Mechanisms of tissue uptake and retention in zotarolimus-coated balloon therapy.

1Harvard-MIT Division of Health Sciences and Technology & Charles Stark Draper Laboratory, Cambridge, MA.
Circulation (Impact Factor: 14.95). 04/2013; DOI: 10.1161/CIRCULATIONAHA.113.002051
Source: PubMed

ABSTRACT BACKGROUND: Drug-coated balloons are increasingly utilized 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 (ZCB) use. Drug diffusivity and binding parameters for use in computational modeling were estimated from 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 multiple peaks displayed by Paclitaxel. Drug release kinetics was measured by inflating ZCBs 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: 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, duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endovascular intervention has become a well-recognized treatment modality for peripheral artery disease; however, mid- and long-term outcomes have been plagued by limited durability. Plain balloon angioplasty and bare-metal stents have historically suffered from high restenosis rates leading to the need for frequent repeat revascularization procedures. The innovation of locally administered, drug-delivering balloons and stents has been a direct result of technological innovations directed toward prevention and treatment of this limitation. Over the last 5 years, numerous clinical trials investigating the use of drug-coated stents and drug-coated balloons indicate a significant improvement in endovascular treatment durability and outcomes. This review provides an up-to-date assessment of the current evidence for the use of drug-coated stents and drug-coated balloons in the treatment of femoropopliteal and infrapopliteal peripheral artery disease. Additionally, it provides an overview of the development of this technology, highlights landmark ongoing and completed clinical trials, examines evidence to support the use of drug-coated technologies in combination with other modalities, and examines promising new technological developments. Last, it summarizes the challenges and safety concerns that have delayed U.S. Food and Drug Administration approval of these devices.
    JACC Cardiovascular Interventions 08/2014; 7(8):827-839. · 7.44 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increasing interests have been raised towards the potential applications of biodegradable poly(lactic-co-glycolic acid) (PLGA) coatings for drug-eluting stents in order to improve the drug delivery and reduce adverse outcomes in stented arteries in patients. This article presents a mathematical model to describe the integrated processes of drug release in a stent with PLGA coating and subsequent drug delivery, distribution, and drug pharmacokinetics in the arterial wall. The model takes into account the PLGA degradation and erosion, anisotropic drug diffusion in the arterial wall, reversible drug binding, and drug internalization. After comparing simulation results for a biodegradable PLGA coating with a biodurable coating for stent-based drug delivery, the simulations further investigate drug internalization, interstitial fluid flow in the arterial wall, and stent embedment for their impact on drug release in the PLGA coating, arterial drug levels, and arterial drug distribution. It is shown that these three factors, while imposing little change in the drug release profiles, can greatly change the average drug concentrations in the arterial wall. In particular, each of the factors leads to significant and yet distinguished alterations in the arterial drug distribution that can potentially influence the treatment outcomes. The detailed integrated model provides insights into the design and evaluation of biodegradable PLGA-coated drug-eluting stents for improved intravascular drug delivery.
    Journal of Biomechanical Engineering 08/2014; · 1.75 Impact Factor
  • Circulation 12/2013; 128(24):e461. · 14.95 Impact Factor


Available from
May 29, 2014