EVALUATION OF LOCAL THERAPY TO LIMIT VASCULAR GRAFT HYPE

描述：（改编自申请人的摘要）新内膜 增生是对血管组织损伤的反应，可促进 血管壁异常增厚，管腔变窄。 在 在临床环境中，这种管腔变窄是对机械的反应 损伤可促进球囊扩张后的血管再狭窄或再狭窄 动脉。 在血管外科手术中，小直径血管移植物在以下情况下会失败 由于不受控制的、损伤引起的，临床上不可接受的发生率 新内膜增生。 beta3 和 alphaV 整合素的拮抗剂 已证明，局部输送至球囊损伤的动脉 研究人员和其他人显着减少新内膜增生 通过限制平滑肌细胞迁移。 该药物类别也已 被证明可以有效限制冠状动脉术后的临床再狭窄 动脉球囊血管成形术。 在拟议的研究中，假设 在最佳条件下，局部传递αV整合素 拮抗剂环RGD肽（环GPENGRGDSPCA）将限制 植入小直径扩张的新生内膜增生 聚四氟乙烯（ePTFE）血管移植物。 此外，这个本地 递送的肽将限制新内膜增生而不影响 EC 浸泡移植物中的 EC 保留和功能。 此次活动的一大目标 研究将开发一种聚合物药物递送制剂，可以 负载环状RGD肽，浸渍成小直径 ePTFE 接枝，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，需要做好 具有特征的可降解、凝胶形成共聚酯系列和可降解 将使用结晶聚合阳离子交换微粒 开发生物相容性制剂，提供广泛的 循环 RGD 的体外释放率。 肽负载制剂 具有理想的释放速率范围，然后将被浸渍在 ePTFE 移植物并在井中评估其对增生的影响 建立大鼠主动脉小直径ePTFE移植物模型。 第二个目标是 该项目将确定如何在本地交付循环 RGD 为减少移植物增生而优化的肽将影响 内皮细胞（EC）在 EC 覆盖的移植物中的保留和功能。 的 将在体外评估局部药物递送对 EC 保留的影响 以及体内的草皮移植物。 RGD 介导的循环对 EC pro- 的影响 还将确定 EC 覆盖的移植物的抗凝血活性 体外。 开发有效的局部药物疗法可能是 对于将进行性新内膜增厚减少到可耐受的程度至关重要 小直径合成血管移植物中的水平，以便临床 可以实现可接受的故障率。

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.