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Drug Delivery to Thrombotic Cardiovascular Disease

血栓性心血管疾病的药物输送

基本信息

批准号：
8965514
负责人：
Nicole Franziska Steinmetz
金额：
$ 22.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-14 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8965514
关键词：
Acids Acute myocardial infarction Address Adverse effects Alteplase Antibodies Biodistribution Biological Assay Bleeding time procedure Blood Platelets Cardiovascular Diseases Cardiovascular system Carotid Arteries Cause of Death Cerebral hemisphere hemorrhage Cessation of life Chemistry Clinical Coagulation Process Data Development Devices Disease Dose Drug Carriers Drug Combinations Drug Delivery Systems Drug Kinetics Elements Engineering Environment Fibrin Fibrinogen Fibrinolysis Fibrinolytic Agents Formulation Genetic Engineering Goals Growth Health Hemorrhage Hemostatic function Home environment Hospitalization Image In Vitro Injury Lasers Mus Penetration Peptides Pharmaceutical Preparations Physiological Physiology Plant Viruses Plasminogen Activator Inhibitor 1 Pre-Clinical Model Protease Inhibitor Reactive Oxygen Species Reperfusion Therapy Research Institute Research Personnel Risk Rodent Safety Secondary to Serpins Serum Site Specificity Stroke Structure System Tail Technology Testing Therapeutic Thromboembolism Thrombolytic Therapy Thrombosis Thrombus Time Tissues Tobacco Mosaic Virus Transplantation Treatment Efficacy Ursidae Family Vascular Diseases Venous Virus Western World arm artery occlusion atherothrombosis base density disability high risk improved in vivo inhibitor/antagonist injured insight intravital microscopy mortality mouse model nanomedicine nanoparticle nanotherapy next generation quantitative imaging restenosis small molecule small molecule inhibitor success targeted delivery targeted treatment

项目摘要

DESCRIPTION: Cardiovascular disease is the number one cause of death and hospitalization throughout the Western World. Reperfusion therapy with fibrinolytic agents has significantly reduced early mortality from acute myocardial infarction and disability from stroke. Despite efforts to enhance the fibrin specificity of genetically engineered fibrinolytic agents, significan bleeding risks have prompted the development of alternative pharmacologic and device approaches for reperfusion. We propose a targeted drug delivery system to improve efficacy and safety. We will engineer a tissue-targeted, filamentous platform technology to deliver inhibitors of plasminogen activator inhibitor-1 (PAI-1). Tissue-specific inhibition of PAI-1 is expected to reduce thrombus burden and vessel reocclusion, while minimizing adverse effects (hemorrhage), and thus improve net clinical benefit. The filamentous structure of the drug carrier has favorable flow dynamics promoting vessel wall and thrombus accumulation, thereby enhancing local endogenous fibrinolysis with reduced bleeding risk. This technology is expected to yield a formulation with high thrombus-specificity and efficacy that will outperform systemic antibody- or small molecule inhibitor-based therapies. A combination of in vitro and in vivo assays will be performed to gain insights into the dynamics of clot-specificity, drug release, efficacy, and potential bleeding risk. A combination of in vivo intravital microscopy, ex vivo imaging, and quantitative tissue analysis will provide detailed information on the efficiency of targeting nanoparticles and PAI-1 inhibitors to the thrombus. We will address whether the nanotherapy improves localized treatment by promoting endogenous fibrinolysis secondary to PAI-1 inhibition and thereby limiting thrombus burden. We will examine the effect of nanotherapy versus free drugs on thrombus growth/stability and carotid artery occlusion time. The effect of PAI-1 inhibition on hemostasis (i.e. tail bleeding time) and blood loss will be assessed. This approach represents a radical shift from current targeting strategies. Nanomedicines targeting the vessel wall could have a significant clinical impact in atherothrombosis, venous thromboembolism, restenosis, and transplant vasculopathy.

描述：心血管疾病是整个西方世界死亡和住院的头号原因。纤溶药物的再灌注治疗显著降低了急性心肌梗死的早期死亡率和卒中致残率。尽管努力增强基因工程纤溶剂的纤维蛋白特异性，但显著的出血风险促使开发了用于再灌注的替代药理学和装置方法。我们提出了一种靶向给药系统，以提高疗效和安全性。我们将设计一种组织靶向的丝状平台技术，以提供纤溶酶原激活物抑制剂-1（派-1）的抑制剂。派-1的组织特异性抑制预期可降低血栓负荷和血管再闭塞，同时最大限度地减少不良反应（出血），从而提高净临床获益。药物载体的丝状结构具有有利的流动动力学，促进血管壁和血栓积聚，从而增强局部内源性纤维蛋白溶解，降低出血风险。预计该技术将产生具有高血栓特异性和功效的制剂，其将优于基于全身性抗体或小分子生物素的疗法。将进行体外和体内试验的组合，以深入了解凝块特异性、药物释放、疗效和潜在出血风险的动态。体内活体显微镜、离体成像和定量组织分析的组合将提供关于靶向纳米颗粒和派-1抑制剂对血栓的效率的详细信息。我们将讨论纳米疗法是否通过促进继发于派-1抑制的内源性纤维蛋白溶解从而限制血栓负荷来改善局部治疗。我们将研究纳米治疗与游离药物对血栓生长/稳定性和颈动脉闭塞时间的影响。将评估派-1抑制对止血（即尾部出血时间）和失血量的影响。这一方法是对目前目标选择战略的根本转变。靶向血管壁的纳米药物可能对动脉粥样硬化血栓形成、静脉血栓栓塞、再狭窄和移植血管病变具有显著的临床影响。