Enhanced anti-inflammatory activity of a liposomal intercellular adhesion molecule-1 antisense oligodeoxynucleotide in an acute model of contact hypersensitivity.
The anti-inflammatory activity of free and liposome-encapsulated oligonucleotide targeted against intercellular adhesion molecule-1 mRNA was investigated in a delayed type hypersensitivity model of acute inflammation in mice. Contact hypersensitivity reactions to 2, 4-dinitrofluorobenzene were monitored by measuring ear thickness and cellular infiltration, both of which were observed to be maximal 24 h after ear challenge. A murine-specific phosphorothioate oligodeoxynucleotide and various control sequences were each passively encapsulated into 100-nm diameter large unilamellar vesicles composed of egg phosphatidylcholine and cholesterol. All formulations were administered as a single-bolus injection into the tail vein approximately 15 min after initiating ear inflammation. Oligodeoxynucleotide dose was varied from 5 to 50 mg/kg and the extent of inflammation was assessed 24 h later. Mice treated with free oligonucleotide, empty vesicles, or encapsulated control sequences showed no measurable effect on ear swelling or cellular infiltration compared with untreated controls. However, mice that received the active sequence encapsulated in lipid vesicles exhibited near baseline levels of ear thickness and leukocyte infiltration, similar to that observed in mice treated with a topical corticosteroid. These data demonstrate the utility of liposome-encapsulated intercellular adhesion molecule-1 antisense oligonucleotide as a novel anti-inflammatory therapeutic.
Klimuk
S K
SK
Department of Biochemistry, The University of British Columbia, Vancouver, British Columbia, Canada. sklimuk@inexpharm.com
Semple
S C
SC
Nahirney
P N
PN
Mullen
M C
MC
Bennett
C F
CF
Scherrer
P
P
Hope
M J
MJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002214:Capsules; D002465:Cell Movement / Q000187:drug effects; D015941:Complement Hemolytic Activity Assay; D003877:Dermatitis, Contact / Q000188:drug therapy*; D004355:Drug Stability; D004423:Ear / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000494:pharmacology*; D008081:Liposomes / Q000493:pharmacokinetics*; D051379:Mice; D008813:Mice, Inbred ICR; D020319:Oligodeoxyribonucleotides, Antisense / Q000097:blood / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D002214:Capsules; D008081:Liposomes; D020319:Oligodeoxyribonucleotides, Antisense; D018799:Intercellular Adhesion Molecule-1