Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugate as an NF-κB siRNA Carrier for the Treatment of Fulminant Hepatitis.
NF-κB and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-κB signaling has been expected to treat various liver diseases including fulminant hepatitis. To clarify the potential use of thioalkylated mannose-appended dendrimer (generation 3; G3) conjugates with α-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-α-CDE (G3, DSM4)) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-κB p65 siRNA (sip65) complex with Man-S-α-CDE (G3, DSM4) both in vitro and in vivo. Man-S-α-CDE (G3, DSM4)/sip65 complex significantly suppressed NF-κB p65 mRNA expression and nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated NR8383 cells, a rat alveolar macrophage cell line, by adequate physicochemical properties and mannose receptor-mediated cellular uptake. Intravenous injection of Man-S-α-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-α-CDE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NF-κB p65 and inflammatory cytokines in the liver of fulminant hepatitis model mice induced by LPS/d-galactosamine (d-Gal) without any significant side effects. Also, the serum levels of enzymes were significantly attenuated by injection of Man-S-α-CDE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-α-CDE (G3, DSM4) has the potential as a novel APC-selective sip65 carrier for the treatment of LPS/d-Gal-induced fulminant hepatitis in mice.
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Keiichi
K
Motoyama
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Ryosuke
R
Mitsuyasu
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Chiho
C
Akao
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.|Faculty of Pharmacy, Mansoura University , Mansoura 35516, Egypt.
Irhan Ibrahim
II
Abu Hashim
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Nana
N
Sato
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Takahiro
T
Tanaka
Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University , 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
Taishi
T
Higashi
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 , Kumamoto, Japan.
Hidetoshi
H
Arima
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry*; D018014:Gene Transfer Techniques; D006505:Hepatitis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D047391:alpha-Cyclodextrins / Q000737:chemistry*
D050091:Dendrimers; D004337:Drug Carriers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047391:alpha-Cyclodextrins; D008358:Mannose; C032613:alpha-cyclodextrin
NF-κB; cyclodextrin; dendrimer; fulminant hepatitis; siRNA