Platelet Liposomal Drug Delivery--Thrombosis /Restenosis

描述(申请人提供)：心血管疾病感染多万美国人，其中1000多万人有心肌梗死和中风。血栓形成是与这些疾病相关的主要风险因素。再狭窄是血管外科干预后的另一个主要临床限制和问题。这项拟议研究的总体目标是生物工程新的脂质体给药系统，该系统选择性地结合或靶向处于血栓闭塞风险部位的激活的血小板，和/或形成再狭窄病变。我们建议通过利用病变中存在的激活的血小板的细胞表面表型的差异来研究直接将包裹的药物靶向血管损伤部位的脂质体的表面修饰。具体地说，我们将专注于设计和开发高亲和力的含有Arg-Gly-Asp(RGD)的脂质体来对抗血栓形成和再狭窄中表达的血小板GPIIb-111a。我们建议：1)制备和表征包裹纤溶/抗凝血/抗增殖药物的RGD脂质体；2)测定RGD脂质体与激活的血小板的体外结合；3)评价药物包埋的脂质体对激活的血小板的体外释放；以及4)在再狭窄模型中对脂质体的体内行为进行初步评价。脂质体的初步体内靶向性将在大鼠急性损伤模型中进行评估。通过这些研究，我们将证明含有RGD的脂质体给药系统有效靶向活化的血小板的可行性。我们预计，该项目将导致高效的脂质体药物输送系统，该系统专门针对血栓闭塞或形成再狭窄病变的风险血管部位，用于管理和预防血栓形成和再狭窄。如果成功，这项拟议的研究将带来显著的医疗节省。每年进行的经皮冠状动脉介入治疗(PCI)超过400,000例，其中200,000例未植入支架。其中很大一部分需要重复血管重建术(以及一些支架手术)。在一个患者群体(MCO)中重复血管再造术可能会花费每个患者高达32,000美元。在大多数情况下，术后抗凝药物的使用也是必要的(与一些支架相关的时间较长)，这增加了经皮冠状动脉介入治疗的费用。建议的靶向脂质体系统可以降低这两个治疗领域的成本，仅血管重建就减少5%，每年可节省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.