title: Phosphorothioate oligodeoxynucleotides distribute similarly in class A scavenger receptor knockout and wild-type mice.
abstract: It has been suggested that binding of phosphorothioate oligodeoxynucleotides (P=S ODNs) to macrophage scavenger receptors (SR-AI/II) is the primary mechanism of P=S ODN uptake into cells in vivo. To address the role of scavenger receptors in P=S ODN distribution in vivo, several pharmacokinetic and pharmacological parameters were compared in tissues from scavenger receptor knockout mice (SR-A-/-) and their wild-type counterparts after i.v. administration of 5- and 20-mg/kg doses of P=S ODN. With an antibody that recognizes P=S ODN, no differences in cellular distribution or staining intensity in livers, kidneys, lungs, or spleens taken from SR-A-/- versus wild-type mice could be detected at the histological level. There were no significant differences in P=S ODN concentrations in these organs as measured by capillary gel electrophoresis as well, although the concentration of P=S ODN in isolated Kupffer cells from livers of SR-A-/- mice was 25% lower than that in Kupffer cells from wild-type mice. Furthermore, a P=S ODN targeting murine A-raf reduced A-raf RNA levels to a similar extent in livers from SRA-/- (92.8%) and wild-type (88.3%) mice. Finally, in vitro P=S ODN uptake studies in peritoneal macrophages from SR-A-/- versus wild-type mice indicate that other high- and low-affinity uptake mechanisms predominate. Taken as a whole, our data suggest that, although there may be some contribution to P=S ODN uptake by the SR-AI/II receptor, this mechanism alone cannot account for the bulk of P=S ODN distribution into tissues and cells in vivo, including macrophages.
authors.affiliation: ISIS Pharmaceuticals, Carlsbad, California, USA. mbutler@isiph.com
authors.forename: M
authors.initials: M
authors.lastname: Butler
authors.forename: R M
authors.initials: RM
authors.lastname: Crooke
authors.forename: M J
authors.initials: MJ
authors.lastname: Graham
authors.forename: K M
authors.initials: KM
authors.lastname: Lemonidis
authors.forename: M
authors.initials: M
authors.lastname: Lougheed
authors.forename: S F
authors.initials: SF
authors.lastname: Murray
authors.forename: D
authors.initials: D
authors.lastname: Witchell
authors.forename: U
authors.initials: U
authors.lastname: Steinbrecher
authors.forename: C F
authors.initials: CF
authors.lastname: Bennett
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019075:Electrophoresis, Capillary; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D011971:Receptors, Immunologic / Q000145:classification* / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013154:Spleen / Q000378:metabolism; D013873:Thionucleotides / Q000493:pharmacokinetics*
chemical_list: D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013873:Thionucleotides; D012313:RNA; C084960:afovirsen sodium