Gelatin microgel-coated balloon catheter with enhanced delivery of everolimus for long-term vascular patency

In-stent restenosis (ISR) after percutaneous coronary intervention is a major reason for limited long-term patency due to complex neointimal proliferation caused by vascular injury. Drug-coated balloon (DCB) has been developed to treat various cardiovascular diseases including ISR by providing anti-...

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Bibliographic Details
Published in:Acta biomaterialia 2024-01, Vol.173, p.314-324
Main Authors: Lee, Simin, Yoon, Chang-Hwan, Oh, Dong Hwan, Anh, Tu Quang, Jeon, Ki-Hyun, Chae, In-Ho, Park, Ki Dong
Format: Article
Language:English
Subjects:
Animals
Cardiovascular Agents
Catheters - adverse effects
Coated Materials, Biocompatible
Coronary Restenosis - etiology
Coronary Restenosis - therapy
Endothelial Cells
Everolimus - pharmacology
Gelatin
Microgels
Paclitaxel
Rabbits
Risk Factors
Swine
Treatment Outcome
Vascular Patency
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Summary:In-stent restenosis (ISR) after percutaneous coronary intervention is a major reason for limited long-term patency due to complex neointimal proliferation caused by vascular injury. Drug-coated balloon (DCB) has been developed to treat various cardiovascular diseases including ISR by providing anti-proliferative drugs into blood vessel tissues. However, a significant proportion of the drug is lost during balloon tracking, resulting in ineffective drug delivery to the target region. In this study, we report an everolimus-coated balloon (ECB) using everolimus-loaded gelatin-hydroxyphenyl propionic acid microgel (GM) with enhanced everolimus delivery to vascular walls for long-term patency. GM with high drug loading (> 97%) was simply prepared by homogenizing enzyme-mediated crosslinked hydrogels. The optimal condition to prepare GM-coated ECB (GM-ECB) was established by changing homogenization time and ethanol solvent concentration (30 ∼ 80%). In vitro sustained everolimus release for 30 d, and cellular efficacy using smooth muscle cells and vascular endothelial cells were evaluated. Additionally, an in vivo drug transfer levels of GM-ECB using rabbit femoral arteries were assessed with reduced drug loss and efficient drug delivery capability. Finally, using ISR-induced porcine models, effective in vivo vascular patency 4 weeks after treatment of ECBs was also confirmed. Thus, this study strongly demonstrates that GM can be used as a potential drug delivery platform for DCB application. STATEMENT OF SIGNIFICANCE: We report an ECB using everolimus-loaded GM prepared by homogenization of enzymatic cross-linked hydrogel. GM showed efficient drug loading (> 97 %) and controllable size. GM-ECB exhibited potential to deliver everolimus in a sustained manner to target area with drug efficacy and viability against SMC and EC. Although GM-ECB had much lower drug content compared to controls, animal study demonstrated enhanced drug transfer and reduced drug loss of GM-ECB due to the protection of encapsulated drugs by GM, and the possible interaction between GM and endothelium. Finally, vascular patency and safety were assessed using ISR-induced porcine models. We suggest an advanced DCB strategy to alleviate rapid drug clearance by bloodstream while improving drug delivery for a long-term vascular patency.
ISSN:1742-7061
1878-7568
1878-7568
DOI:10.1016/j.actbio.2023.11.001