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A Novel Drug Delivery System to Treat Peripheral Arterial Disease

治疗外周动脉疾病的新型药物输送系统

基本信息

批准号：
9017659
负责人：
Saami K Yazdani
金额：
$ 41.31万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-05 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017659
关键词：
Address Adult Affect Aftercare Anti-Inflammatory Agents Anti-inflammatory Arteries Balloon Angioplasty Blood Vessels Bromodeoxyuridine Caliber Cardiovascular system Catheters Cell Proliferation Cell physiology Data Deposition Devices Drug Carriers Drug Delivery Systems Drug Kinetics Drug Transport Effectiveness Endothelial Cells Ensure Excipients FDA approved Family suidae Fracture Goals Growth Hair Healed Histopathology Human Immunohistochemistry Impaired wound healing Infiltration Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Injury Intercellular Junctions Intervention Keratin Kinetics Knee Lesion Limb Salvage Lower Extremity Measures Mechanics Medial Metals Methods Microscopy Modeling Oryctolagus cuniculus Outcome PECAM1 gene Paclitaxel Patients Perfusion Peripheral Peripheral arterial disease Pharmaceutical Preparations Phase Phenotype Pre-Clinical Model Procedures Process Production Proliferating Proteins Quality of life Recovery Risk Role Safety Scanning Electron Microscopy Smooth Muscle Myocytes Staging Staining method Stains Stents System Techniques Testing Thrombosis Time Tissues animal resource base cytokine design diabetic patient healing improved in vivo macrophage novel novel therapeutics pressure public health relevance response restenosis treatment strategy

项目摘要

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.

描述（由申请人提供）：下肢周围动脉疾病 (PAD) 影响着美国超过 500 万成年人，且仍未通过干预得到解决。部署在外周动脉中的裸金属支架由于缺乏抗增殖药物而失败，并且由于严重的外周动脉变形（扭曲、弯曲和缩短）而导致断裂率很高（高达 68%）。药物洗脱支架 (DES) 会失败，因为其抗增殖药物无法输送至内壁或被内壁保留。 DES 还受到血管尺寸的限制，这妨碍了它们在血管直径小于 2.0 毫米的膝下 (BTK) 应用中的使用。 BTK 血管的治疗对于糖尿病 PAD 患者的保肢至关重要，但在这种情况下，球囊血管成形术是唯一的选择。不幸的是，与支架相比，球囊血管成形术的再狭窄率更高。拟议的研究将开发一种新策略，在不使用金属平台作为载体的情况下递送和保留抗增殖药物。治疗 PAD 的方法。这将通过使用最先进的球囊灌注导管和药物载体角蛋白（一种从人发中提取的蛋白质）来实现。角蛋白提供了一种以受控速率递送抗增殖剂紫杉醇并增加保留的方法在血管壁中。此外，角蛋白在愈合的早期阶段会引发有益的炎症反应。据推测，通过灌注导管以受控速率将紫杉醇-角蛋白赋形剂递送至病变壁，导致内侧平滑肌细胞静止并快速重新内皮化。首先将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）。这些研究将使用新型离体猪动脉循环系统来完成，该系统可以准确预测药物保留并节省资源和动物利用率。此外，还将在相关的临床前模型中评估血管对角蛋白-紫杉醇的反应（具体目标 2）。具体而言，将通过长达 28 天的药代动力学分析来测量紫杉醇动脉水平。平滑肌细胞增殖、血管重塑、损伤和炎症将通过组织病理学进行量化。内皮细胞的恢复将通过扫描电子显微镜和荧光显微镜进行量化。通过这些目标，我们将证明灌注导管输送紫杉醇角蛋白赋形剂、抑制新内膜生长、减少炎症浸润和改善再内皮化的有效性。最终，这种方法可以克服当前介入设备的局限性，并改善数百万 PAD 患者的生活质量。