Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy
Author(s)Kolachalama, Vijaya B.; Pacetti, Stephen D.; Franses, Joseph W.; Stankus, John J.; Zhao, Hugh Q.; Shazly, Tarek; Nikanorov, Alexander; Schwartz, Lewis B.; Tzafriri, Abraham R.; Edelman, Elazer R.; ... Show more Show less
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Background—Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. Methods and Results—Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. Conclusions—A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue–lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.
DepartmentHarvard University--MIT Division of Health Sciences and Technology
American Heart Association
Kolachalama, V. B., S. D. Pacetti, J. W. Franses, J. J. Stankus, H. Q. Zhao, T. Shazly, A. Nikanorov, L. B. Schwartz, A. R. Tzafriri, and E. R. Edelman. “Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy.” Circulation 127, no. 20 (April 12, 2013): 2047–2055.
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