Defining drug and target protein distributions after stent-based drug release: Durable versus deployable coatings
Name
nihms943255.pdf
Description
Accepted version
Size
698.51 KB
Format
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Checksum (MD5)
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Author(s)
Tzafriri, Abraham R.
Garcia-Polite, Fernando
Li, Xiaojian
Keating, John
Balaguer, Josep-Maria
Zani, Brett
Bailey, Lynn
Markham, Peter
Kiorpes, Timothy C.
Carlyle, Wenda
Date Issued
March 2018
Journal
Journal of Controlled Release
Publisher
Elsevier BV
Citation
Tzafriri, Abraham R. et al. "Defining drug and target protein distributions after stent-based drug release: Durable versus deployable coatings." Journal of Controlled Release 274 (March 2018): 102-108 © 2018 Elsevier
Version
Author's final manuscript
Abstract
Background: Innovations in drug eluting stent designs make it increasingly important to develop models for differentiating performance through spatial definition of drug, receptor binding and cell state. Methods: Two designs of sirolimus analog eluting stents were implanted into porcine coronary arteries for 28, 60 or 90 days (n = 9/time point), durable coating (Xience) and deployable absorbable coating (MiStent). Explanted arteries were evaluated for drug content (n = 3/time point) by LC-MS/MS and for drug and target protein (mTOR) distributions by immunofluorescence (IF, n = 6/time point). A computational model was developed to predict drug release and arterial distribution maps. Results: Both stents released the majority of drug load by 28 days, with different tissue retention efficiencies (91.4 ± 4.9% MiStent versus 21.5 ± 1.9% Xience, P < 0.001). Computational modeling of MiStent coating deployment and microcrystal dissolution recapitulated in vivo drug release and net tissue content and predicted that >98.5% of deployed drug remains crystalline through 90 days. Immunofluorescence and computational modeling showed peristrut drug localization for both stents, with similar peaks, but high interstrut levels only at sites of coating deployment from the absorbable coating. Co-localization of mTOR-IF with drug-IF for both devices showed persistent drug effects, though with differential drug–receptor pharmacokinetics. Conclusions: Immunofluorescence and computational modeling provide insights into drug distribution and binding status that can help differentiate drug delivery technologies. Herein we found that tissue deployment of slow dissolving crystalline drug particles results in temporally and spatially more uniform drug delivery to interstrut zones that might otherwise be under-dosed without excess peristrut drug.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.jconrel.2018.02.007
