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LOCAL THERAPY TO LIMIT VASCULAR GRAFT HYPERPLASIA

限制血管移植物增生的局部治疗

基本信息

批准号：
6537399
负责人：
STEPHEN P MASSIA
金额：
$ 20.25万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-10 至 2004-06-30
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from the applicant's abstract) Neointimal hyperplasia is a response to injury in vascular tissues which promotes abnormal thickening of vascular walls with luminal narrowing. In the clinical setting, this luminal narrowing in response to mechanical injury can promote renarrowing or restenosis of balloon-dilated arteries. In vascular surgery, small diameter vascular grafts fail at clinically unacceptable rates because of uncontrolled, injury-induced neointimal hyperplasia. Antagonists of beta3 and alphaV integrins delivered locally to balloon-injured arteries have been shown by the investigator and others to significantly reduce neointimal hyperplasia by limiting smooth muscle cell migration. This drug class has also been shown to effectively limit clinical restenosis following coronary arterial balloon angioplasty. In the proposed study, it is hypothesized that under optimal conditions, locally delivered alphaV integrin antagonist cyclic RGD peptide (cyclic GPENGRGDSPCA) will limit neointimal hyperplasia in implanted small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts. Further, this locally delivered peptide will limit neointimal hyperplasia without affecting EC retention and function in EC-sodden grafts. One major goal of this study will be to develop a polymeric drug delivery formulation that can be loaded with cyclic RGD peptide, impregnated into a small diameter ePTFE graft, and deliver cyclic RGD peptide at an optimal rate for maximal reduction of graft hyperplasia. To achieve this goal, a well characterized degradable, gel-forming co-polyester family and degradable crystalline, polymeric cation exchanger microparticles will be utilized to develop biocompatible formulations that provide a broad range of in vitro release rates for cyclic RGD. Peptide-loaded formulations that have a desirable range of release rates will then be impregnated in ePTFE grafts and evaluated for their effect on hyperplasia in a well defined rat aorta small diameter ePTFE graft model. A second goal of this project will be to determine how locally delivered cyclic RGD peptide that is optimized for reducing graft hyperplasia will influence endothelial cell (EC) retention and function in EC-sodded grafts. The effects of local drug delivery on EC retention will be assessed in vitro and in vivo in sodded grafts. Cyclic RGD-mediated effects on EC pro- and anticoagulant activity in EC-sodded grafts will also be determined in vitro. The development of efficacious local drug therapies may be critical for reducing progressive neointimal thickening to tolerable levels in small diameter synthetic vascular grafts so that clinically acceptable failure rates can be realized.

描述：（改编自申请人摘要）新生内膜增生是对血管组织损伤的反应，血管壁异常增厚伴管腔狭窄。在在临床环境中，这种管腔狭窄是对机械性损伤可促进球囊扩张后血管再狭窄或再狭窄动脉在血管手术中，小直径血管移植物在临床上不可接受的比率，因为不受控制，损伤诱导新生内膜增生 β 3和α V整联蛋白拮抗剂局部输送到球囊损伤的动脉，研究者和其他人显著减少新生内膜增生通过限制平滑肌细胞迁移。这类药物也被显示有效限制冠状动脉后临床再狭窄动脉球囊血管成形术在拟议的研究中，假设在最佳条件下，局部递送的α V整合素拮抗剂环RGD肽（环GPENGRGDSPCA）将限制植入的小直径扩张中的新生内膜增生聚四氟乙烯（ePTFE）血管移植物。此外，这在当地递送的肽将限制新生内膜增生而不影响 EC浸润移植物中的EC保留和功能。其中一个主要目标是研究将是开发一种聚合物药物递送制剂，其可装载有环状RGD肽，浸渍到小直径的 ePTFE移植物，并以最佳速率递送环状RGD肽，最大限度地减少移植物增生。为了实现这一目标，特征在于可降解的、形成凝胶的共聚酯族和可降解的将使用结晶的聚合阳离子交换剂微粒为了开发生物相容性制剂，环RGD的体外释放速率。负载肽的制剂，具有所需的释放速率范围， ePTFE移植物，并评价其对孔中增生的影响大鼠主动脉小直径ePTFE移植物模型。第二个目标是该项目将确定如何在当地交付的循环RGD 优化用于减少移植物增生的肽将影响内皮细胞（EC）的保留和功能的EC sodded移植。的将在体外评估局部给药对EC保留的影响以及在体内的草皮移植物中。环RGD介导的对EC前体的作用还将测定EC-soded移植物中的抗凝活性体外有效的局部药物治疗的发展可能是对于将进行性新生内膜增厚降低至可耐受水平至关重要小直径合成血管移植物中的水平，可以实现可接受的故障率。