VASCULAR DRUG DELIVERY

描述（由申请人提供）： NIH RO1基金使我们能够帮助了解局部药物输送和动脉疾病之间的相互作用。我们证明了给药的方向性和部位以及动脉解剖超微结构和疾病的重要性。我们完成了一个三维模型的血管药物输送能够预测点到点的药物浓度在整个动脉壁从任何几何形状的输送装置，并与任何形式的释放。在开发了一个严格的定量框架来表征药物分布之后，我们现在将药物分布与最终的生物学效应相关联。虽然我们可以预测药物沉积的位置，但下一步的重要性，知道药物的作用，不能被夸大。普遍的假设是，生物效应直接与药物分布映射，虽然这可能证明对某些药物是正确的，但药物定位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性，而不是局部药物浓度。此外，对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，表征药物分布可能只是起点，即最终决定生物反应分布如何演变的更为复杂的生物回路的一个组成部分。因此，在此修订的资助申请中，我们现在建议（a）检查药物分布是否与最终生物反应的定位相关，（B）描述细胞互连性和局部组织状态如何调节这种相关性，（c）定义局部药代动力学如何决定血管组织中的生物反应，以及（d）表征细胞通讯的修饰如何增强损伤组织中对药物的反应。在细胞培养中，细胞连接性、细胞状态和药物给药可以很容易地定义和控制，研究将扩展到全动脉，其中局部药代动力学被定义，以及心肌，其中影响药物分布的机械因素和药代动力学因素都是未知的。将根据理化性质、生物活性、临床性能和细胞反应机制考虑一系列药物。

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.