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(Circulation. 2008;117:2096-2103.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Local Delivery of Gene Vectors From Bare-Metal Stents by Use of a Biodegradable Synthetic Complex Inhibits In-Stent Restenosis in Rat Carotid Arteries

Ilia Fishbein, MD, PhD; Ivan Alferiev, PhD; Marina Bakay, PhD; Stanley J. Stachelek, PhD; Peter Sobolewski, PhD; Meizan Lai, MD; Hoon Choi, PhD; I. -W. Chen, PhD; Robert J. Levy, MD

From the Division of Cardiology (I.F., I.A., M.B., S.J.S., P.S., M.L., R.J.L.), The Children’s Hospital of Philadelphia, Philadelphia, Pa, and the Department of Materials (H.C., I.-W.C.), The School of Engineering and Applied Sciences, The University of Pennsylvania, Philadelphia, Pa.

Correspondence to Robert J. Levy, MD, Children’s Hospital of Philadelphia, Abramson Research Center, Suite 702, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318. E-mail levyr{at}email.chop.edu

Received October 16, 2007; accepted February 27, 2008.

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°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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 117: 2041. [Extract] [Full Text]