title: Novel site-specific systemic delivery of Rapamycin with perfluorobutane gas microbubble carrier reduced neointimal formation in a porcine coronary restenosis model.
abstract: Earlier studies demonstrated that perfluorobutane gas microbubble carrier (PGMC) adheres to injured arteries and enhances the drug uptake specifically into the cells of the denuded vessel segment. The purpose of this study was to investigate the effect of PGMC-based systemic delivery of Rapamycin on expression of p27 in vascular tissue and restenosis in porcine coronary arteries after stent implantation. Eight pigs underwent coronary stent implantation (three stents per animal). Five pigs were treated with i.v. injection of PGMC with 2 mg of Rapamycin and three animals served as control. Four hours postprocedure, three pigs were sacrificed and stented segments were analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, five pigs (15 stent sites) were sacrificed at 28 days following intervention and vessels were perfusion-fixed. HPLC of the treated arteries demonstrated high drug concentration in the vessel tissue, and Western blot analysis showed elevated expression of p27 at 4 hr postprocedure. Histomorphometry revealed significantly reduced (by 40%) neointimal formation in the PGMC/Rapamycin group compared with controls (1.84 +/- 0.84 vs. 4.77 +/- 1.71 mm2, respectively; P < 0.001). In the porcine coronary model, site-specific systemic delivery of Rapamycin utilizing PGMC resulted in overexpression of p27 and a significant reduction of neointimal formation within the stented segments.
authors.affiliation: Department of Interventional Cardiac and Vascular Services, Lenox Hill Hospital, New York, NY 10021, USA. nkipshidze@lenoxhill.net
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Kipshidze
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Porter
authors.forename: George
authors.initials: G
authors.lastname: Dangas
authors.forename: Hamid
authors.initials: H
authors.lastname: Yazdi
authors.forename: Fermin
authors.initials: F
authors.lastname: Tio
authors.forename: Feng
authors.initials: F
authors.lastname: Xie
authors.forename: David
authors.initials: D
authors.lastname: Hellinga
authors.forename: Roswitha
authors.initials: R
authors.lastname: Wolfram
authors.forename: Rufus
authors.initials: R
authors.lastname: Seabron
authors.forename: Ron
authors.initials: R
authors.lastname: Waksman
authors.forename: Alexander
authors.initials: A
authors.lastname: Abizaid
authors.forename: Gary
authors.initials: G
authors.lastname: Roubin
authors.forename: Sriram
authors.initials: S
authors.lastname: Iyer
authors.forename: Antonio
authors.initials: A
authors.lastname: Colombo
authors.forename: Martin B
authors.initials: MB
authors.lastname: Leon
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Moses
authors.forename: Patrick
authors.initials: P
authors.lastname: Iversen
mesh_terms: D000818:Animals; D019917:Blood Vessel Prosthesis Implantation; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D023903:Coronary Restenosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005466:Fluorocarbons; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007261:Infusions, Intra-Arterial; D045423:Microbubbles; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015607:Stents; D013552:Swine; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D018797:Cell Cycle Proteins; D005466:Fluorocarbons; D007166:Immunosuppressive Agents; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C108042:perfluorobutane; D020123:Sirolimus