LOCAL THERAPY TO LIMIT VASCULAR GRAFT HYPERPLASIA

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 开发生物相容性制剂，提供广泛的信息 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 将在体外评估局部药物递送对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。

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.