Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy
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 transfe...
| Main Authors: | , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Heart Association
2016
|
| Online Access: | http://hdl.handle.net/1721.1/102576 https://orcid.org/0000-0002-7832-7156 |
| _version_ | 1826210893270089728 |
|---|---|
| author | 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. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology 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. |
| author_sort | Kolachalama, Vijaya B. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:57:07Z |
| format | Article |
| id | mit-1721.1/102576 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:57:07Z |
| publishDate | 2016 |
| publisher | American Heart Association |
| record_format | dspace |
| spelling | mit-1721.1/1025762022-09-29T11:41:36Z Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy 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. Harvard University--MIT Division of Health Sciences and Technology Kolachalama, Vijaya B. Franses, Joseph W. Shazly, Tarek Tzafriri, Abraham R. Edelman, Elazer R. 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. National Institutes of Health (U.S.) (Grant R01 GM-49039) Abbott Vascular 2016-05-22T20:02:00Z 2016-05-22T20:02:00Z 2013-04 2012-11 Article http://purl.org/eprint/type/JournalArticle 0009-7322 1524-4539 http://hdl.handle.net/1721.1/102576 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. https://orcid.org/0000-0002-7832-7156 en_US http://dx.doi.org/10.1161/circulationaha.113.002051 Circulation Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Heart Association PMC |
| spellingShingle | 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. Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title | Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title_full | Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title_fullStr | Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title_full_unstemmed | Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title_short | Mechanisms of Tissue Uptake and Retention in Zotarolimus-Coated Balloon Therapy |
| title_sort | mechanisms of tissue uptake and retention in zotarolimus coated balloon therapy |
| url | http://hdl.handle.net/1721.1/102576 https://orcid.org/0000-0002-7832-7156 |
| work_keys_str_mv | AT kolachalamavijayab mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT pacettistephend mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT fransesjosephw mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT stankusjohnj mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT zhaohughq mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT shazlytarek mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT nikanorovalexander mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT schwartzlewisb mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT tzafririabrahamr mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy AT edelmanelazerr mechanismsoftissueuptakeandretentioninzotarolimuscoatedballoontherapy |