Suppression of TNFalpha production in LPS induced liver failure in mice after intravenous injection of cationic liposomes/NFkappaB decoy complex.
NFkappaB decoy, double stranded oligonucleotides containing NFkappaB binding sequences, inhibits NFkappaB-mediated production of inflammatory cytokines, and therefore NFkappaB decoy has been applied to several diseases. However, naked NFkappaB decoy, which is quickly cleared from the circulation in mice after intravenous injection, is readily absorbed into the systemic circulation. In order to deliver enough NFkappaB decoy for a therapeutic effect, it is necessary to develop a carrier, which enables much more NFkappaKB decoy to transfer to the target cells. In this study, using N-[1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride (DOTMA)/cholesterol (1 :1) liposomes, the therapeutic effect of NFkappaB decoy was investigated in an LPS induced acute hepatitis model mice. The mean diameter of the cationic liposomes/NFkappaB decoy complex was about 70.9 nm and the zeta potential of complex was about 37.4 mV. Tissue distribution was determined by measuring the radioactivity of a cationic liposomes/ [32P] NFkappaB decoy complex after intravenous injection. The cationic liposomes/[32P] NFkappaB decoy complex was rapidly accumulated in the lung and gradually moved to the liver. The therapeutic effect was determined by the serum concentration of TNFalpha in LPS treated mice. The production of TNFalpha was significantly inhibited by cationic liposomes/NFkappaB decoy complex but not by cationic liposomes/random decoy complex or naked NFkappaB decoy. These results suggested that NFkappaB decoy therapy could be achieved using cationic liposomes. This information is of great value for the design of NFkappaB decoy carrier systems.
Higuchi
Y
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Kawakami
S
S
Oka
M
M
Yamashita
F
F
Hashida
M
M
D000818:Animals; D002412:Cations; D055598:Chemical Phenomena; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy*; D002627:Chemistry, Physical; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D016503:Drug Delivery Systems; D015316:Genetic Therapy; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity*; D008081:Liposomes; D051379:Mice; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000627:therapeutic use*; D009841:Oligonucleotides / Q000627:therapeutic use; D010316:Particle Size; D010766:Phosphorylation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D002412:Cations; D016207:Cytokines; D008070:Lipopolysaccharides; D008081:Liposomes; D016328:NF-kappa B; D009841:Oligonucleotides; D014409:Tumor Necrosis Factor-alpha; D004247:DNA