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.

项目摘要 研究表明，成年干细胞（例如间充质干细胞（MSC）修复） 心肌梗塞（MI）或缺血/再灌注（I/R）通过间接旁分泌机制而不是 分化和组织替代。在过去的十年中，外泌体已成为有希望的无细胞 治疗缺血性损伤的药物。几家基于外部的治疗公司已经成立了早期阶段 临床试验。像大多数治疗学一样，迫切需要有效的交付策略来确保 足够数量的外泌体到达受伤的组织。由于它们是纳米天然脂质双层的 颗粒，一种选择是血管递送。但是，由于很大的程度，需要高剂量和重复给药 单核分布到单核吞噬细胞系统和其他器官，例如肝脏，脾脏和 肺。此外，MSC衍生的外泌体（MSC-XOS）需要与自然存在的外泌体竞争 体液。 MSC-XOS的细胞结合和摄取也阻碍了治疗作用。新颖的方法是 需要将治疗性外泌体运送到受伤组织中的细胞。理想情况下，修改的外泌体应1） 减少单核吞噬细胞系统的清除率，2）与受伤的血管结合，3） 受伤组织中的靶细胞类型有效摄取。已经确定急性MI可以诱导 血管损伤并暴露了包括胶原蛋白，纤连蛋白和von的下皮基质的成分 Willebrand因子（VWF）招募血小板。血小板可以与受伤的脉管系统结合并积聚 遵循Mi。我们使用 血小板膜到包膜外泌体（制造P-XO）并增加其大胞毒性介导的 细胞内在化及其靶向受伤组织的能力。在这项拟议的研究中，我们计划 研究P-XOS的制造，表征和毒性（AIM 1）。之后，我们将测试治疗性 P-XO对小鼠模型（AIM 2）和心脏损伤的猪模型（AIM 3）的影响。我们的研究愿意 提供有关外泌体细胞内在化机制，靶向特性和机制的新见解 P-XOS处理。共同提出的机械和翻译实验将提供 科学的前提了解系统管理外泌体，同时提出新方法 促进治疗外泌体的靶向和治疗作用。