title: Intravenous administration of stabilized antisense lipid particles (SALP) leads to activation and expansion of liver natural killer cells.
abstract: Stabilized antisense lipid particles (SALP) have been developed for the systemic delivery of oligonucleotides. The impact of intravenous SALP administration was measured with respect to activation of natural killer (NK) and NK1.1+ T (NKT) cells in the livers of immunocompetent mice. Treatment with a SALP containing a highly mitogenic oligonucleotide (INX-6295) generated an increase in NK cytolytic activity and cell number within the liver but did not appear to affect the number of hepatic NKT cells or their cytolytic activity. The same results were observed after intravenous administration of the mitogenic oligonucleotide alone. Interestingly, treatment with a SALP containing a weakly mitogenic oligonucleotide (INX-6300) also activated the liver NK cells, whereas the oligonucleotide alone was unable to elicit these effects. The NK stimulatory activity of a SALP containing INX-6300 required both lipid and oligonucleotide components. These results demonstrate that in addition to modifying the pharmacokinetics and biodistribution of intravenously administered oligonucleotides, SALP possess immunostimulatory activity independent of oligonucleotide mitogenicity, which can serve as an adjuvant to antisense therapies for cancer.
authors.affiliation: Center for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Bramson
authors.forename: C A
authors.initials: CA
authors.lastname: Bodner
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.forename: S
authors.initials: S
authors.lastname: Semple
authors.forename: M J
authors.initials: MJ
authors.lastname: Hope
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D018899:CpG Islands / Q000187:drug effects / Q000276:immunology; D004337:Drug Carriers; D005260:Female; D007275:Injections, Intravenous; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008055:Lipids / Q000008:administration & dosage*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008934:Mitogens / Q000008:administration & dosage*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*
chemical_list: D000276:Adjuvants, Immunologic; D004337:Drug Carriers; D008055:Lipids; D008934:Mitogens; D016376:Oligonucleotides, Antisense