PERIVASCULAR DRUG DELIVERY

同时，局部药物递送被吹捧为一种令人兴奋的治疗方法， 对于许多疾病，包括心血管疾病， 理论上的希望和初步动物研究的兴奋， 在临床上还没有实现。R01支持的第一阶段帮助 我们认识到：1）地方行政不是地方的同义词 2）我们还没有完全理解潜在的好处， 局部给药的局限性和机制，以及3）药理学 定义和表征系统给药的工具并不完全 描述药物直接应用于特定节段时的事件 血管壁。 我们已经表明，药物在组织中的沉积和分布 局部输送后的动脉壁是复杂的，并依赖于 壁内运输和结合过程。 我们制定了一个严格的 描述局部血管药代动力学特征的框架，以及 说明了我们预测药物沉积和分布的能力， 高分辨率，使用模型血管活性化合物肝素。 在 与此同时，我们已经展示了如何监管的复杂性， 生物靶点（例如细胞周期癌基因和生长因子受体） 调节药物的生物效应。 因此，任何地方的成功 递送策略取决于使药物释放的动力学与 药物在靶区的沉积和分布机制 组织和靶病变病理学的时间序列。 我们希望研究生物学和提高临床效用的地方 通过验证和扩展我们的局部血管， 对高等动物物种的药代动力学分析， 动脉结构、改变状态和复杂动脉病变，以及 不同理化性质的药物。 了解哪里 药物的分配和存放细节不仅可以确保 充分的药物动力学，以实现生物效应，但也将使 在更适用和更完整的模型中研究特定的药物， 疾病 因此，我们现在力求： .确定血管药代动力学模型是否预测空间 药物在动脉壁内的分布。 .赋予运输的结构和解剖学基础， 我们观察到的沉积。 .将药代动力学参数与溶质化学性质相关联 对溶质运输至关重要， .研究血管状态的改变如何影响药代动力学，药物 沉积和生物效应。

While, local drug delivery has been touted as an exciting therapeutic option for many diseases, including cardiovascular pathologies, this theoretical promise and the excitement of preliminary animal studies has not been realized in the clinic. The first phase of R01 support helped us realize that: 1) local administration is not synonymous with local delivery, 2) we do not yet fully understand the potential benefits, limitations and mechanisms of local delivery, and 3) pharmacological tools that define and characterize systemic administration do not fully describe events when drugs are applied directly to specific segments of the vessel wall. We have shown that the deposition and distribution of drug in the arterial wall following local delivery to be complex and dependent upon intramural transport and binding processes. We developed a rigorous framework by which to characterize local vascular pharmacokinetics, and illustrated our ability to predict drug deposition and distribution with high resolution, using a model vasotherapeutic compound, heparin. At the same time, we have shown how the complexity of the regulation of the biologic target (e.g. cell cycle oncogenes and growth factor receptors) modulates a drug's biologic effect. Thus, the success of any local delivery strategy depends on matching the kinetics of drug release to the mechanisms of drug deposition and distribution in the target tissues, and the temporal sequence of target lesion pathology. We hope to examine the biology and enhance the clinical utility of local vascular delivery systems by validating and extending our local vascular pharmacokinetic analyses to higher animal species, more sophisticated arterial architectures, altered states and complex arterial lesions, and drugs of different physicochemical properties. Understanding where drugs distribute and are deposited in detail might not only ensure adequate drug kinetics to achieve biologic effect, but will also enable study of specific agents in more applicable and complete models of disease. We therefore now seek to: . determine if vascular pharmacokinetic models predict spatial distribution of drug within the arterial wall. . ascribe a structural and anatomic basis for the transport and deposition we have observed. . correlate pharmacokinetic parameters with solute chemical properties crucial to solute transport, and . examine how altered vascular states influence pharmacokinetics, drug deposition and biologic effects.