Molecular Targeted, Focused, Ultrasound-Based Delivery of Antiproliferative Drugs

描述(申请人提供)：病变血管的血运重建目前是通过球囊血管成形术和金属支架的部署来完成的。支架置入后血管通畅性的维持是一个主要的临床障碍。也就是说，在支架置入后，构成血管壁的平滑肌细胞迅速增殖和分裂，并可能导致伴随的血管再狭窄；这一临床过程称为支架内再狭窄。为了解决这一问题，几家主要的医疗器械公司已经开发出释放抗增殖剂的支架，以防止再狭窄，目前正在美国市场上销售。这些药物从支架上的一层薄薄的聚合物涂层中释放出来；药物洗脱支架或DES。然而，2006年12月，FDA发布了一份声明，反映了国际上对接受DES治疗的患者发生支架血栓(即支架内的血液凝块)的广泛关注，导致死亡和心肌梗死的人数略有上升，但幅度很大。正如FDA和该领域的专家所指出的那样，这种鲜为人知的现象被认为是由于一旦抗增殖剂完全释放，对不可降解的聚合物涂层的炎症反应所致。最近使用DESS的快速增长，以及这些令人不安的发现直到现在才被观察到，这突显了一场影响大约200万美国人的重大健康危机的可能性--对受影响者的发病率和死亡率有明显影响。目前对患有DES的患者的治疗需要维持使用氯吡格雷(Plavix)，这是一种抗凝血剂，以将亚急性血栓形成的风险降至最低，这并不是没有风险的，而且长期疗效尚未得到证实。本文提出的工作解决了开发新的器械、方法和生物材料的需要，以将抗增殖剂输送到接受血管成形术和支架植入的病变血管。这项建议将集中于利用现有的方法和试剂，在超声成像的引导下，利用超声引导抗增殖剂从微泡向血管内的局部释放，使血管成形术引起的狭窄。我们建议研究的方法包括静脉注射超声微泡造影剂，以包括少量的抗增殖药物。这项提案解决了美国一个非常重要的公共卫生问题(支架血栓形成)--这是美国国家卫生研究院使命的核心。在过去的几个月里，介入心脏病学社区(包括管理该领域的FDA)已经意识到，被广泛植入作为冠心病治疗方法的药物洗脱支架带来的风险比最初预期的更大。具体地说，这些支架作为维持冠状动脉开放的一种手段的有效性随着时间的推移而减弱。与公共健康相关：这笔赠款通过研究早期、高风险、有希望的新超声图像引导、微创疗法的可能性，解决这一问题，将“抗增殖”药物集中输送到相关血管的精确区域，从而解决这一深刻的公共卫生问题。

DESCRIPTION (provided by applicant): Revascularization of a diseased blood vessel is currently performed by balloon angioplasty and deployment of a metal stent. A major clinical hurdle is the maintenance of vessel patency following stent deployment. That is, following stent deployment, smooth muscle cells that compose the vessel wall, rapidly proliferate and divide and can lead to concomitant vessel re-narrowing; a clinical process known as in-stent restenosis. To address this, several major medical device companies have developed stents that release anti-proliferative agents to prevent restenosis and are currently on the US market. These drugs are released from a thin polymer coating on the stent; drug eluting stent or DES. However, in December 2006, the FDA released a statement reflecting widespread international concern relating to stent thrombosis (i.e. a blood clot in the stent) occurring in patients who have received a DES, resulting in a small, but significant, rise in deaths and myocardial infarctions. As noted by the FDA and experts in the field, this poorly understood phenomenon is believed to result from an inflammatory response to the non-degradable polymer coating once the anti-proliferative agent has been completely released. The very recent and rapid growth of the use of DESs and the fact that these troubling findings are only now being observed, underscores the potential for a major health crisis affecting an estimated two million Americans - with obvious implications on morbidity and mortality for those affected. Current treatment in patients that have a DES requires the maintained use of clopidogrel (Plavix), an anti-clotting agent, to minimize the risk of sub-acute thrombosis which is not without risk and long term efficacy is, as yet, unproven. The work proposed herein addresses the need to develop new instrumentation, methods and biomaterials to deliver anti-proliferative agents to diseased blood vessels that have undergone angioplasty and stent implantation. This proposal will focus on the use of existing modalities and reagents to employ ultrasound to direct the focal release of an anti-proliferative agent from microbubbles to a blood vessel following angioplasty-induced stenosis under ultrasound imaging guidance. The method that we propose to investigate involves an intravenous injection of ultrasound microbubble contrast agent modified so as to include a small amount of an antiproliferative drug. This proposal addresses a very significant public health concern (stent thrombosis) in the US - central to the mission of the NIH. In the past few months, the interventional cardiology community (including the FDA that regulates the field) has come to realize that drug eluting stents, that have been widely implanted as a therapy for coronary artery disease, pose greater risk than initially anticipated. Specifically, the efficacy of these stents as a means for maintaining an open coronary artery diminishes over time. PUBLIC HEALTH RELEVANCE: This grant addresses this profoundly important public health concern by investigating the potential of early stage, high risk, promising new ultrasound image guided, minimally invasive, therapies for resolving this problem using focused delivery of "antiproliferative" drugs to the precise region of a vessel of concern.