PERIVASCULAR DRUG DELIVERY

对治疗癌症的创新技术的急切追求 动脉粥样硬化性血管疾病一直伴随着一种警醒 并发症；快速重述初始细胞事件在 接下来的几个月。新生内膜内细胞的堆积可以是 如此巨大以至于阻塞动脉管腔并威胁组织/器官 正直。新的内膜损伤涉及内皮完整性的丧失， 血栓和止血中的纤维蛋白沉积和局部改变， 单核/巨噬细胞的渗透，异常的血管收缩， 中膜平滑肌细胞的迁移和增殖 血管内膜平滑肌细胞增殖。结果，一大群 已经针对这些细胞中的一个或多个 希望停止这一进程的事件。不幸的是，虽然许多特工 抑制组织培养中的平滑肌细胞生长，以及一系列 这些化合物可抑制血管动物模型的增殖。 疾病，使用的剂量如果扩大会引起严重的副作用 供人类使用。此外，在耐受剂量下，还没有任何药物证明 能有效抑制人体再狭窄。因此，第二波 热情带来了许多针对特定地点的替代方案 或者局部治疗。希望这些模式将允许 有效化合物的使用仅限于血管床或可能 动脉壁的特定部分，不伴全身侧支 效果。 我们已经证明了基于聚合物的药物控制释放到 损伤动脉的血管周围间隙是最有效的方法 使用一些促有丝分裂、抗增殖和抗肿瘤药物 血栓药物，以及建立一种治疗性 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 管理血管愈合。其他人在吸毒后注射毒品 直接压入动脉壁或直接转染DNA或 通过将细胞转化为血管的方式，成功程度参差不齐。 目前尚不清楚的是，这些管理模式是否 有效只是因为他们提供了强化的当地药物 浓度，或者是否有特定的生物学必要性 在血液内和血液周围的特定位置放置药物 船只。 我们现在希望研究在不同的血管周围给药 血管细胞和组织损伤与修复的状态 了解当地形式的治疗的力量。我们的实验将 继续利用基于聚合物的受控药物输送技术来 提供精确的释放动力学，细胞的组织培养检查 生长以可视化单个细胞或细胞在共培养中的反应， 血管损伤的动物模型来验证我们的体外结果，以及 生物化学和免疫组织学鉴定及表征 了解这些影响的细胞和血管壁。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，这样它们将以最佳的方式与 血管的独特的局部节段。 (B)确定血管壁在健康和疾病中是否会 响应化合物的受控局部释放，并定义 观察到不同形式的生物效应 行政管理。 (C)研究血管周围空间内的细胞和元素如何 改变血管的生长和修复，特别是当药物 直接进入这一区域。

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.