title: Potential use of fucose-appended dendrimer/α-cyclodextrin conjugates as NF-κB decoy carriers for the treatment of lipopolysaccharide-induced fulminant hepatitis in mice.
abstract: The purpose of the present study is to treat lipopolysaccharide (LPS)-induced fulminant hepatitis by NF-κB decoy complex with fucose-appended dendrimer (generation 2; G2) conjugate with α-cyclodextrin (Fuc-S-α-CDE (G2)). Fuc-S-α-CDE (G2, average degree of substitution of fucose (DSF2))/NF-κB decoy complex significantly suppressed nitric oxide and tumor necrosis factor-α (TNF-α) production from LPS-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and fucose receptor-mediated cellular uptake. Intravenous injection of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex extended the survival of LPS-induced fulminant hepatitis model mice. In addition, Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex administered intravenously highly accumulated in the liver, compared to naked NF-κB decoy alone. Furthermore, the liver accumulation of Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex was inhibited by the pretreatment with GdCl3, a specific inhibitor of Kupffer cell uptake. Also, the serum aspartate aminotransferase, alanine aminotransferase and TNF-α levels in LPS-induced fulminant hepatitis model mice were significantly attenuated by the treatment with Fuc-S-α-CDE (G2, DSF2)/NF-κB decoy complex, compared with naked NF-κB decoy alone. Taken together, these results suggest that Fuc-S-α-CDE (G2, DSF2) has the potential for a novel Kupffer cell-selective NF-κB decoy carrier for the treatment of LPS-induced fulminant hepatitis in mice.
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Akao
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Risako
authors.initials: R
authors.lastname: Onodera
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Ohyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Program for Leading Graduate Schools "HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Japan. Electronic address: arimah@gpo.kumamoto-u.ac.jp.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D005643:Fucose / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy*; D008111:Liver Function Tests; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D013499:Surface Properties; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D047391:alpha-Cyclodextrins / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D004337:Drug Carriers; D008070:Lipopolysaccharides; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha; D047391:alpha-Cyclodextrins; D005643:Fucose; D009569:Nitric Oxide; C032613:alpha-cyclodextrin
keywords: Cyclodextrin; Dendrimer; Fucose; Fulminant hepatitis; NF-κB decoy carrier