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

抗增殖药物的分子靶向、聚焦、超声递送

• 批准号: 8076886
• 负责人: John A Hossack
• 金额: $ 36.18万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076886
• 关键词: Acoustics; Acute; Address; Adverse effects; Affect; American; Anatomy; Angioplasty; Antibodies; Aorta; Attenuated; Balloon Angioplasty; Biocompatible Materials; Biological Assay; Blood Clot; Blood Vessels; Blood coagulation; Cardiology; Carotid Arteries; Catheters; Cell Adhesion Molecules; Cell Death; Cell Proliferation; Cell surface; Cells; Cessation of life; Characteristics; Chemistry; Clinical; Coagulation Process; Collaborations; Communities; Coronary Arteriosclerosis; Coronary artery; Data; Deposition; Doctor of Medicine; Dose; Drops; Drug Carriers; Drug Delivery Systems; Drug usage; Endothelial Cells; Engineering; FDA approved; Figs - dietary; Focused Ultrasound Therapy; Frequencies; Future; Gleevec; Grant; Health; High Pressure Liquid Chromatography; Human; Hyperplasia; Image; Implant; In Situ; In Vitro; Industry; Inflammatory Response; Inhibitory Concentration 50; Injection of therapeutic agent; Injury; Integrins; International; Label; Lateral; Lead; Left; Lesion; Letters; Lipids; Literature; Maintenance; Marketing; Measures; Medical Device; Metals; Methods; Microbubbles; Microbubbles Ultrasound Contrast Medium; Mission; Modality; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Myocardial Infarction; Pathology; Patients; Pharmaceutical Preparations; Plavix; Play; Polymers; Procedures; Process; Proliferating; Property; Proteins; Public Health; Radiation; Rattus; Reagent; Research; Resolution; Risk; STI571; Sirolimus; Smooth Muscle Myocytes; Spottings; Staging; Stenosis; Stents; Surface; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Thick; Thrombosis; Time; Tissues; Transducers; Ultrasonic Transducer; Ultrasonics; Ultrasonography; United States National Institutes of Health; Vascular Cell Adhesion Molecule-1; Ventricular; Work; antiproliferative agents; antiproliferative drugs; base; biomaterial compatibility; cell growth; clopidogrel; design; drug distribution; drug mechanism; fluorophore; high risk; implantation; improved; in vivo; instrumentation; interest; intravenous injection; irradiation; meetings; minimally invasive; mortality; particle; plasmid DNA; pre-clinical; prevent; programs; rapid growth; response; restenosis; targeted delivery; vascular smooth muscle cell proliferation

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.

描述（由申请人提供）：目前，患病血管的血运重建是通过球囊血管成形术和金属支架的展开来进行的。一个主要的临床障碍是支架部署后维持血管通畅。也就是说，支架展开后，构成血管壁的平滑肌细胞迅速增殖和分裂，并可导致伴随的血管重新狭窄；称为支架内再狭窄的临床过程。为了解决这个问题，几家主要的医疗器械公司开发了可释放抗增殖剂以防止再狭窄的支架，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；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 的患者发生支架内血栓（即支架内的血凝块）的广泛关注，导致死亡和心肌梗死人数小幅但显着上升。梗塞。正如 FDA 和该领域专家所指出的，这种人们知之甚少的现象被认为是由于抗增殖剂完全释放后不可降解聚合物涂层的炎症反应造成的。最近 DES 使用的快速增长以及这些令人不安的发现现在才被观察到这一事实，强调了影响估计 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具有明显的影响。目前接受 DES 的患者的治疗需要持续使用氯吡格雷（波立维）（一种抗凝血剂），以最大限度地降低亚急性血栓形成的风险，亚急性血栓形成的风险并非没有风险，且长期疗效尚未得到证实。本文提出的工作解决了开发新仪器、方法和生物材料的需要，以将抗增殖剂递送至已进行血管成形术和支架植入的患病血管。该提案将重点关注使用现有的方式和试剂，在超声成像引导下，在血管成形术引起的狭窄后，利用超声引导抗增殖剂从微泡集中释放到血管。我们建议研究的方法涉及静脉注射经过修改的超声微泡造影剂，以包含少量的抗增殖药物。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 使命的核心。在过去的几个月里，介入心脏病学界（包括监管该领域的 FDA）逐渐意识到，作为冠状动脉疾病治疗方法而广泛植入的药物洗脱支架带来的风险比最初预期的更大。具体而言，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。公共健康相关性：这笔赠款通过研究早期、高风险、有前途的新型超声图像引导、微创疗法的潜力，解决了这一极其重要的公共卫生问题，通过将“抗增殖”药物集中输送到精确区域来解决这一问题关注的船只。