title: Mechanisms of tissue uptake and retention in zotarolimus-coated balloon therapy.
abstract: 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.
  
  
  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.
authors.affiliation: Harvard–MIT Division of Health Sciences and Technology, Cambridge, MA, USA. vkolachalama@draper.com
authors.forename: Vijaya B
authors.initials: VB
authors.lastname: Kolachalama
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Pacetti
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Franses
authors.forename: John J
authors.initials: JJ
authors.lastname: Stankus
authors.forename: Hugh Q
authors.initials: HQ
authors.lastname: Zhao
authors.forename: Tarek
authors.initials: T
authors.lastname: Shazly
authors.forename: Alexander
authors.initials: A
authors.lastname: Nikanorov
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Schwartz
authors.forename: Abraham R
authors.initials: AR
authors.lastname: Tzafriri
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
mesh_terms: D000800:Angioplasty, Balloon / Q000379:methods*; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013552:Swine; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: C489443:zotarolimus; D017239:Paclitaxel; D020123:Sirolimus
keywords: animal model; binding; computational modeling; diffusion; drug-coated balloon; peripheral vascular disease; zotarolimus