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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

基本信息

批准号：
8296580
负责人：
John A Hossack
金额：
$ 35.65万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8296580
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

项目摘要

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）：目前通过球囊血管成形术和金属支架展开进行病变血管的血运重建。一个主要的临床障碍是支架展开后血管通畅性的维持。也就是说，在支架展开后，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再狭窄;临床过程称为支架内再狭窄。为了解决这个问题，几家主要的医疗器械公司已经开发出释放抗增殖剂以防止再狭窄的支架，目前已在美国市场上销售。这些药物从支架上的薄聚合物涂层释放;药物洗脱支架或DES。然而，在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（即支架中的血凝块）的广泛关注，导致死亡和心肌梗死的人数小幅但显著增加。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一旦抗增殖剂完全释放后对不可降解聚合物涂层的炎症反应所致。最近，DES的使用迅速增长，而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DES患者的治疗需要持续使用氯吡格雷（Plaidogrel）（一种抗凝剂），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、方法和生物材料以将抗增殖剂递送到已经经历血管成形术和支架植入的患病血管的需要。该提案将重点关注使用现有的方式和试剂，以采用超声引导抗增殖剂从微泡到血管的局部释放，血管成形术诱导的狭窄后，在超声成像引导下。我们建议调查的方法涉及静脉注射超声微泡造影剂修改，以便包括少量的抗增殖药物。该提案解决了美国非常重要的公共卫生问题（支架血栓形成）-NIH的使命的核心。在过去的几个月里，介入心脏病学界（包括监管该领域的FDA）已经意识到，作为冠状动脉疾病治疗方法而广泛植入的药物洗脱支架所带来的风险比最初预期的要大。具体而言，这些支架作为维持开放冠状动脉的手段的功效随着时间的推移而降低。公共卫生相关性：这项拨款通过调查早期、高风险、有前途的新的超声图像引导、微创治疗的潜力来解决这一极其重要的公共卫生问题，该治疗使用集中的“抗增殖”药物递送到受关注血管的精确区域来解决这一问题。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pipe Phantoms With Applications in Molecular Imaging and System Characterization.

DOI：
10.1109/tuffc.2016.2626465
发表时间：
2017-01
期刊：
IEEE transactions on ultrasonics, ferroelectrics, and frequency control
影响因子：
0
作者：
Wang S;Herbst EB;Pye SD;Moran CM;Hossack JA
通讯作者：
Hossack JA

Targeted gene transfection from microbubbles into vascular smooth muscle cells using focused, ultrasound-mediated delivery.

DOI：
10.1016/j.ultrasmedbio.2010.06.010
发表时间：
2010-09
期刊：
ULTRASOUND IN MEDICINE AND BIOLOGY
影响因子：
2.9
作者：
Phillips, Linsey C.;Klibanov, Alexander L.;Wamhoff, Brian R.;Hossack, John A.
通讯作者：
Hossack, John A.

Real-time technique for improving molecular imaging and guiding drug delivery in large blood vessels: in vitro and ex vivo results.