Novel coatings releasing synergistic polyphenols promote vascular healing

项目摘要 心血管疾病（CVD）仍然是美国的头号死亡原因。 未经治疗，CVD可导致关键动脉闭塞，从而导致主要心脏病。 活动临床医生通常使用球囊扩张机械纠正动脉阻塞， 病变区域和金属支架的放置，以帮助保持动脉开放。但 在介入过程中发生的血管过度拉伸会损害动脉壁。 这种损伤通常会导致由于增殖引起的动脉再狭窄（再狭窄）。 血管壁内的平滑肌细胞。药物洗脱支架（DES）的开发是为了 抑制平滑肌细胞增殖，但具有的缺点是， 动脉开放时，它们也会阻止功能性内皮细胞重新排列血管壁 层.这就要求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通常致命的晚期凝血事件。 申请人已经开发了一种新的涂层，用于协同的血管内药物递送。 天然产品，防止对血管成形术治疗的负面反应， 动脉再狭窄然而，与目前用于支架涂层的药物不同， 化合物已经显示出有效地加速内皮伤口愈合。而且我们 利用支架和血管成形术的大鼠模型的初步数据显示， 白藜芦醇和槲皮素（RQ-DES）显著降低了再狭窄，同时， 加速再内皮化以完成愈合过程。这些的意义 新的RQ-DES是通过促进血管愈合（即，再内皮化），它们在 血管介入可以减少双重抗血小板治疗的需要， 更安全的长期结果。 在本I期提案中，申请人将使用FDA认可的临床相关家兔 测试与市售药物相比，RQ-DES是否促进再内皮化的模型 支架装置。使用其他公司资金的补充研究将测试RQ- DES还降低了再狭窄的程度。这些研究将为更大规模的第二阶段奠定基础 该项目旨在全面表征我们涂料的安全性和有效性， 商业化我们的商业化努力将旨在使用RQ涂层， 不同的应用，包括冠状动脉和外周动脉疾病，以及其他 其中新生内膜增生导致临床并发症的应用，例如， 动静脉移植失败。

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.