Novel coatings releasing synergistic polyphenols promote vascular healing

描述（由申请人提供）：心血管疾病（CVD）仍然是美国的头号死亡原因，如果不及时治疗，CVD可能导致关键动脉闭塞，从而引发重大心脏事件。临床医生通常使用球囊扩张病变区域和放置金属支架来帮助保持动脉畅通，从而机械地纠正动脉阻塞。然而，介入治疗过程中血管的过度伸展会损害动脉壁。由于血管壁内平滑肌细胞的增生，这种损伤常常导致动脉再狭窄（再狭窄）。药物洗脱支架（DES）的发展是为了抑制平滑肌细胞的增殖，但其缺点是，在保持动脉畅通的同时，它们也阻碍了血管壁与功能性内皮细胞层的重新粘合。这就要求患者接受双重抗血小板治疗的长期治疗，以防止在植入部位发生罕见但往往致命的晚期凝血事件。申请人已经开发了一种新的涂层，用于血管内药物递送的协同天然产物，防止血管成形术治疗的负面反应，促进动脉再狭窄。然而，与目前用于支架涂层的药物不同，这些化合物已被证明能积极加速内皮伤口愈合。此外，我们利用大鼠支架植入和血管成形术模型的初步数据显示，白藜芦醇和槲皮素（RQ-DES）包被的DES显著减少再狭窄，同时加速再内皮化以完成愈合过程。这些新的RQ-DES的意义在于，通过促进血管愈合（即再内皮化），它们在血管干预中的应用可以减少对双重抗血小板治疗的需求，并提供更安全的长期结果。在这个I期申请中，申请人将使用fda认可的临床相关的兔子模型来测试RQ-DES与商业支架装置相比是否能促进再内皮化。使用其他公司资金的补充研究将测试RQ- DES是否也能减少再狭窄的程度。这些研究将为更大的二期项目奠定基础，旨在全面表征我们涂料的安全性和有效性，以进一步商业化。我们的商业化努力将旨在将RQ涂层用于各种应用，包括冠状动脉和外周动脉疾病，以及其他新内膜增生导致临床并发症的应用，如动静脉移植失败。

DESCRIPTION (provided by applicant): 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, 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.