Novel coatings releasing synergistic polyphenols promote vascular healing

简介(申请人提供)：心血管疾病(CVD)在美国仍然是头号死亡原因。如果不进行治疗，CVD可能会导致关键动脉闭塞，从而引发重大心脏事件。临床医生通常使用球囊扩张受损区域并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，介入过程中发生的血管过度伸展会损害动脉壁。这种损伤通常会导致动脉再狭窄(再狭窄)，这是由于血管壁内的平滑肌细胞增殖所致。药物洗脱支架(DES)是用来抑制血管平滑肌细胞增殖的，但其缺点是在保持动脉通畅的同时，也阻止了具有功能的内皮细胞层的血管壁再通。这需要患者接受双重抗血小板疗法的长期治疗，以防止植入部位罕见但往往是致命的晚期凝血事件。申请人已经开发了一种新的涂层，用于血管内给药协同天然产品，防止促进动脉再狭窄的血管成形术治疗的负面反应。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促进内皮伤口的愈合。此外，我们利用大鼠支架和血管成形术模型的初步数据显示，白藜芦醇和槲皮素包裹的DES(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使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。在这个第一阶段的提案中，申请人将利用FDA接受的临床相关的兔模型来测试与商业支架装置相比，RQ-DES是否促进再内皮化。使用其他公司资金的补充性研究将测试RQ-DES是否也能降低再狭窄的程度。这些研究将为一个更大的第二阶段项目奠定基础，该项目旨在全面表征我们涂料的安全性和有效性，以便进一步商业化。我们的商业化努力将致力于将RQ涂层用于各种应用，包括冠状动脉和外周动脉疾病，以及其他导致临床并发症的新内膜增生的应用，例如动静脉移植失败。

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.