title: Stabilized lipid coated lipoplexes for the delivery of antisense oligonucleotides to liver endothelial cells in vitro and in vivo.
abstract: We report on the preparation and in vivo/in vitro disposition of antisense ODN encapsulating coated cationic lipoplexes (CCLs), prepared by a procedure essentially developed by Stuart and Allen (Stuart, D.D. and Allen, T.M. (2000) "A new liposomal formulation for antisense oligodeoxynucleotides with small size, high incorporation efficiency and good stability", Biochim. Biophys. Acta 1463, pp. 219-229). The behavior of untargeted CCLs was compared with CCLs that were targeted to scavenger receptors on liver endothelial cells by covalent coupling of the poly-anion aconitylated human serum albumin (Aco-HSA) to the particle surface. By means of cryo transmission electron microscopy (cryo-TEM) particles of high electron density could be distinguished from electron-translucent particles, representing high and low ODN encapsulation, respectively. The two populations were separated by sucrose density gradient centrifugation. Upon injection into rats, the untargeted particles showed long circulating properties with a half-life of >10 h. These untargeted CCLs barely bound to liver endothelial cells in vitro while Aco-HSA CCLs massively and specifically interacted with scavenger receptors on these cells. With J774 cells, a macrophage cell line expressing scavenger receptors, downregulation of ICAM-1 mRNA levels was achieved when the ODN was specifically delivered by Aco-HSA targeted CCLs.
authors.affiliation: Department of Cell Biology, Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Groningen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Bartsch
authors.forename: Alida H
authors.initials: AH
authors.lastname: Weeke-Klimp
authors.forename: Evelien P D
authors.initials: EP
authors.lastname: Hoenselaar
authors.forename: Marc C A
authors.initials: MC
authors.lastname: Stuart
authors.forename: Dirk K F
authors.initials: DK
authors.lastname: Meijer
authors.forename: Gerrit L
authors.initials: GL
authors.lastname: Scherphof
authors.forename: Jan A A M
authors.initials: JA
authors.lastname: Kamps
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D008081:Liposomes; D016376:Oligonucleotides, Antisense