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Novel coatings releasing synergistic polyphenols promote vascular healing

新型涂层释放协同多酚促进血管愈合

基本信息

批准号：
8918078
负责人：
TAMMY R DUGAS
金额：
$ 2.38万
依托单位：
REQUISITE BIOMEDICAL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918078
关键词：
Address Americas Angioplasty Animal Model Animals Antiplatelet Drugs Area Arteries Biological Factors Blood Platelets Blood Vessels Blood coagulation Blood flow Cardiac Cardiovascular Diseases Cause of Death Cell Proliferation Clinical Clinical Trials Coagulation Process Consultations Coronary Coronary artery Data Development Devices Disadvantaged Drug Delivery Systems Drug Formulations Drug Kinetics Drug usage Endothelial Cells Endothelium Event FDA approved Family suidae Funding Generations Goals Healed Health Hyperplasia Implant Inflammation Injury Intervention Left Lesion Letters Licensing Lower Extremity Marketing Medical Medical Device Metals Modeling Oryctolagus cuniculus Outcome Patients Peripheral Peripheral arterial disease Pharmaceutical Preparations Phase Physicians Poison Procedures Process Property Quercetin Rattus Research Design Resveratrol Risk Rodent Model Safety Site Small Business Technology Transfer Research Smooth Muscle Myocytes Solutions Source Staging Stenosis Stents Testing Thrombosis Time Tubular formation United States Validation Wound Healing artery occlusion biomaterial compatibility clinically relevant commercial application commercialization graft failure healing high risk human FRAP1 protein implantation improved new technology novel phase 1 study phase 2 study polyphenol prevent red wine research study response restenosis vascular smooth muscle cell proliferation

项目摘要

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.

描述（由申请人提供）：心血管疾病（CVD）仍然是美国的头号死因。如果不进行治疗，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机械地纠正动脉阻塞，以帮助保持动脉开放。然而，干预期间发生的血管过度伸展会损害动脉壁。由于血管壁内平滑肌细胞的增殖，这种损伤通常会导致动脉再狭窄（再狭窄）。药物洗脱支架（DES）被开发用于抑制平滑肌细胞增殖，但缺点是在保持动脉开放的同时，它们也阻止了血管壁与功能性内皮细胞层的重新排列。这要求患者接受双重抗血小板治疗的长期治疗，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用于协同天然产物的血管内药物递送的新涂层，其防止对血管成形术治疗的促进动脉再狭窄的负面反应。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可以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，涂覆有白藜芦醇和槲皮素的DES（RQ-DES）显著降低了再狭窄，同时加速了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），它们在血管介入中的使用可以减少双重抗血小板疗法的需要，以及提供更安全的长期结果。在本I期提案中，申请人将使用FDA认可的临床相关家兔模型来测试与市售支架器械相比，RQ-DES是否促进再内皮化。使用其他公司资金的补充研究将测试RQ-DES是否也降低了再狭窄的程度。这些研究将为一个更大的第二阶段项目奠定基础，该项目旨在充分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，以及新生内膜增生导致临床并发症的其他应用，如动静脉移植物失败。