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

项目摘要 动脉粥样硬化性血管狭窄的治疗在过去经历了重大进展。 几十年来，挑战依然存在。裸露金属支架(BMS)被不可接受的高支架置入率所困扰 再狭窄(ISR)。尽管药物洗脱支架(DES)的开发主要是为了减少新生内膜的增生 (NIH)，ISR的比率保持在至少5%-15%。此外，支架的使用在某些方面仍然存在争议。 情况，包括小直径、长病变、分叉、重复的ISR和 外周动脉疾病节段(PAD)。据估计，仅在美国就有850万人患有PAD， 这可能会导致进一步的疾病，包括生活方式的限制性跛行、截肢和中风。在某些情况下 在腿部的位置，支架具有很大的支架断裂风险：支架断裂率可接近37%，通常 导致再狭窄或血管完全闭塞。药物涂层球囊(DCB)的使用已经成为一种 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， 最近的研究对紫杉醇涂层球囊的安全性提出了质疑；因此，替代的抗再狭窄药物 战略是必要的。此外，用于DCB的药物会损害再内皮化，这可能导致 晚期血栓形成、炎症、再狭窄和新的动脉粥样硬化。理想情况下，DCB可以防止新生内膜 促进血管内皮细胞的生长和血管功能的恢复。 Enomimtics，LLC已经为DCB开发了一种新的双作用涂层，可以减少NIH和再狭窄 促进血管再内皮化和血管愈合。涂层由一氧化氮(NO)的释放组成 由生物相容的多肽材料和脂质体包裹的西罗莫司组成的生物支架。 脂质体包裹的西罗莫司和生物肿瘤基质能有效地转移到血管壁，并 提供持续的分娩，以减少NIH和再狭窄。此外，生物异常线虫提供了持续的 从多层生物肿瘤基质中释放NO，以刺激内皮化和减轻炎症。这 双作用策略可以通过减少NIH和ISR来克服目前治疗PAD和ISR的局限性 再狭窄，促进再内皮化和血管愈合。 在第一阶段SBIR中，我们建议对双作用DCB涂层进行评估和优化。这将包括 评价包衣的稳定性、释放动力学以及评价药物在体外的转移和保留 生理状态下模拟水凝胶血管系统和体外猪动脉生物反应器模型 条件。然后，我们将在兔模型中对新型双作用DCB进行体内评估。 DCB涂层的开发可减少NIH和再狭窄，并增强再内皮化和 血管功能对PAD和ISR患者的治疗有重要影响。随着成功 完成第一阶段，我们计划在第二阶段推进到更大的动物研究，然后到GLP评估。

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.