Drug Delivery to Thrombotic Cardiovascular Disease

描述：心血管疾病是整个西方世界死亡和住院的头号原因。使用纤溶剂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的残疾。尽管人们努力提高基因工程纤溶剂的纤维蛋白特异性，但巨大的出血风险促使人们开发替代的药物和设备来进行再灌注。我们提出了靶向给药系统，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来输送纤溶酶原激活物抑制物-1(PAI-1)的抑制物。组织特异性抑制PAI-1有望减少血栓负担和血管再闭塞，同时将不良反应(出血)降至最低，从而提高临床净收益。药物载体的丝状结构具有良好的流动动力学，促进了血管壁和血栓的聚集，从而增强了局部的内源性纤溶作用，降低了出血风险。这项技术有望产生一种具有高度血栓特异性和有效性的配方，其效果将超过基于全身抗体或小分子抑制剂的治疗。将进行体外和体内试验相结合，以深入了解血栓特异性、药物释放、疗效和潜在出血风险的动态变化。体内活体显微镜、体外成像和定量组织分析相结合，将提供有关靶向纳米颗粒和PAI-1抑制剂治疗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PAI-1抑制的内源性纤溶而改善局部治疗，从而限制血栓负荷。我们将考察纳米疗法和免费药物对血栓生长/稳定性和颈动脉闭塞时间的影响。将评估抑制PAI-1对止血(即尾部出血时间)和失血的影响。这一方法代表着与当前目标战略的根本转变。靶向血管壁的纳米药物在动脉粥样硬化血栓形成、静脉血栓栓塞症、再狭窄和移植血管病变方面可能有显著的临床影响。

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.