Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries
Authors
Fishbein, IliaAlferiev, Ivan S.
Bakay, Marina
Stachelek, Stanley J.
Sobolewski, Peter
Lai, Meizan
Choi, Hoon
Chen, I-W
Levy, Robert J.
UMass Chan Affiliations
Department of PhysiologyDivision of Cardiology
Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2008-04-17Keywords
Life Sciences
Metadata
Show full item recordAbstract
BACKGROUND: Local drug delivery from polymer-coated stents has demonstrated efficacy for preventing in-stent restenosis; however, both the inflammatory effects of polymer coatings and concerns about late outcomes of drug-eluting stent use indicate the need to investigate innovative approaches, such as combining localized gene therapy with stent angioplasty. Thus, we investigated the hypothesis that adenoviral vectors (Ad) could be delivered from the bare-metal surfaces of stents with a synthetic complex for reversible vector binding. METHODS AND RESULTS: We synthesized the 3 components of a gene vector binding complex: (1) A polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethyleneimine (PEI) with pyridyldithio groups for amplification of attachment sites [PEI(PDT)], and (3) a bifunctional (amine- and thiol-reactive) cross-linker with a labile ester bond (HL). HL-modified Ad attached to PABT/PEI(PDT)-treated steel surfaces demonstrated both sustained release in vitro over 30 days and localized green fluorescent protein expression in rat arterial smooth muscle cell cultures, which were not sensitive to either inhibition by neutralizing anti-Ad antibodies or inactivation after storage at 37 degrees C. In rat carotid studies, deployment of steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated both site-specific arterial Ad(GFP) expression and adenovirus-luciferase transgene activity per optical imaging. Rat carotid stent delivery of adenovirus encoding inducible nitric oxide synthase resulted in significant inhibition of restenosis. CONCLUSIONS: Reversible immobilization of adenovirus vectors on the bare-metal surfaces of endovascular stents via a synthetic complex represents an efficient, tunable method for sustained release of gene vectors to the vasculature.Source
Circulation. 2008 Apr 22;117(16):2096-103. Epub 2008 Apr 14. Link to article on publisher's siteDOI
10.1161/CIRCULATIONAHA.107.746412Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32930PubMed ID
18413497Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1161/CIRCULATIONAHA.107.746412