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。

• 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
• 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

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.

项目摘要 动脉粥样硬化性血管疾病和下游组织缺血(心脏病发作、中风)仍然是 导致美国人发病和死亡的主要原因。动脉粥样硬化(血管增厚和硬化- 血管壁)优先发生在血流紊乱的动脉曲度和分叉处 目前动脉粥样硬化的药物治疗主要针对“全身性”危险因素。 比如血液中的高胆固醇。我们相信，靶向纳米医学具有独特的潜力，可以彻底改变未来 动脉粥样硬化的医学实践--“区域性”纠正致病分子机制。 舒缓血管。 考虑到动脉粥样硬化在可预测血管的局灶性，基于动脉壁的治疗很有吸引力 网站。紊乱的血流增加内皮通透性并促进内皮炎症，导致 低密度脂蛋白(LDL)胆固醇颗粒内皮下滞留和单核细胞聚集。 病变单核细胞成熟为巨噬细胞，并内化脂蛋白。过多的细胞胆固醇排出 巨噬细胞通过一个过程将高密度脂蛋白(Hdl)输送到肝脏排泄。 被称为反向胆固醇运输(RCT)。RCT不足与胆固醇负荷过高的Mac- 噬菌体“泡沫细胞”。广泛的研究表明，抑制内皮细胞炎症和促进 巨噬细胞胆固醇外流是预防或逆转动脉粥样硬化的理想策略。尽管如此，它还是- 在病变中“在空间上”调节这些致病分子机制是极其困难的。 MicroRNAs(MiRNAs)是动脉粥样硬化相关细胞事件的关键基因调节因子。烦躁不安 FLOW增加内皮细胞miR-92a促进血管炎症，而miR-33a升高抑制CHO-2 Lesterol外流。该项目的总体目标是开发一种新的基于纳米药物的治疗策略。 抗动脉粥样硬化，旨在抑制病变内皮细胞miR-92a和巨噬细胞miR-33a- 特定的时尚。我们的关键前提是，如果这一新战略成功，可以缓解巨大的健康 动脉粥样硬化的负担。事实上，我们的初步数据表明，这是可以做到的。我们雇佣了焦油- 获得抗纤维蛋白和血管细胞黏附分子1(VCAM-1)的多肽以驱动纳米 材料分别为动脉粥样硬化病变和炎性内皮细胞。此外，抗C-C多肽 趋化因子受体2型(CCR2)成功地将纳米颗粒运送到病变单核/巨噬细胞。 为了实现我们的总体目标，我们有两个直接目标。首先，我们将提炼和测试一部小说 聚电解质复合胶束系统将miR-92a抑制剂特异性地输送到动脉粥样硬化敏感的内皮细胞-- 恩。其次，这种聚电解质复合胶束将被重新配方，以显示针对皮损宏观的多肽。 噬菌体递送针对miR-33a的抑制剂。这些研究应该进一步发展临床前研究，每- HAPS最终的临床测试，治疗动脉粥样硬化的新治疗策略，仍然是至关重要的 疾病过程。