title: Local delivery of gene vectors from bare-metal stents by use of a biodegradable synthetic complex inhibits in-stent restenosis in rat carotid arteries.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.forename: Ivan
authors.initials: I
authors.lastname: Alferiev
authors.forename: Marina
authors.initials: M
authors.lastname: Bakay
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Stachelek
authors.forename: Peter
authors.initials: P
authors.lastname: Sobolewski
authors.forename: Meizan
authors.initials: M
authors.lastname: Lai
authors.forename: Hoon
authors.initials: H
authors.lastname: Choi
authors.forename: I-W
authors.initials: IW
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D020341:Absorbable Implants; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000166:cytology; D016893:Carotid Stenosis / Q000517:prevention & control* / Q000628:therapy*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008670:Metals; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009500:Neutralization Tests; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055502:Secondary Prevention; D015607:Stents
chemical_list: D003432:Cross-Linking Reagents; D008670:Metals; D049452:Green Fluorescent Proteins; D052247:Nitric Oxide Synthase Type II