The potential role of fucosylated cationic liposome/NFkappaB decoy complexes in the treatment of cytokine-related liver disease.
Cytokine production by Kupffer cells, which is regulated by NFkappaB, causes severe liver injury in endotoxin syndrome. NFkappaB decoy has been reported to inhibit NFkappaB-mediated transcription. The purpose of this study is to inhibit LPS-induced cytokine production by Kupffer cell-targeted delivery of NFkappaB decoy using fucosylated cationic liposomes (Fuc-liposomes). Cholesten-5-yloxy-N-{4-[(1-imino-2-L-thiofucosyl-ethyl)-amino] butyl-}formamide (Fuc-C4-Chol) was synthesized to prepare Fuc-liposomes. Tissue accumulation, intrahepatic distribution and serum cytokine concentrations were investigated after intravenous injection of Fuc-liposomes/NFkappaB decoy complexes. Intravenously injected Fuc-liposome complexes rapidly and highly accumulated in the liver while little naked NFkappaB decoy accumulated in the liver. An intrahepatic distribution study showed that Fuc-liposome complexes are mainly taken up by non-parenchymal cells. The liver accumulation of Fuc-liposome complexes was inhibited by GdCl(3) pretreatment, which selectively inhibited Kupffer cell uptake. This result suggested that Kupffer cells contribute to liver accumulation. TNFalpha, IFNgamma, ALT and AST serum levels in LPS-infected mice were significantly attenuated by treatment with Fuc-liposome complexes compared with naked NFkappaB decoy. Fuc-liposome complexes also reduced the amount of activated NFkappaB in the liver nuclei. Fuc-liposomes would be a useful carrier for Kupffer cell-selective delivery of NFkappaB decoy by intravenous injection.
Higuchi
Yuriko
Y
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
Kawakami
Shigeru
S
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D002412:Cations; D016207:Cytokines / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D005260:Female; D005643:Fucose / Q000737:chemistry*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007728:Kupffer Cells / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D008107:Liver Diseases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000737:chemistry*
D002412:Cations; D016207:Cytokines; D004731:Endotoxins; D008081:Liposomes; D016328:NF-kappa B; D005643:Fucose