PERIVASCULAR DRUG DELIVERY

血管周围药物输送

• 批准号: 2186557
• 负责人: Elazer R Edelman
• 金额: $ 20.81万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2186557
• 关键词: acetates; alginates; arteriosclerosis; cardiovascular disorder chemotherapy; cardiovascular pharmacology; clearance rate; copolymer; drug delivery systems; fibroblast growth factor; glycolates; heparin; human therapy evaluation; immunocytochemistry; implant; inulin; laboratory rabbit; laboratory rat; lactates; microcapsule; mixed tissue /cell culture; pharmacokinetics; polyvinyls; protamines; transforming growth factors; vasoactive agent

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.

急于创新技术以治疗 动脉粥样硬化血管疾病伴随着清醒 并发症;初始细胞事件的快速概括 随后的几个月。 细胞在新神经内的积累可以是 如此巨大以至于阻碍动脉腔并威胁组织/器官 正直。 新内膜病变涉及内皮完整性的丧失， 血栓形成和止血的纤维蛋白沉积和局部改变， 单核细胞/巨噬细胞的浸润，异常血管收缩， 内侧平滑肌细胞的迁移和增殖 内膜平滑肌细胞的增殖。 结果 有效的剂已针对这些细胞中的一个或多个 希望停止此过程的事件。 不幸的是，虽然许多代理商 抑制组织培养中平滑肌细胞的生长，子集 这些化合物减少了血管动物模型中的增殖 疾病，使用的剂量如果缩放会引起显着副作用 供人类使用。 而且，只要剂量，没有任何代理人证明 有效抑制人的再狭窄。 因此，第二波 热情提出了许多特定网站的替代方案 或局部疗法。 希望这些方式能允许 利用有效化合物限于血管床或也许 动脉壁的特定部分，没有全身侧面 效果。 我们已经证明了基于聚合物的受控药物释放到 受伤动脉的血管周空间是最有效的手段 用于管理许多有丝分裂，抗增生和抗抗增殖的 血栓形成剂，也是建立治疗性的唯一手段 其他化合物的效果。 该系统的效率扩展到 多种形式的动脉损伤/修复以及许多参数 管理血管康复。 其他人则注入了高处的药物 直接直接进入动脉壁或直接转染的DNA或 通过将细胞转化为具有可变成功的血管。 尚不清楚这些管理模式是否是 仅仅是因为它们提供了当地毒品的增强 浓度，或是否有特定的生物学命令 在血液中和周围的特定位置放置药物 血管。 我们现在希望调查各种药物的血管周围递送 血管细胞和组织损伤和修复状态，希望 了解局部治疗的力量。 我们的实验会 继续利用基于聚合物的受控药物输送技术 提供精确的释放动力学，细胞的组织培养检查 生长以可视化共同培养中单细胞或细胞的响应， 血管损伤的动物模型，以验证我们的体外结果，并 生化和免疫组织学识别和表征 细胞和血管壁了解这些作用。我们现在将： （a）检查是否可以控制血管活性化合物的释放 以生物活性形式，以便它们将与 血管的独特而局部的部分。 （b）确定健康和疾病中的血管壁是否会 响应受控的化合物的本地释放，并定义 由不同形式的生物学作用产生的生物学作用 行政。 （c）研究周围空间内的细胞和元素如何 修改血管生长和修复，特别是当药物为 直接管理到该区域。