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

Conclusion: Sustained release of gene vectors is possible through reversible immobilization of adenovirus vectors on bare-metal surfaces of vascular stents. Summary: Polymer-coated stents facilitate local drug delivery to the vasculature and have proven efficacious in preventing in-stent restenosis. There are, however, concerns about the inflammatory effects of polymer coatings and late outcomes of drug-eluting stents. The authors investigated whether adenoviral vectors could be delivered from bare metal surfaces of stents using a synthetic complex for reversible vector binding. Three components of a gene vector-binding complex were synthesized: (1) a polyallylamine bisphosphonate with latent thiol groups (PABT), (2) a polyethylenimine (PEI) with pyridyldithio groups for amplification of attachments sites [PEI (PVT)], and (3) a bifunctional amine-reactive and thiol-reactive cross-linker with labile ester bond (HL). The HL-modified adenovirus attached to PABT/PEI(PDT)-treated steel surfaces and demonstrated in vitro sustained release for 30 days. They also demonstrated localized green fluorescent protein expression in rat arterial smooth muscle cell cultures. This expression was not sensitive to inhibition by neutralizing antiadenovirus antibodies or inactivation after storage at 37°C. In rat carotid studies, steel stents configured with PABT/PEI(PDT)/HL-tethered adenoviral vectors demonstrated site-specific arterial adenovirus green fluorescent protein expression and adenovirus-luciferase transgene activity by optical imaging. Adenovirus encoding inducible nitric oxide synthase delivered by a carotid stent resulted in significant inhibition of restenosis. Comment: This study investigated local delivery of gene therapy from bare-metal stent surfaces using reversible chemical attachment of vectors to the bare-metal stents. Adenovirus vectors on the surfaces of the stents demonstrated >1-month release kinetics and site-specific transduction of target cell types in vitro and in vivo in this rat model. Deployment of stents configured with 109 adenovirus vectors encoded for inducible nitric oxide synthase resulted in significant reduction of in-stent restenosis. It appears that the concept of gene-eluting stents is valid and may provide a mechanism of local and systemic delivery of gene products by the vasculature.