title: Macrophage specific delivery of TNF-α siRNA complexed with β-1,3-glucan inhibits LPS-induced cytokine production in a murine acute hepatitis model.
abstract: RNA interference therapy utilizes physiological gene silencing that is originally found as a defense function against foreign RNAs. To silence the target gene, short double stranded RNA has to be delivered to cytosol. However, lack of a suitable delivering carrier is the major obstacle to practical usage. In this study, we present a novel complex consisting of β-1,3-glucan and short interference RNA (siRNA) as a solution for the problem. We used a β-1,3-glucan schizophyllan (SPG) and a siRNA (dA-siTNFα) that is designed to suppress tumor necrosis factor alpha (TNF-α), where the sense strand of siRNA has (dA(40)) tail to induce complexation with SPG. The dA-siTNFα/SPG complex showed higher affinity to recombinant dectin-1 than SPG itself, where dectin-1 is a β-1,3-glucan receptor expressed on antigen presenting cells and can be a target for specific delivery. The complex suppressed lipopolysaccharide (LPS)-induced TNF-α secretion by peritoneal macrophages in vitro. When the complex was intravenously injected, the oligonucleotide accumulated in liver; especially distributed into Kupffer cells. The complex significantly decreased the serum TNF-α level for the mouse model of LPS-induced acute hepatitis. This new siRNA delivery system may overcome the problem for RNA interference therapy because of its non-toxicity and high target specificity.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Morishita
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006505:Hepatitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D047071:beta-Glucans / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; C033363:beta-1,3-glucan