A Novel Drug Delivery System to Treat Peripheral Arterial Disease

 描述（由申请人提供）：下肢外周动脉疾病（PAD）影响美国超过500万成年人，并且通过干预仍未解决。在外周动脉中展开的裸金属支架失败，因为它们缺乏抗增殖药物，并且由于严重的外周动脉变形（扭曲、弯曲和缩短）而断裂率高（高达68%）。药物洗脱支架（DES）失败的原因是其抗增殖药物没有输送到内侧壁或被内侧壁保留。DES也受限于血管尺寸，这排除了其在血管直径小于2.0 mm的膝下（BTK）应用中的使用。BTK血管的治疗对于PAD糖尿病患者的保肢至关重要，但在这些情况下，球囊血管成形术是唯一的选择。不幸的是，球囊血管成形术的再狭窄率高于支架。这项拟议的研究将开发一种新的策略，在不使用金属平台的情况下输送和保留抗增殖药物。 治疗PAD的方法。这将使用最先进的球囊灌注导管和药物载体角蛋白（一种从人类头发中提取的蛋白质）来完成。角蛋白提供了以受控速率递送抗增殖剂紫杉醇并增加保留的手段 在血管壁上。此外，角蛋白在愈合的早期阶段激发有益的炎症反应。据推测，紫杉醇-角蛋白赋形剂通过灌注导管以受控速率递送至病变壁导致中膜平滑肌细胞静止和快速再内皮化。首先测试不同的角蛋白浓度和负载参数，以优化使用灌注导管的紫杉醇输送和保留（具体目标1）。这些研究将使用一种新的离体猪动脉循环系统来完成，该系统可准确预测药物滞留并节省资源和动物利用。此外，将在相关临床前模型中评价对角蛋白-紫杉醇的血管反应（特定目标2）。具体而言，将通过长达28天的药代动力学分析测量紫杉醇动脉水平。将通过组织病理学定量平滑肌细胞增殖、血管重塑、损伤和炎症。将通过扫描电子显微镜和荧光显微镜定量内皮细胞恢复。通过这些目的，我们将证明灌注导管输送紫杉醇-角蛋白赋形剂以及抑制新生内膜生长、减少炎症浸润和改善再内皮化的有效性。最终，这种方法可以克服目前介入设备的局限性，改善数百万PAD患者的生活质量。

 DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) of the lower extremities affects more than 5 million adults in the US and remains unresolved by intervention. Bare metal stents deployed in peripheral arteries fail because they lack anti-proliferative drugs and fracture at high rates (up to 68%) due to severe peripheral artery deformation (twisting, bending, and shortening). Drug eluting stents (DES) fail as their anti-proliferative drugs are not delivered to or retained by the medial wall. DES are also limited to vessel size, which precludes their use in below-the-knee (BTK) applications where vessel diameters are less than 2.0 mm. Treatment of BTK vessels are essential for limb salvage in diabetic patients with PAD, however in these circumstances, balloon angioplasty is the only option. Unfortunately, restenosis rates of balloon angioplasty are higher compare to stents. The proposed study will develop a new strategy to deliver and retain anti-proliferative drugs without the use of a metallic platform as a means of treating PAD. This will be accomplished using a state-of-the-art balloon perfusion catheter and a drug carrier keratin, a protein extracted from human hair. Keratin provides a mean to deliver the anti-proliferative agent paclitaxel at a controlled rate and increase retention in the vessel wall. In addition, keratin elicits beneficial inflammatory responses during early phase of healing. It is hypothesized that a paclitaxel-keratin excipient delivered at a controlled rate by the perfusion catheter to the lesion wall results in medial smooth muscle cell quiescence and rapid re-endothelialization. Varying keratin concentration and loading parameters will first be tested to optimize paclitaxel delivery and retention using the perfusion catheter (Specific Aim 1). These studies will be accomplished using a novel ex vivo porcine artery circulatory system that accurately predicts drug retention and saves resources and animal utilization. In addition, the vascular response to the keratin-paclitaxel will be evaluated in a relevant pre-clinical model (Specific Aim 2). Specifically, paclitaxel arterial levels will be measured by pharmacokinetic analysis up to 28 days. Smooth muscle cell proliferation, vessel remodeling, injury and inflammation will be quantified by histopathology. Endothelial cell recovery will be quantified by scanning electron microscopy and fluorescent microscopy. Through these aims, we will demonstrate the effectiveness of the perfusion catheter to deliver paclitaxel-keratin excipient and to inhibit neointimal growth, reduce inflammatory infiltrates and improve re- endothelialization. Ultimately, this approach can overcome limitations of current interventional devices and improve the quality of life for millions of patients suffering with PAD.