VASCULAR DRUG DELIVERY

描述(由申请人提供)： NIH RO1的资助使我们能够为了解局部药物输送和动脉疾病之间的相互作用做出贡献。我们论证了给药的方向性和部位的重要性，以及动脉解剖超微结构与疾病的关系。我们完成了一个血管药物输送的三维模型，能够从任何几何形状和任何形式的释放装置预测整个动脉壁的点对点药物浓度。在建立了一个描述药物分布的严格量化框架之后，我们现在将把药物分布与最终的生物效应联系起来。尽管我们可以预测毒品在哪里储存，但了解毒品在哪里起作用的下一步的重要性怎么强调都不为过。普遍的假设是，生物效应直接与药物分布相对应，虽然这对某些药物可能是正确的，但药物本地化和效应之间的关系仍然知之甚少。初步数据显示，对血管活性化合物的反应可能更多地取决于细胞的相互连接，而不是局部药物浓度。此外，许多药物的反应可能受到局部损伤、炎症过程甚至局部机械状态变化的影响。事实上，确定药物分布的特征可能只是一个起点，即一个复杂得多的生物回路的一个组成部分，它最终决定了生物反应的分布如何演变。因此，在这一修订的赠款申请中，我们现在建议(A)检查药物分布是否与最终生物反应的局部化相关，(B)描绘细胞互连和局部组织状态如何调节这种相关性，(C)确定局部药代动力学如何决定血管组织中的生物反应，以及(D)表征细胞通讯的改变如何增强受损组织中的药物反应。在细胞培养中，细胞连通性、细胞状态和给药易于定义和控制的研究将扩展到定义了局部药代动力学的全动脉和心肌，其中影响药物分布的机械因素和药代动力学因素都不清楚。将根据物理化学性质、生物活性、临床表现和细胞反应机制来考虑一系列药物。

DESCRIPTION (provided by applicant): NIH RO1 funding has enabled us to contribute to understanding the interplay between local drug delivery and arterial disease. We demonstrated the importance of directionality and site of drug administration, and arterial anatomic ultrastructure and disease. We completed a three-dimensional model of vascular drug delivery capable of predicting point-to-point drug concentrations throughout the arterial wall from delivery devices of any geometry and with any form of release. Having developed a rigorous quantitative framework for characterizing drug distribution, we will now correlate drug distribution with ultimate biological effect. Although we can predict where drug deposits, the importance of this next step, knowing where drug acts, cannot be overstated. The prevailing assumption is that biological effect maps directly with drug distribution, and while this may prove true for some drugs, the relationship between localization of drug and effect remains poorly understood. Preliminary data show that response to vasoactive compounds may depend more on cell interconnectivity than on local drug concentration. Moreover, response to many drugs may be affected by local injury, inflammatory processes or even changes in local mechanical state. Indeed, characterizing drug distribution may only be the starting point, i.e. one component of a vastly more complicated biological circuitry which ultimately determines how the distribution of biologic response evolves. In this revised grant application we now propose to therefore (a) examine whether drug distribution correlates with localization of ultimate biologic response, (b) delineate how cell interconnectivity and local tissue state modulate this correlation, (c) define how local pharmacokinetics dictates biologic response in vascular tissues, and (d) characterize how modifications of cell communications can enhance response to drug in injured tissue. Studies in cell culture in which cell connectivity, cell state, and drug administration can be easily defined and controlled, will be extended to whole arteries wherein local pharmacokinetics are defined, and in the myocardium, in which neither the mechanical nor pharmacokinetic factors influencing drug distribution are known. A range of drugs will be considered based on physicochemical properties, biological activity, clinical performance and mechanism of cell responsiveness.