Spatial Delivery of MicroRNA Inhibitor via Targeted Polyelectrolyte Complex Micelles to Treat Atherosclerosis.

通过靶向聚电解质复合胶束空间递送 MicroRNA 抑制剂来治疗动脉粥样硬化。

基本信息

批准号：
10004707
负责人：
Yun Fang
金额：
$ 39.48万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004707
关键词：
ATP-Binding Cassette Transporters Address Affect American Arterial Fatty Streak Arteries Atherosclerosis Attention Attenuated Binding Blood Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cholesterol Cholesterol Homeostasis Communities Complex Data Disease Effectiveness Encapsulated Endothelial Cells Endothelium Engineering Event Excretory function Fibrin Foam Cells Future Goals Health Hematological Disease High Density Lipoproteins In Vitro Inflammation Investigation Ischemia LDL Cholesterol Lipoproteins Lesion Lipoproteins Liver Malignant Neoplasms Medical Micelles MicroRNAs Molecular Morbidity - disease rate Myocardial Infarction Nature Peptides Permeability Pharmacological Treatment Process Regulator Genes Risk Factors Site Stroke System Testing Therapeutic Tissues Vascular Cell Adhesion Molecule-1 athero susceptible base beta-Chemokines chemokine receptor gamma-Chemokines in vivo inhibitor/antagonist innovation macrophage monocyte mortality nanomaterials nanomedicine nanoparticle nanoparticle delivery novel novel strategies novel therapeutic intervention particle preclinical development prevent recruit research clinical testing reverse cholesterol transport vascular inflammation

项目摘要

Project Summary Atherosclerotic vascular disease and downstream tissue ischemia (heart attacks, strokes) remain the leading cause of morbidity and mortality among Americans. Atherosclerosis (thickening and hardening of vas- cular walls) develops preferentially at arterial sites of curvature and bifurcation where disturbed blood flow is prevalent; yet, current pharmacological treatments of atherosclerosis principally target “systemic” risk factors such as high blood cholesterol. We believe targeted nanomedicine has unique potential to revolutionize future medical practice of atherosclerosis by correcting disease-causing molecular mechanisms “regionally” in dis- eased blood vessels. Arterial wall-based therapy is attractive given the focal nature of atherosclerosis at predictable vascular sites. Disturbed flow increases endothelial permeability and promotes endothelial inflammation, leading to the subendothelial retention of low-density lipoprotein (LDL) cholesterol particles and monocytes accumulation. Lesion monocytes mature into macrophages and internalize lipoproteins. Excess cellular cholesterol effluxed from macrophages is transported by high density lipoproteins (HDL) to the liver for excretion through a process known as Reverse Cholesterol Transport (RCT). Inadequate RCT is associated with cholesterol-loaded mac- rophage “foam cells”. Extensive studies suggest that inhibition of endothelial inflammation and promotion of macrophage cholesterol efflux are ideal strategies to prevent or regress atherosclerosis. Nevertheless, it re- mains extremely difficult to modulate these disease-causing molecular mechanisms “spatially” in lesions. microRNAs (miRNAs) are critical gene regulators of cellular events related to atherosclerosis. Disturbed flow increases endothelial miR-92a to promote vascular inflammation while elevated miR-33a suppresses cho- lesterol efflux. The overall goal of this project is to develop a new nanomedicine-based therapeutic strategy against atherosclerosis, aiming to inhibit endothelial miR-92a and suppress macrophage miR-33a in a lesion- specific fashion. Our key premise is that this new strategy, if successful, could mitigate the tremendous health burden of atherosclerosis. Indeed, our preliminary data suggest that this can be done. We have employed tar- geting peptides against fibrin and Vascular Cell Adhesion Molecule 1 (VCAM-1) to drive active binding of nano- materials to atherosclerotic lesions and inflamed endothelia, respectively. Moreover, peptides against C-C chemokine receptor type 2 (CCR2) successfully delivered nanoparticles to lesion monocytes/macrophages. To address our overall goal, we hold two immediate objectives. First, we will refine and test a novel polyelectrolyte complex micelle system to deliver miR-92a inhibitor specifically to athero-susceptible endotheli- um. Second, this polyelectrolyte complex micelle will be reformulated to display peptides against lesion macro- phages to deliver inhibitors against miR-33a. These studies should further preclinical development, and per- haps eventual clinical testing, of a new therapeutic strategy to treat atherosclerosis, a still critically important disease process.

项目概要动脉粥样硬化性血管疾病和下游组织缺血（心脏病、中风）仍然是最常见的疾病美国人发病和死亡的主要原因。血管壁）优先在动脉曲率和分叉部位发育，此处血流受到干扰普遍存在；然而，目前动脉粥样硬化的药物治疗主要针对“全身”危险因素我们相信靶向纳米医学具有彻底改变未来的独特潜力。通过“区域性”纠正动脉粥样硬化的致病分子机制来治疗动脉粥样硬化缓解了血管。鉴于动脉粥样硬化在可预测的血管中的局灶性质，基于动脉壁的治疗很有吸引力血流紊乱会增加内皮通透性并促进内皮炎症，从而导致低密度脂蛋白（LDL）胆固醇颗粒的内皮下滞留和单核细胞积聚。病变单核细胞成熟为巨噬细胞并内化过量的细胞胆固醇外流。来自巨噬细胞的物质通过高密度脂蛋白（HDL）转运至肝脏并通过一个过程排泄称为反向胆固醇转运 (RCT) 的 RCT 不足与胆固醇负荷相关。大量研究表明，噬菌体“泡沫细胞”可以抑制内皮炎症并促进炎症。巨噬细胞胆固醇流出是预防或逆转动脉粥样硬化的理想策略。在病变中“空间”调节这些致病分子机制是极其困难的。 microRNA (miRNA) 是与动脉粥样硬化相关的细胞事件的关键基因调节因子。血流增加内皮 miR-92a 促进血管炎症，而升高的 miR-33a 抑制血管炎症该项目的总体目标是开发一种新的基于纳米医学的治疗策略。抗动脉粥样硬化，旨在抑制病变内皮细胞 miR-92a 并抑制巨噬细胞 miR-33a 我们的关键前提是，这一新策略如果成功，可以减轻巨大的健康影响。事实上，我们的初步数据表明，我们已经采用了焦油。获取针对纤维蛋白和血管细胞粘附分子 1 (VCAM-1) 的肽，以驱动纳米-的主动结合分别针对动脉粥样硬化病变和发炎内皮细胞的材料此外，还有针对 C-C 的肽。 2 型趋化因子受体 (CCR2) 成功地将纳米颗粒递送至病变单核细胞/巨噬细胞。为了实现我们的总体目标，我们有两个近期目标：首先，我们将完善和测试一部小说。聚电解质复合胶束系统可将 miR-92a 抑制剂特异性递送至动脉粥样硬化易感内皮细胞嗯，其次，这种聚电解质复合胶束将被重新配制以展示针对病变宏观的肽。这些研究应进一步促进临床前开发和后续研究。治疗动脉粥样硬化的新治疗策略的最终临床测试仍然至关重要疾病过程。