title: Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction.
abstract: The use of arterial stents and other medical implants as a delivery platform for surface immobilized gene vectors allows for safe and efficient localized expression of therapeutic transgenes. In this study we investigate the use of hydrolyzable cross-linkers with distinct kinetics of hydrolysis for delivery of gene vectors from polyallylamine bisphosphonate-modified metal surfaces. Three cross-linkers with the estimated t1/2 of ester bonds hydrolysis of 5, 12 and 50 days demonstrated a cumulative 20%, 39% and 45% vector release, respectively, after 30 days exposure to physiological buffer at 37 °C. Transgene expression in endothelial and smooth muscles cells transduced with substrate immobilized adenovirus resulted in significantly different expression profiles for each individual cross-linker. Furthermore, immobilization of adenoviral vectors effectively extended their transduction effectiveness beyond the initial phase of release. Transgene expression driven by adenovirus-tethered stents in rat carotid arteries demonstrated that a faster rate of cross-linker hydrolysis resulted in higher expression levels at day 1, which declined by day 8 after stent implantation, while inversely, slower hydrolysis was associated with increased arterial expression at day 8 in comparison with day 1. In conclusion, adjustable release of transduction-competent adenoviral vectors from metallic surfaces can be achieved, both in vitro and in vivo, through surface immobilization of adenoviral vectors using hydrolyzable cross-linkers with structure-specific release kinetics.
authors.affiliation: Division of Cardiology, The Children's Hospital of Philadelphia, Abramson Research Center, and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA. fishbein@email.chop.edu
authors.forename: Ilia
authors.initials: I
authors.lastname: Fishbein
authors.forename: Scott P
authors.initials: SP
authors.lastname: Forbes
authors.forename: Michael
authors.initials: M
authors.lastname: Chorny
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Connolly
authors.forename: Richard F
authors.initials: RF
authors.lastname: Adamo
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Corrales
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Alferiev
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013193:Stainless Steel; D015607:Stents; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D013193:Stainless Steel