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

描述（由申请人提供）：病变血管的血运重建目前通过球囊血管成形术和金属支架的部署进行。一个主要的临床障碍是支架部署后血管通畅的维持。也就是说，在支架部署后，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。为了解决这个问题，几家主要的医疗设备公司已经开发出释放抗增殖剂的支架，以防止再狭窄，目前已在美国市场上市。这些药物从支架上的薄聚合物涂层中释放出来；然而，2006年12月，FDA发布了一份声明，反映了国际上对接受DES的患者发生支架血栓形成（即支架内的血栓）的广泛关注，导致死亡和心肌梗死的人数虽小但显著增加。正如FDA和该领域的专家所指出的，这种知之甚少的现象被认为是由于抗增殖剂完全释放后，对不可降解的聚合物涂层的炎症反应造成的。最近使用des的人数迅速增加，而且这些令人不安的发现直到现在才被观察到，这突出表明可能会发生一场影响约200万美国人的重大健康危机，对受影响者的发病率和死亡率产生明显影响。目前对DES患者的治疗需要持续使用氯吡格雷（Plavix），一种抗凝血剂，以尽量减少亚急性血栓形成的风险，但这并非没有风险，长期疗效尚未得到证实。本文提出的工作解决了开发新的仪器、方法和生物材料的需求，以将抗增殖药物输送到已接受血管成形术和支架植入的病变血管。本提案将侧重于利用现有的模式和试剂，在超声成像指导下，利用超声引导抗增殖剂从微泡向血管的局部释放，从而引起血管成形术引起的狭窄。我们建议研究的方法是静脉注射超声微泡造影剂，使其含有少量的抗增殖药物。该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NIH的核心任务。在过去的几个月里，介入心脏病学界（包括监管该领域的FDA）已经意识到，作为冠状动脉疾病治疗的药物洗脱支架已被广泛植入，其风险比最初预期的要大。具体来说，这些支架作为维持冠状动脉开放的手段的功效随着时间的推移而减弱。公共卫生相关性：该资助通过研究早期、高风险、有前途的新型超声图像引导、微创治疗的潜力，解决这一问题，通过将“抗增殖”药物集中输送到相关血管的精确区域，解决这一问题。

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.