急性动脉粥样硬化事件是由斑块组成的变化引起的，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），一种脂质和载脂蛋白-I（apoA-I）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，开发用于易损斑块检测的凋亡巨噬细胞非侵入性成像的靶向纳米技术，并启动利用HDL的血管保护作用的预防性治疗，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HDL模拟NP。有了这一成功，我们假设，开发一种新的诊断和治疗选择，使用巨噬细胞靶向NP，使用HDL和apoA-I组分，线粒体膜电位（Δ μ m）的崩溃作为巨噬细胞凋亡的指标，并含有纳米级造影剂氧化铁（IO）晶体的磁共振成像，可以提供一个很好的替代诊断为基础的治疗方法动脉粥样硬化。该假设是基于巨噬细胞能够摄取过量胆固醇的事实构建的，并且众所周知，胆固醇向线粒体的递送是肝脏中胆固醇降解的限速步骤。因此，线粒体靶向的HDL模拟NP将能够将过量的胆固醇从胞质溶胶携带到巨噬细胞的线粒体，从而在维持细胞内脂质稳态中发挥重要作用。为了构建该NP平台并证明其潜力，我们定义了以下具体目的：（1）构建和体外优化巨噬细胞和Δ Δ μ m靶向的HDL模拟含IO的NP用于斑块检测和预防性治疗;（2）HDL模拟NP在小鼠中的安全性和毒性以及在动脉粥样硬化小鼠中的组合成像和治疗;（3）在动脉粥样硬化尤卡坦小型猪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比所有癌症的总和还要多，但没有针对无症状动脉粥样硬化的国家筛查指南，也没有政府或医疗保健机构赞助的动脉粥样硬化筛查报销。如果成功，这项拟议的研究可用于为所有动脉粥样硬化检测阳性的个体提供靶向治疗。