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.
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