title: Vascular delivery of c-myc antisense from cationically modified phosphorylcholine coated stents.
abstract: c-Myc is involved in the formation of neointimal hyperplasia. We investigated in vitro, ex vivo and in vivo release of antisense c-myc from cationically modified phosphorylcholine-coated stents, as well as the effects on c-Myc expression and neointima formation in a porcine coronary stent model. In vitro experiments were performed to determine optimal loading of stents with antisense. Stents loaded with labelled antisense were deployed in porcine arteries ex vivo and in vivo. Antisense was detected in the vessel wall directly surrounding the stent of pig carotid and coronary artery up to 48 h after stent deployment. Nuclear uptake was observed in endothelial and vascular smooth muscle cells. Labelled antisense within peripheral tissues in vivo was <1.0% of that within stented arterial segments. Control and antisense loaded stents implanted into 10 pig coronary arteries and analysed at 28 days post-stenting showed that lumen area within the antisense stents was significantly increased (i.e. 30.5% greater, P<0.01), whilst both neointimal area and neointimal thickness were significantly reduced (17.5% and 19.5%, respectively, P<0.01) compared to control stents. Cationically modified phosphorylcholine coated stent-based delivery of c-myc antisense is feasible with minimal systemic delivery and is associated with a reduction of in-stent neointimal hyperplasia in pig coronary arteries.
authors.affiliation: Cardiovascular Research Unit, Royal Hallamshire Hospital, University of Sheffield, UK.
authors.forename: K H
authors.initials: KH
authors.lastname: Chan
authors.forename: J
authors.initials: J
authors.lastname: Armstrong
authors.forename: S
authors.initials: S
authors.lastname: Withers
authors.forename: N
authors.initials: N
authors.lastname: Malik
authors.forename: D C
authors.initials: DC
authors.lastname: Cumberland
authors.forename: J
authors.initials: J
authors.lastname: Gunn
authors.forename: C M
authors.initials: CM
authors.lastname: Holt
mesh_terms: D000818:Animals; D001807:Blood Vessel Prosthesis; D020099:Coated Materials, Biocompatible / Q000008:administration & dosage / Q000737:chemistry*; D016373:DNA, Antisense / Q000008:administration & dosage* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004343:Drug Implants / Q000008:administration & dosage / Q000737:chemistry; D019544:Equipment Failure Analysis; D005240:Feasibility Studies; D018390:Gene Targeting / Q000379:methods; D006083:Graft Occlusion, Vascular / Q000235:genetics / Q000517:prevention & control*; D066298:In Vitro Techniques; D010767:Phosphorylcholine / Q000737:chemistry*; D011474:Prosthesis Design; D015607:Stents; D013552:Swine; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D020099:Coated Materials, Biocompatible; D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D004343:Drug Implants; C116115:MYCBP protein, human; D014157:Transcription Factors; D010767:Phosphorylcholine