Platelet Liposomal Drug Delivery--Thrombosis /Restenosis

描述（申请人提供）：心血管疾病感染了6400多万美国人，其中1000多万人患有心肌梗死和中风。血栓形成是与这些疾病相关的主要危险因素。呼吸暂停是血管外科干预后的另一个主要临床局限性和问题。拟议的研究的总体目标是生物工程新的脂质体药物递送系统，选择性地结合，或靶向，在血栓闭塞的风险，和/或发展再狭窄病变的网站激活血小板。我们建议研究脂质体的表面修饰，靶向封装的药物直接到血管损伤的部位，通过利用病变中存在的活化血小板的细胞表面表型特征的差异。具体而言，我们将专注于设计和开发高亲和力的精氨酸-甘氨酸-天冬氨酸（RGD）的脂质体血小板GPIIb-IIIa表达血栓形成和再狭窄。我们建议：1）制备和表征包封纤维蛋白溶解/抗凝血/抗增殖药物的含RGD的脂质体; 2）测定含RGD的脂质体与活化血小板的体外结合; 3）评价治疗剂从靶向活化血小板的药物包封的脂质体的体外释放;和4）再狭窄模型中脂质体行为的初步体内评价。将在大鼠急性损伤模型中评价脂质体的初步体内靶向。从这些研究中，我们将证明含有RGD的脂质体药物递送系统有效靶向活化血小板的可行性。我们预计，该项目将导致高度有效的脂质体药物输送系统，专门针对血管部位的血栓闭塞或发展再狭窄病变的风险，管理和预防血栓形成和再狭窄。如果成功，拟议的研究将导致显着的医疗保健储蓄。每年有超过400，000例经皮冠状动脉介入治疗（PCI），其中> 200，000例未植入支架。其中大量患者需要重复血运重建手术（以及一些支架植入手术）。在一个患者群体（MCO）中重复血运重建的费用可能高达每名患者32，000美元。在大多数情况下，还需要使用术后抗凝药物（与一些支架植入术相关的时间较长），这增加了PCI的成本。所提出的靶向脂质体系统可以降低两个治疗领域的成本，仅血运重建就减少5%，每年可节省超过6000万美元的医疗成本。

DESCRIPTION (provided by applicant): Cardiovascular diseases infect more than 64 million Americans, among which more than 10 million have myocardial infarction and stroke. Thrombosis is a major risk factor associated with these diseases. Restenosis represents another major clinical limitation and concerns after vascular surgical intervention. The overall goal of the proposed research is to bioengineer new liposomal drug delivery systems that selectively bind, or target, activated platelets at sites at risk for thrombotic occlusions, and/or developing restenotic lesions. We propose to investigate surface modifications of liposomes that target encapsulated drugs directly to the sites of vascular injury, by exploiting differences in cell surface phenotypes characteristic of activated platelets present in the lesion. Specifically, we shall focus on the design and development of high affinity Arg-Gly-Asp (RGD)-containing liposomes to platelet GPIIb-llla expressed in thrombosis and restenosis. We propose to: 1) Prepare and characterize RGD-containing liposomes that encapsulate fibrinolytic/anti-clotting/antiproliferative drugs; 2) Determine the in vitro binding of RGD-containing liposomes to activated platelets; 3) Evaluate the in vitro release of therapeutic agents from drug encapsulated liposomes targeted to activated platelets; and 4) Preliminary in vivo evaluation of liposome behavior in a restenosis model. Preliminary in vivo targeting of liposome will be evaluated in a rat acute injury model. From these studies, we shall demonstrate the feasibility of the RGD-containing liposomal drug delivery system for effective targeting to the activated platelets. We anticipate that this project will lead to highly effective liposomal drug delivery system that specifically target to the vascular sites at risk of thrombotic occlusion or developing restenotic lesions for the management and prevention of thrombosis and restenosis. If successful, the proposed research would lead to significant health care savings. Over 400,000 percutaneous coronary interventions (PCI) are performed each year, of those >200,000 are not stented. A significant number of these require repeat Revascularization surgery (as well as some of the stented ones). Repeat revascularizations in one patient population (MCOs) can cost up to $32,000 per patient. In most cases the use of post procedure anti-clotting medications is also required (with long periods associated with some stenting) that increases the costs of PCI. The targeted liposomal system proposed could reduce the costs in both treatment areas with a 5% reduction in revascularizations alone leading to >$60 million annual medical cost savings.