PERIVASCULAR DRUG DELIVERY

对治疗糖尿病的创新技术的追求 动脉粥样硬化性血管疾病已经伴随着一个发人深省的 并发症;快速重演最初的细胞事件， 接下来的几个月 细胞在新生内膜内的积聚可以是 如此巨大以致阻塞动脉腔并威胁组织/器官 完整 新生内膜损伤包括内皮完整性的丧失， 纤维蛋白沉积和血栓形成和止血的局部改变， 单核细胞/巨噬细胞浸润，异常血管收缩， 中膜平滑肌细胞的迁移和增殖， 内膜平滑肌细胞增殖。 因此， 已经针对一种或多种这些细胞， 希望能阻止这一进程。 不幸的是，虽然许多代理商 在组织培养中抑制平滑肌细胞生长， 这些化合物减少血管炎动物模型中的增殖 疾病，如果按比例使用剂量会引起显着的副作用 供人类使用。 此外，在可耐受的剂量下，没有任何药物证明 有效抑制人体内的再狭窄。 因此，第二波 热情带来了一些替代方案， 或局部治疗。 希望这些模式将使 利用仅限于血管床的有效化合物， 动脉壁的特定部分，无伴随体循环侧 方面的影响. 我们已经证明，基于聚合物的药物控释到 损伤动脉的血管周围间隙是最有效的方法 给予一些促有丝分裂、抗增殖和抗- 血栓形成剂，以及建立治疗的唯一手段， 对其他化合物的影响 该系统的效率扩展到 多种形式的动脉损伤/修复和许多参数 控制血管愈合 其他人在高血压下注射药物 压力直接进入动脉壁或直接转染DNA，或 通过将细胞转化成血管的方式，成功率各不相同。 目前尚不清楚的是，这些管理模式是否 有效仅仅是因为他们提供了更高的当地药物 浓度，或者是否存在特定的生物学必要性， 将药物放置在血液中和血液周围的特定位置 容器。 我们现在希望研究在各种不同的情况下药物的血管周围递送。 血管细胞和组织损伤和修复的状态，希望 了解当地疗法的力量 我们的实验将 继续利用基于聚合物的药物控释技术， 提供精确的释放动力学，细胞的组织培养检查 生长以使单细胞或共培养物中的细胞的反应可视化， 血管损伤的动物模型，以验证我们的体外结果， 生物化学和免疫组织学鉴定和表征 细胞和血管壁来了解这些影响。我们现在将： (A)检查是否可以控制血管活性化合物的释放 以生物活性的形式，这样它们就能最佳地与 血管的独特局部部分。 (B)确定血管壁，在健康和疾病， 响应于化合物的受控局部释放，并定义 观察到的不同形式的 局 (C)研究血管周围空间的细胞和元素如何 改变血管生长和修复，特别是当药物 直接管理到这个区域。

The rush towards innovative technologies for the treatment of atherosclerotic vascular diseases has been accompanied by a sobering complication; the rapid recapitulation of initial cellular events in the months that follow. The accumulation of cells within a neointima can be so massive as to obstruct the arterial lumen and threaten tissue/organ integrity. The neointimal lesion involves loss of endothelial integrity, fibrin deposition and local alterations in thrombosis and hemostasis, infiltration of monocyte/macrophages, aberrant vasoconstriction, migration and proliferation of medial smooth muscle cells and proliferation of intimal smooth muscle cells. As a result a multitude of potent agents has been directed against one or more of these cellular events in hopes of halting this process. Unfortunately while many agents suppress smooth muscle cell growth in tissue culture, and a subset of these compounds reduce proliferation in animal models of vascular disease, the doses used would induce significant side effects if scaled up for human use. Moreover, at the doses tolerated, no agent has proven effective in inhibiting restenosis in the human. Thus, a second wave of enthusiasm has brought forth a number of alternatives for site-specific or local therapy. It is hoped that these modalities would allow for the utilization of potent compounds limited to a vascular bed or perhaps specific portions of the arterial wall without accompanying systemic side effects. We have demonstrated that polymer-based controlled release of drugs into the perivascular space of injured arteries is the most effective means of administering a number of mitogenic, antiproliferative and anti- thrombotic agents, and the only means of establishing a therapeutic effect for other compounds. The efficiency of this system extends to many forms of arterial injury/repair and for a number of parameters governing vascular healing. Others have infused drugs under high pressure directly into the arterial wall or transfected DNA directly or by way of transformed cells into blood vessels with variable success. What is not as yet clear is whether these modes of administration are effective simply because they provide heightened local drug concentrations, or whether there is a specific biological imperative for the placement of drugs at specific locations in and around the blood vessel. We now wish to investigate perivascular delivery of drugs in various states of vascular cell and tissue injury and repair in hopes of understanding the power of local forms of therapy. Our experiments will continue to utilize polymer based controlled drug delivery technology to provide precise release kinetics, tissue culture examination of cell growth to visualize the response of single cells or cells in co-culture, animal models of vascular injury to verify our in vitro results, and biochemical and immunohistologic identification and characterization of the cells and blood vessel wall to understand these effects. We will now: (A) examine whether one can control the release of vasoactive compounds in biologically active form, so that they will interact optimally with a unique and local segment of a blood vessel. (B) determine whether the blood vessel wall, in health and disease, will respond to the controlled local release of a compound, and define the resultant biological effects observed with different forms of administration. (C) study how the cells and elements within the perivascular space might modify vascular growth and repair, in particular when drugs are administered directly into this area.