title: Stents Eluting 6-Mercaptopurine Reduce Neointima Formation and Inflammation while Enhancing Strut Coverage in Rabbits.
abstract: BACKGROUND
  The introduction of drug-eluting stents (DES) has dramatically reduced restenosis rates compared with bare metal stents, but in-stent thrombosis remains a safety concern, necessitating prolonged dual anti-platelet therapy. The drug 6-Mercaptopurine (6-MP) has been shown to have beneficial effects in a cell-specific fashion on smooth muscle cells (SMC), endothelial cells and macrophages. We generated and analyzed a novel bioresorbable polymer coated DES, releasing 6-MP into the vessel wall, to reduce restenosis by inhibiting SMC proliferation and decreasing inflammation, without negatively affecting endothelialization of the stent surface.
  
  
  METHODS
  Stents spray-coated with a bioresorbable polymer containing 0, 30 or 300 μg 6-MP were implanted in the iliac arteries of 17 male New Zealand White rabbits. Animals were euthanized for stent harvest 1 week after implantation for evaluation of cellular stent coverage and after 4 weeks for morphometric analyses of the lesions.
  
  
  RESULTS
  Four weeks after implantation, the high dose of 6-MP attenuated restenosis with 16% compared to controls. Reduced neointima formation could at least partly be explained by an almost 2-fold induction of the cell cycle inhibiting kinase p27Kip1. Additionally, inflammation score, the quantification of RAM11-positive cells in the vessel wall, was significantly reduced in the high dose group with 23% compared to the control group. Evaluation with scanning electron microscopy showed 6-MP did not inhibit strut coverage 1 week after implantation.
  
  
  CONCLUSIONS
  We demonstrate that novel stents coated with a bioresorbable polymer coating eluting 6-MP inhibit restenosis and attenuate inflammation, while stimulating endothelial coverage. The 6-MP-eluting stents demonstrate that inhibition of restenosis without leaving uncovered metal is feasible, bringing stents without risk of late thrombosis one step closer to the patient.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Matthijs S
authors.initials: MS
authors.lastname: Ruiter
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Doornbos
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Goran
authors.initials: G
authors.lastname: Marinković
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Aart C
authors.initials: AC
authors.lastname: Strang
authors.affiliation: Central Laboratory Animal Research Facility, Faculty of Veterinary Medicine, University of Utrecht, Utrecht, The Netherlands.
authors.forename: Nico J M
authors.initials: NJ
authors.lastname: Attevelt
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Vivian
authors.initials: V
authors.lastname: de Waard
authors.affiliation: Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.affiliation: InnoCore Pharmaceuticals, Groningen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Steendam
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
mesh_terms: D000818:Animals; D020099:Coated Materials, Biocompatible / Q000737:chemistry; D054855:Drug-Eluting Stents / Q000009:adverse effects*; D007083:Iliac Artery / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000627:therapeutic use; D058426:Neointima / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011108:Polymers / Q000737:chemistry; D011817:Rabbits
chemical_list: D020099:Coated Materials, Biocompatible; D007166:Immunosuppressive Agents; D011108:Polymers; D015122:Mercaptopurine