title: Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE).
abstract: OBJECTIVE
  Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration.
  
  
  METHODS
  Effects of Dz13 in a formulation containing DOTAP/DOPE on smooth muscle cell (SMC) growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia.
  
  
  RESULTS
  Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G>C). The Dz13(500 μg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1h on ice (0°C) and 30 min at 37°C, allowing sufficient uptake by the veins. Dz13 (500 μg) inhibited neointima formation 28 d after end-to-side transplantation.
  
  
  CONCLUSIONS
  This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Ravinay
authors.initials: R
authors.lastname: Bhindi
authors.forename: Zhou J
authors.initials: ZJ
authors.lastname: Deng
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
mesh_terms: D000818:Animals; D002412:Cations; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D021881:DNA, Catalytic / Q000008:administration & dosage* / Q000737:chemistry; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000737:chemistry; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000008:administration & dosage* / Q000737:chemistry; D007601:Jugular Veins / Q000187:drug effects* / Q000473:pathology / Q000637:transplantation; D008081:Liposomes; D008297:Male; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage* / Q000737:chemistry; D011817:Rabbits; D058017:Vascular Grafting / Q000009:adverse effects / Q000379:methods*
chemical_list: C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D002412:Cations; D021881:DNA, Catalytic; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D048031:JNK Mitogen-Activated Protein Kinases; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
keywords: DNAzymes; Intimal thickening; Smooth muscle cells; Vein bypass graft