LOCAL THERAPY TO LIMIT VASCULAR GRAFT HYPERPLASIA

描述：(改编自申请人的摘要)新生内膜 增殖是血管组织对损伤的反应，它促进 管壁异常增厚伴管腔狭窄。在 临床环境下，这种管腔狭窄的反应是机械性的 损伤可促进球囊扩张后的再狭窄或再狭窄 动脉。在血管外科中，小直径的血管移植物在 由于不受控制的伤害导致的临床不可接受的比率 新生内膜增生。β3和αV整合素拮抗剂 局部输送到球囊损伤的动脉的实验结果显示 研究人员和其他人将显著减少新生内膜增生 通过限制平滑肌细胞的迁移。这个药物类别也一直是 显示能有效地限制冠脉再狭窄 动脉球囊血管成形术。在拟议的研究中，它是假设的 在最佳条件下，局部传递的αV整合素 拮抗剂环状RGD多肽(环状GPENGRGDSPCA)将限制 植入物小径扩张后新生内膜增生 聚四氟乙烯(EPTFE)血管移植。此外，这在当地 传递的多肽将限制新生内膜增生而不影响 EC在EC浸泡的移植物中的滞留和功能。这其中的一个主要目标 研究将开发一种聚合物药物输送配方，该配方可以 负载环状RGD多肽，浸渍成小直径 EPTFE接枝，并以最佳速率传递环状RGD多肽 最大限度地减少移植物的增生。为了实现这一目标，一口井 表征可降解、凝胶形成的共聚聚酯系列和可降解 将使用结晶的、聚合的阳离子交换剂微粒 开发生物相容配方，提供广泛的体内 环状RGD的体外释药速率。多肽制剂， 有一个理想的释放速率范围，然后被浸泡在 EPTFE植入物及其对井壁增生的影响 建立大鼠主动脉小直径ePTFE移植模型。第二个目标是 该项目将确定如何在当地交付循环RGD 为减少移植物增生而优化的多肽将影响 内皮细胞(EC)在EC覆盖的移植物中的保留和功能。这个 将在体外评估局部给药对EC滞留的影响 以及体内浸泡过的移植物。循环RGD介导的EC-PRO-1效应 还将检测EC浸泡的移植物的抗凝血活性。 在试管中。有效的局部药物疗法的发展可能是 将进行性新生内膜增厚减少到可耐受的关键 小直径人造血管移植物的水平因此临床上 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.