Harnessing Platelet-Endothelial Interactions for Exosome Delivery

利用血小板-内皮相互作用进行外泌体递送

• 批准号: 10669452
• 负责人: Ke Cheng
• 金额: $ 76.71万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669452
• 关键词: Acute Lung Injury; Acute myocardial infarction; Animal Model; Animals; Applications Grants; Binding; Biological; Biological Assay; Biology; Biomedical Engineering; Blood Platelets; Blood Vessels; Blood flow; Body Fluids; Cardiovascular Diseases; Cardiovascular Models; Cells; Chemical Engineering; Clinical Trials; Collagen; Development; Dimensions; Dose; Endothelium; Engineering; Ensure; Exposure to; Extravasation; Family suidae; Fibronectins; Grant; Heart; Heart Injuries; Homing; Human; Hybrids; In Vitro; Infusion procedures; Injury; Interdisciplinary Study; Intravenous; Ischemia; Lipid Bilayers; Liver; Lung; Lung diseases; Macrophage; Mechanics; Mediating; Membrane; Mesenchymal Stem Cells; Mononuclear; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Names; Nature; Organ; Outcome; Paper; Patients; Phagocytes; Postdoctoral Fellow; Property; Regenerative Medicine; Regenerative research; Reperfusion Therapy; Research; Rodent Model; Safety; Science; Scientist; Societies; Spleen; Surface; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; United States National Institutes of Health; Ventricular; adult stem cell; cancer cell; cardiac repair; cell type; cellular engineering; combat; early phase clinical trial; engineered exosomes; exosome; experimental study; extracellular vesicles; fabrication; first-in-human; graduate student; injured; insight; interest; intravenous injection; ischemic injury; minority student; mouse model; nanoparticle; nanosized; novel strategies; paracrine; particle; porcine model; preclinical study; programs; recruit; repaired; replacement tissue; stem; stem cell delivery; stem cell exosomes; stem cells; stem-like cell; targeted delivery; therapeutic evaluation; tissue regeneration; training opportunity; uptake; von Willebrand Factor

PROJECT SUMMARY Studies have demonstrated that adult stem cells such as mesenchymal stem cells (MSCs) repair myocardial infarction (MI) or ischemia/reperfusion (I/R) injury by indirect paracrine mechanisms rather than by differentiation and tissue replacement. In the past decade, exosomes have emerged as promising cell-free agents for treating ischemic injury. Several exosome-based therapeutic companies have launched early phase clinical trials. Like most therapeutics, there is an urgent need for effective delivery strategy to ensure a sufficient number of exosomes to reach the injured tissue. Since they are nanosized natural lipid bilayer particles, one option is vascular delivery. However, high and repeated dosing is needed due to a large degree of off-target distribution to the mononuclear phagocyte system and other organs, such as the liver, spleen and lungs. Moreover, MSC-derived exosomes (MSC-XOs) need to compete with naturally existing exosomes in body fluids. Cellular binding and uptake of MSC-XOs also hinder the therapeutic effects. Novel approaches are required to deliver therapeutic exosomes to cells in injured tissues. Ideally, modified exosomes should 1) reduce the clearance by the mononuclear phagocyte system, 2) bind to injured blood vessels, and 3) be efficiently uptake by target cell types in injured tissues. It has been established that acute MI can induce vascular damage and expose components of the subendothelial matrix including collagen, fibronectin and von Willebrand factor (vWF) to recruit platelets. Platelets can bind to and accumulate on injured vasculature following MI. Instead of generically modifying the parental cells or chemically engineering exosomes, we used platelet membranes to envelope exosomes (to make P-XOs) and increase their macropinocytosis-mediated cellular internalization, and their ability to target the injured tissue. In this proposed study, we plan to investigate the fabrication, characterization and toxicity of P-XOs (AIM 1). After that, we will test the therapeutic effect of P-XOs on a mouse model (AIM 2) and a porcine model (AIM 3) with cardiac injury. Our study will provide new insights on cellular internalization mechanism of exosomes, targeting properties and mechanism of the P-XOs treatment. Together, the proposed mechanistic and translational experiments will provide a scientific premise to understand system administrated exosomes while suggesting new approaches for promoting targeting and therapeutic effect of therapeutic exosomes.

项目概要 研究表明，间充质干细胞（MSC）等成体干细胞可以修复 心肌梗塞（MI）或缺血/再灌注（I/R）损伤是通过间接旁分泌机制而不是通过 分化和组织替代。在过去的十年中，外泌体已成为一种有前途的无细胞 用于治疗缺血性损伤的药物。几家基于外泌体的治疗公司已启动早期阶段 临床试验。与大多数疗法一样，迫切需要有效的递送策略以确保 足够数量的外泌体到达受损组织。由于它们是纳米级的天然脂质双层 颗粒，一种选择是血管输送。然而，由于很大程度上，需要高剂量和重复给药。 脱靶分布到单核吞噬细胞系统和其他器官，如肝脏、脾脏和 肺。此外，MSC衍生的外泌体（MSC-XO）需要与自然存在的外泌体竞争 体液。 MSC-XO 的细胞结合和摄取也会阻碍治疗效果。新颖的方法是 将治疗性外泌体递送至受损组织中的细胞所需。理想情况下，修饰的外泌体应该 1) 减少单核吞噬细胞系统的清除，2) 与受损血管结合，3) 受损组织中的靶细胞类型可有效摄取。已证实急性心肌梗死可诱发 血管损伤并暴露内皮下基质成分，包括胶原蛋白、纤连蛋白和冯 血友病因子 (vWF) 招募血小板。血小板可以结合并积聚在受伤的脉管系统上 以下 MI。我们没有使用一般性的修饰亲本细胞或化学工程外泌体的方法，而是使用 血小板膜包裹外泌体（生成 P-XO）并增强其巨胞饮作用介导的能力 细胞内化及其针对受损组织的能力。在这项拟议的研究中，我们计划 研究 P-XO 的制造、表征和毒性 (AIM 1)。之后我们将测试治疗效果 P-XOs 对心脏损伤小鼠模型 (AIM 2) 和猪模型 (AIM 3) 的影响。我们的研究将 为外泌体的细胞内化机制、靶向特性和机制提供新的见解 P-XOs 治疗的过程。总之，所提出的机制和转化实验将提供 了解系统管理的外泌体的科学前提，同时提出新的方法 促进治疗性外泌体的靶向和治疗效果。