Vascular Drug Delivery

描述（由申请人提供）：我们很高兴提交这一修订后的竞争性赠款续期审查血管药物输送的基本生理学。这项工作在临床和基础科学领域具有新的紧迫性。药物洗脱支架系统（DES）是局部血管治疗的典型例子，DES显著减少临床再狭窄已导致压倒性采用。然而，早期的热情现在被对超敏反应、延迟血管愈合、不完全再内皮化和血栓形成的晚期血管毒性的担忧所冲淡。再狭窄与灾难性并发症的明显权衡预示着强烈要求严格限制DES的临床使用，直到有效性与安全性相结合。临床并发症的风险因素显著反映了我们在临床前动物模型中观察到的事件。组织对应用药物的反应与局部药物渗透、保留和分布最相关。但这不仅仅是一个静态的药代动力学问题。雷帕霉素和紫杉醇（临床可用DES上使用的两种药物）的分布模式取决于靶血管的超微结构方面;流过和通过血管的血流、全身和环境状态以及单个药物的理化性质。这些分布随着时间的推移以及干预和药物暴露而变化。临床意义深远。我们最近分析了7项临床试验，据称这些试验显示了不同DES的不同结果，并发现了病变范围和成分的统一主题。雷帕霉素和紫杉醇洗脱支架在具有简单病变的自体血管中表现相似，但随着病变变得更加迂曲、狭窄和不均匀，其疗效和副作用特征扩大。分布的差异可以解释这种效应。这些问题为接下来的一系列研究提供了自然的演变。作为我们先前工作的延伸，我们将确定动脉组成、几何形状和超微结构对药物分布和药物效应的影响。这一统一的具体目标吸引了越来越有针对性的工作的多个方面。我们将以这种方式检查（1）在大体积组织水平上，在血管室中，不同动脉的药物摄取如何不同;和透壁，从管腔到外膜（2）组织成分和细胞如何作为物理扩散屏障和作为特异性结合元件（3）局部给药药物作用随时间的演变，以及（4）血管形态异质性，重塑，介入性修改和对疾病的反应（5）血管几何形状和机械干预对药物分布效果的影响（6）以及最终将上述研究与概念和数学模型相结合，进一步推动实验设计和假设的制定。组成、几何形状和超微结构以及组织状态对局部递送的相互作用的不断发展的概念可以很好地阐明局部递送化合物的挑战。NIH的资助使我们能够帮助理解局部运输现象和血管修复之间的相互作用。这些知识有助于确定局部给药的局限性和潜力。我们已经开发了一个定量的框架，用于表征局部给药后动脉壁内出现的药物分布的独特模式。我们现在试图了解药物的分布和效果是如何由靶血管的超微结构方面，通过血管的流动，全身和环境状态，以及个别药物的物理化学性质决定的。

DESCRIPTION (provided by applicant): We are pleased to submit this revised competing grant renewal examining the basic physiology of vascular drug delivery. This work has taken on renewed urgency in the clinical and fundamental scientific domains. Drug eluting stent systems (DES) are paradigmatic examples of local vascular therapy, and the dramatic reduction of clinical restenosis by DES has led to overwhelming adoption. Yet, early enthusiasm is now tempered by concerns for late blood vessel toxicity from hypersensitivity reactions, delayed vascular healing, incomplete re-endothelialization, and thrombosis. The apparent tradeoff of restenosis for catastrophic complications has heralded an outcry to curtail severely the clinical use of DES until efficacy can be coupled with safety. Risk factors for clinical complications remarkably mirror events we have observed in our preclinical animal models. Tissue response to applied drugs correlates best with local drug penetration, retention and distribution. But this is not a static pharmacokinetic issue alone. The distribution patterns of rapamycin and paclitaxel, the two drugs used on clinically available DES, are dependent upon ultrastructural aspects of target vessels; flow over and through vessels, systemic and environmental states, as well as physico-chemical properties of individual drugs. These distributions evolve over time and with intervention and drug exposure. The clinical relevance is profound. We recently analyzed seven clinical trials that purportedly showed disparate findings with different DES and found a unifying theme in lesion extent and composition. Rapamycin and paclitaxel-eluting stents behaved similarly in native vessels with simple lesions, but their efficacy and side- effect profile widened as lesions became more tortuous, constrictive and heterogeneous. Differences in distribution may explain this effect. These issues provide a natural evolution of the next series of studies. As an extension of our previous work, we will determine the impact of arterial composition, geometry and ultrastructure on drug distribution and drug effect. This unified specific aim draws in multiple aspects of increasingly directed work. We will in this fashion examine (1) how drug uptake differs across different arteries on a bulk tissue level; in vascular compartments; and transmurally, from lumen to adventitia (2) how tissue components & cells serve as physical diffusion barriers AND as specific binding elements (3) the evolution of effect of locally administered drugs over time, and with & (4) vascular morphologic heterogeneity, remodeling, interventional modification and response to disease (5) the impact of flow imposed by vessel geometry & mechanical intervention, on drug distribution effect (6) and finally integration of the above studies with conceptual and mathematical models that further drive design of experiments and formulation of hypotheses. The evolving notions of the interplay of composition, geometry, and ultrastructure and tissue state on local delivery may well clarify the challenges with locally delivered compounds. NIH funding has enabled us to contribute to understanding the interplay between local transport phenomena and vascular repair. This knowledge has helped define the limits and potential of local drug delivery. We have developed a quantitative framework for characterizing the unique patterns of drug distribution that arise within the arterial wall after local drug delivery. We now seek to understand how drug distribution and effect are determined by ultrastructural aspects of target vessels, flow through vessels, and systemic and environmental states, as well as physico-chemical properties of individual drugs.