Novel coatings releasing synergistic polyphenols promote vascular healing

项目总结 心血管疾病(CVD)仍然是美国左翼人士的头号死因 如果不进行治疗，心血管疾病可能导致关键动脉闭塞，从而导致心脏大血管 事件。临床医生经常使用球囊扩张来机械地纠正动脉阻塞。 金属支架的受损区域和放置位置，以帮助保持动脉的畅通。然而， 介入过程中发生的血管过度伸展对动脉壁造成损害。 这种损伤通常会导致动脉再狭窄(再狭窄)，这是由于血管的增殖 血管壁内的平滑肌细胞。药物洗脱支架(DES)被开发用于 抑制平滑肌细胞的增殖，但有一个缺点，就是在保持 动脉是开放的，它们也阻止了血管壁与功能内皮细胞的重新连接 一层。这需要患者接受长期的双重抗血小板治疗。 以防止植入部位发生罕见但往往致命的晚期凝血事件。 申请人已经开发出一种用于协效血管内给药的新涂层 防止血管成形术治疗的负面反应的天然产品 动脉再次狭窄。然而，与目前用于支架涂层的药物不同，这些药物 化合物已被证明能积极促进内皮细胞伤口的愈合。而且，我们的 利用大鼠支架和血管成形术模型的初步数据显示，DES涂层有 白藜芦醇和槲皮素(RQ-DES)显著减少再狭窄，同时， 加速再内皮化以完成愈合过程。这些因素的意义 新的RQ-DES是通过促进血管愈合(即重新内皮化)，它们在 血管干预可以减少双重抗血小板疗法的需要，并提供 为了更安全的长期结果。 在这个第一阶段的提案中，申请人将使用FDA认可的、临床相关的兔子 模型以测试RQ-DES是否促进再内皮化 支架装置。使用其他公司资金的补充性研究将测试RQ- DES还可以减少再狭窄的程度。这些研究将为更大的第二阶段奠定基础 该项目旨在充分表征我们的涂料的安全性和有效性，以便进一步 商业化。我们的商业化努力将致力于将RQ涂层用于 应用广泛，包括冠状动脉和外周动脉疾病以及其他 新生内膜增生导致临床并发症的应用，如在 动静脉移植物衰竭。

PROJECT SUMMARY Cardiovascular disease (CVD) remains the number one cause of death in the U.S. Left untreated, CVD can result in the occlusion of key arteries that can precipitate a major cardiac event. Clinicians routinely correct arterial blockages mechanically using a balloon expansion of the lesioned area and placement of a metallic stent to help keep the arteries open. However, the overstretch of the vessel that takes place during the intervention is damaging to the artery wall. This damage often precipitates a re-narrowing of the artery (restenosis) due to the proliferation of smooth muscle cells within the vascular wall. Drug-eluting stents (DES) were developed to inhibit smooth muscle cell proliferation, but have the disadvantage that while keeping the arteries open, they also prevent the relining of the vessel wall with a functional endothelial cell layer. This requires that patients undergo long-term treatment with dual anti-platelet therapies in order to prevent rare, but often fatal late-term clotting events at the site of the implant. The applicant has developed a new coating for the endovascular drug delivery of synergistic natural products that prevent the negative responses to angioplasty treatment that promote artery re-narrowing. However, unlike the drugs currently used for stent coatings, these compounds have been shown to actively accelerate endothelial wound healing. Moreover, our preliminary data utilizing a rat model of stenting and angioplasty showed that DES coated with resveratrol and quercetin (RQ-DES) dramatically reduced restenosis, while at the same time, accelerated re-endothelialization to complete the healing process. The significance of these new RQ-DES is that by promoting vascular healing (i.e., re-endothelialization), their use in vascular interventions could reduce the need for dual anti-platelet therapies, as well as provide for safer long term outcomes. In this phase I proposal, the applicant will utilize an FDA-accepted, clinically relevant rabbit model to test whether the RQ-DES promotes re-endothelialization compared to a commercial stent device. Complementary studies using other company funding will test whether the RQ- DES also reduces the extent of restenosis. These studies will set the stage for a larger phase II project aimed at fully characterizing the safety and efficacy of our coatings for further commercialization. Our commercialization efforts will be aimed at the use of an RQ coating for diverse applications, including coronary artery and peripheral artery diseases, as well as other applications in which neointimal hyperplasia contributes to clinical complications, such as in arteriovenous graft failure.