Potential Use of Thioalkylated Mannose-Modified Dendrimer (G3)/α-Cyclodextrin Conjugate as an NF-κB siRNA Carrier for the Treatment of Fulminant Hepatitis

NF-kappa B and its associated pathways are complicatedly concerned about hepatic homeostasis. Discriminating inhibition of NF-kappa 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 alpha-cyclodextrin with average degree of substitution of mannose (DSM4) (Man-S-alpha-CDE (G3, DSM4) as a novel antigen presenting cell (APC)-specific siRNA carrier, we evaluated the RNAi effect of NF-kappa B p65 siRNA (sip65) complex with Man-S-alpha-CDE (G3, DSM4) both in vitro and in vivo. Man-S-alpha-CDE (G3, DSM4)/sip65 complex significantly suppressed NP-kappa 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-alpha-CDE (G3, DSM4)/sip65 complex extended the survival rate of LPS-induced fulminant hepatitis model mice. In addition, intravenous administration of Man-S-alpha-ODE (G3, DSM4)/sip65 complex had the potential to induce the in vivo RNAi effect by significant suppression of mRNA expression of NT-kappa 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-alpha-ODE (G3, DSM4)/sip65 complex in fulminant hepatitis model mice. Collectively, these results suggest that Man-S-alpha-ODE (G3, DSM4) has the potential as a novel APC-selective sip65 carrier for the treatment of LPS/D-Gal-induced fulminant hepatitis in mice.