Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/伪-Cyclodextrin Conjugate as an NF-魏B siRNA Carrier for the Treatment of Fulminant Hepatitis
详细信息 查看全文
- 作者：Keiichi Motoyama ; Ryosuke Mitsuyasu ; Chiho Akao ; Irhan Ibrahim Abu Hashim ; Nana Sato ; Takahiro Tanaka ; Taishi Higashi ; Hidetoshi Arima
- 刊名：Molecular Pharmaceutics
- 出版年：2015
- 出版时间：September 8, 2015
- 年：2015
- 卷：12
- 期：9
- 页码：3129-3136
- 全文大小：413K
- ISSN：1543-8392
文摘
NF-魏B and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-魏B 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 伪-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-伪-CDE (G3, DSM4)) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-魏B p65 siRNA (sip65) complex with Man-S-伪-CDE (G3, DSM4) both in vitro and in vivo. Man-S-伪-CDE (G3, DSM4)/sip65 complex significantly suppressed NF-魏B 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-伪-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-伪-CDE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NF-魏B 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-伪-CDE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-伪-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.