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: 10229491
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229491
• 关键词: ATP-Binding Cassette Transporters; Address; Affect; American; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; Attenuated; Binding; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Cholesterol Homeostasis; Communities; Complex; Data; Disease; 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; effectiveness evaluation; gamma-Chemokines; hypercholesterolemia; 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 是美国人发病率和死亡率的主要原因。动脉粥样硬化（血管增厚和硬化） 血管壁）优先在弯曲和分叉的动脉部位发展，在这些部位， 然而，目前动脉粥样硬化的药物治疗主要针对“全身性”风险因素， 例如高血胆固醇。我们相信靶向纳米医学具有革命性未来的独特潜力 动脉粥样硬化的医疗实践，通过纠正疾病引起的分子机制“区域性”， 放松血管。 考虑到动脉粥样硬化的局灶性性质，基于动脉壁的治疗是有吸引力的， 网站.扰动的血流增加内皮通透性并促进内皮炎症，导致内皮细胞损伤。 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脂蛋白。过量细胞胆固醇流出 由高密度脂蛋白（HDL）转运到肝脏，通过一个过程排泄 胆固醇逆向转运（RCT）不充分的RCT与胆固醇负荷的MAC相关， 噬菌体“泡沫细胞”。广泛的研究表明，抑制内皮炎症和促进内皮细胞增殖是一种有效的方法。 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。然而，它重新- 在病变中“空间上”调节这些致病分子机制是极其困难的。 microRNA（miRNAs）是动脉粥样硬化相关细胞事件的关键基因调控因子。干扰 血流增加内皮细胞miR-92 a促进血管炎症，而升高的miR-33 a抑制cho。 胆固醇外排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 针对动脉粥样硬化，旨在抑制病变中的内皮miR-92 a和巨噬细胞miR-33 a， 具体的时尚。我们的关键前提是，如果这项新战略成功， 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。我们雇用了焦油- 获得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- 材料分别对动脉粥样硬化病变和发炎的内皮细胞。此外，针对C-C 趋化因子受体2型（CCR 2）成功地将纳米颗粒递送至损伤单核细胞/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 微球复合物胶束系统特异性递送miR-92 a抑制剂至动脉粥样硬化易感内皮细胞 嗯.第二，将重新配制该复合物胶束以展示针对损伤宏观的肽。 用于递送针对miR-33 a的抑制剂。这些研究应进一步临床前开发，并根据- 一种治疗动脉粥样硬化的新治疗策略的最终临床试验，仍然是一个至关重要的 疾病过程。

项目成果

Polymorphism in peptide self-assembly visualized.

• DOI: 10.1073/pnas.2123197119
• 发表时间: 2022-02-08
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Tirrell M

Harnessing the Therapeutic Potential of Biomacromolecules through Intracellular Delivery of Nucleic Acids, Peptides, and Proteins.

• DOI: 10.1002/adhm.202102600
• 发表时间: 2022-06
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Tian, Yu;Tirrell, Matthew, V;LaBelle, James L.
• 通讯作者: LaBelle, James L.