Dual-action drug coated balloon to mitigate neointimal hyperplasia and promote endothelialization.

双作用药物涂层球囊可减轻内膜增生并促进内皮化。

• 批准号: 10482211
• 负责人: Jennifer Sherwood
• 金额: $ 49.73万
• 依托单位: ENDOMIMETICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482211
• 关键词: Acute; Adhesions; Agreement; Amputation; Angioplasty; Animals; Area; Arteries; Atherectomy; Balloon Angioplasty; Bioreactors; Blood Platelets; Blood Vessels; Caliber; Cell Proliferation; Data; Development; Dose; Drug Utilization; Drug usage; Elements; Encapsulated; Endothelial Cells; Endothelium; Evaluation; Excipients; Family suidae; Fracture; Goals; Histologic; Hydrogels; Hydrophobicity; Hyperplasia; Impairment; In Vitro; Inflammation; Inflammatory Response; Infusion procedures; Injury; Kinetics; Lead; Leg; Legal patent; Lesion; Life Style; Liposomes; Location; Metals; Methods; Modeling; Morbidity - disease rate; Nitric Oxide; Organic solvent product; Oryctolagus cuniculus; Paclitaxel; Patients; Peptides; Peripheral arterial disease; Persons; Pharmaceutical Preparations; Phase; Physiological; Process; Recurrence; Risk; Safety; Sirolimus; Small Business Innovation Research Grant; Smooth Muscle Myocytes; Stenosis; Stents; Stroke; Symptoms; System; Thrombosis; Tissues; Ultrasonics; antiproliferative drugs; base; biomaterial compatibility; cell growth; cell motility; claudication; design; dosage; drug action; experience; healing; iliac artery; improved; in vitro Model; in vivo; industry partner; innovation; novel; novel strategies; phase 1 study; prevent; recruit; restenosis; restoration

Project Summary The management of atherosclerotic vascular stenosis has undergone major advances over the past decades, yet challenges remain. Bare metal stents (BMS) were plagued by unacceptably high rates of in-stent restenosis (ISR). Although drug-eluting stents (DES) were developed primarily to reduce neointimal hyperplasia (NIH), rates of ISR remain at least 5-15%. Furthermore, the use of stents remains controversial in certain situations, including within vessels with small diameters, long lesions, bifurcations, repeated ISR, and in segments of peripheral artery disease (PAD). It is estimated that 8.5 million people in the U.S. alone have PAD, which can lead to further morbidities including life-style limiting claudication, amputation, and stroke. In certain locations in the legs, stents carry a significant risk of stent fracture: stent fracture rates can approach 37%, often resulting in restenosis or total vessel occlusion. The use of drug-coated balloons (DCB) has emerged as an attractive alternative to treat both PAD and ISR lesions without leaving behind a permanent stent. DCB are angioplasty balloons coated with an anti-proliferative drug to prevent restenosis, usually paclitaxel. However, recent studies have called the safety of paclitaxel-coated balloons into question; thus, alternative anti- restenosis strategies are needed. Furthermore, the drugs utilized on DCBs impair re-endothelialization, which can lead to late thrombosis, inflammation, restenosis, and neoatherosclerosis. Ideally, the DCB would prevent neointimal proliferation and restenosis while encouraging endothelial cell growth and restoration of vascular function. Endomimetics, LLC has developed a novel dual-action coating for DCB that could reduce NIH and restenosis and enhance re-endothelialization and vascular healing. The coating consists of a nitric oxide (NO) releasing bionanomatrix composed of biocompatible peptide-based material along with liposome-encapsulated sirolimus. The liposome encapsulated sirolimus and bionanomatrix can be effectively transferred to the vessel wall and provide sustained delivery to reduce NIH and restenosis. Additionally, the bionanomatrix provides sustained release of NO from the multi-layered bionanomatrix to stimulate endothelialization and reduce inflammation. This dual- action strategy could overcome the limitations of current therapies for PAD and ISR by reducing NIH and restenosis and enhancing re-endothelialization and vascular healing. In this Phase I SBIR, we propose to evaluate and optimize the dual-action DCB coating. This will include evaluation of coating stability, release kinetics, and assessment of drug transfer and retention in an in vitro hydrogel vessel mimicking system as well as an ex vivo porcine artery bioreactor model under physiological conditions. We will then evaluate the novel dual-action DCB in vivo in a rabbit model. Development of a DCB coating that can reduce NIH and restenosis and enhance re-endothelialization and vascular function may have significant impact for treatment of patients with PAD and ISR. With successful completion of Phase I, we plan to move forward in Phase II to larger animal studies and then to GLP evaluation.

项目摘要 动脉粥样硬化性血管狭窄的治疗在过去已经取得了重大进展 几十年来，挑战依然存在。裸金属支架（BMS）受到支架内不可接受的高比率的困扰， 再狭窄（ISR）。虽然药物洗脱支架（DES）的开发主要是为了减少新生内膜增生 (NIH)ISR的发生率至少保持在5- 15%。此外，在某些情况下，支架的使用仍然存在争议。 情况，包括小直径血管、长病变、分叉、反复ISR和 外周动脉疾病（PAD）。据估计，仅在美国就有850万人患有PAD， 这可导致进一步的发病率，包括生活方式限制性跛行、截肢和中风。在某些 在腿部的位置，支架具有显著的支架断裂风险：支架断裂率可接近37%，通常 导致再狭窄或全部血管闭塞。药物涂层球囊（DCB）的使用已成为 治疗PAD和ISR病变而不留下永久性支架的有吸引力的替代方案。DCB是 血管成形术球囊涂有抗增殖药物，以防止再狭窄，通常是紫杉醇。然而，在这方面， 最近的研究对紫杉醇涂层球囊的安全性提出了质疑;因此， 需要战略。此外，用于DCB的药物损害再内皮化，这可导致 晚期血栓形成、炎症、再狭窄和新动脉粥样硬化。理想情况下，DCB将防止新生内膜 增殖和再狭窄，同时促进内皮细胞生长和血管功能恢复。 Endomimetics，LLC开发了一种新型DCB双作用涂层，可减少NIH和再狭窄 并增强再内皮化和血管愈合。该涂层由一氧化氮（NO）释放剂组成， 生物纳米基质由生物相容性肽基材料沿着与脂质体包封的西罗莫司组成。 包封西罗莫司和生物纳米基质的脂质体可以有效地转移到血管壁， 提供持续输送以减少NIH和再狭窄。此外，生物纳米基质提供持续的 从多层生物纳米基质中释放NO以刺激内皮化并减少炎症。这 双重作用策略可以通过减少NIH和 再狭窄和增强再内皮化和血管愈合。 在第一阶段SBIR中，我们建议评估和优化双作用DCB涂层。这将包括 评价包衣稳定性、释放动力学以及体外药物转移和保留的评估 水凝胶血管模拟系统以及生理条件下的离体猪动脉生物反应器模型 条件然后，我们将在兔模型中评价新型双作用DCB的体内作用。 开发可减少NIH和再狭窄并增强再内皮化的DCB涂层， 血管功能可能对PAD和ISR患者的治疗有重要影响。与成功 在完成第一阶段后，我们计划在第二阶段进行更大的动物研究，然后进行GLP评估。