Novel Engineered Particle Platform for Endothelium Regeneration

描述（由申请人提供）：尽管经皮冠状动脉介入（PCI）方式（如血管成形术）通常用作治疗心血管疾病的标准程序，心血管疾病是美国的头号死因，但是它们具有许多局限性，包括晚期再狭窄和血栓形成。经皮冠状动脉介入治疗血管损伤后内皮细胞再生延迟被认为是这些缺陷的主要原因，尤其是晚期血栓形成。事实上，内皮层作为动脉的天然屏障，在防止血小板粘附和平滑肌细胞增殖和迁移中起重要作用。因此，我们的长期目标是设计新的多功能靶向纳米颗粒（MTN），可以特异性结合到受损的动脉部位，作为临时屏障， 防止血小板粘附和平滑肌细胞迁移，同时募集干细胞如内皮祖细胞（EPCs）以增强内皮再生。新的工程MTN将防止血小板粘附并促进损伤部位的快速内皮愈合，从而允许原位再内皮化的潜力。 为了达到我们的目标，提出了三个具体的目标：（1）合成和表征新型生物降解，生物相容性，血液相容性生物材料，包括掺杂聚酯（UPE）的血管组织工程应用。(2)为了配制MTN，其由UPE制成，负载有包括生长因子的治疗试剂，并与损伤的动脉壁靶向配体和EPC结合分子缀合。MTN的各种性质，包括MTN对血小板沉积和内皮再生的影响，将在体外进行进一步研究。(3)使用动物模型确定新型MTN在体内对PCI损伤后原位内皮再生的有效性。 这项研究有几个创新的方面。我们的工程MTN，基于组织工程和纳米技术的最新进展，提供了一种独特的策略，以促进内皮再生，从而刺激PCI后的血管愈合，同时防止血小板粘附。我们研究的另一个新方面是工程化MTN利用以下组合：（1）靶向受损动脉，（2）通过充当临时屏障减少血小板粘附，（3）在靶向部位捕获EPC，间接减少受损区域的血小板沉积，以及（4）使用工程化组织纳米支架促进内皮再生。拟议的MTN将带来PCI相关血管损伤治疗的显着改善，并应在心血管疾病治疗中产生高度的科学和经济影响。

DESCRIPTION (provided by applicant): Although percutaneous coronary intervention (PCI) modalities such as angioplasty are often used as the standard procedure for treatment of cardiovascular disease, the number one cause of death in the U.S., they have many limitations including late restenosis and thrombosis. Delayed endothelium regeneration after vascular injury by PCI has been indicated as a major cause for these drawbacks, especially late thrombosis. Indeed, endothelium layer serves as a nature barrier for the artery and plays an important role in the prevention of platelet adhesion and smooth muscle cell proliferation and migration. Thus our long-term goal is to engineer novel multifunctional targeting nanoparticles (MTNs) that can bind specifically onto the injured arterial site to serve as a temporary barrier to prevent platelet adhesion and smooth muscle cell migration while recruiting stem cells such as endothelial progenitor cells (EPCs) for enhancing endothelium regeneration. The novel engineered MTNs will prevent platelet adhesion and encourage rapid endothelium healing at the injured site, allowing the potential of re-endothelialization in situ. To reach our goal, three specific aims are proposed: (1) To synthesize and characterize novel biodegradable, biocompatible, and hemo-compatible biomaterials including urethane-doped polyesters (UPEs) for vascular tissue engineering applications. (2) To formulate MTNs, which are made of UPEs, loaded with therapeutic reagents including growth factors, and conjugated with both the injured arterial wall targeting ligands and the EPC binding molecules. Various properties of MTNs including the effects of MTNs on platelet deposition and endothelium regeneration in vitro will be further investigated. (3) To determine the effectiveness of novel MTNs in vivo for endothelium regeneration in situ following PCI injury using animal models. There are several innovative aspects associated with this research. Our engineered MTNs, based on recent advances in both tissue engineering and nanotechnology, provide a unique strategy to promote endothelium regeneration and hence to stimulate vascular healing after PCI while preventing platelet adhesion. Another novel aspect of our research is that the engineered MTNs utilize the combination of (1) targeting injured arteries, (2) reducing platelet adhesion by serving as a temporary barrier, (3) capturing EPC at the targeted sites, which indirectly reduce platelet deposition on the damaged areas, and (4) promoting endothelium regeneration using engineered tissue nanoscaffolds. The proposed MTNs will bring in a significant improvement in the treatment of PCI-associated vascular injury and should generate highly scientific and economic impacts in cardiovascular disease therapy.