title: Dectin-1 targeting delivery of TNF-α antisense ODNs complexed with β-1,3-glucan protects mice from LPS-induced hepatitis.
abstract: Antisense therapy, the first concept of oligonucleotide therapeutics, was proposed more than two decades ago. However, the lack of suitable delivering carriers continues to be a major obstacle to practical therapy. In this study, we present a novel complex consisting of β-1,3-glucan and antisense oligonucleotide (AS-ODN) as a new candidate of the carriers. We used schizophyllan (SPG) as a β-1,3-glucan and an AS-ODN sequence to suppress tumor necrosis factor alpha (TNF-α), where the AS-ODN has a (dA)(60) tail to induce complex with SPG. When the complexes were applied to peritoneal macrophages, they were incorporated into the cells via dectin-1 (a β-1,3-glucan receptor expressed on antigen presenting cells) and suppressed lipopolysaccharide (LPS)-induced TNF-α secretion. In-vivo, AS-ODN/SPG decreased the secretion of TNF-α in serum and drastically reduced the inflammation of LPS-induced hepatitis. This new complex could overcome the long outstanding problem for antisense therapy because of its complexation ability, non-toxicity and high target specificity.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Kitakyushu, 1-1 Hibikino, Wakamatsu-ku, Kitakyushu, Fukuoka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mochizuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D016503:Drug Delivery Systems / Q000379:methods*; D006524:Hepatitis, Viral, Animal / Q000378:metabolism / Q000517:prevention & control; D037181:Lectins, C-Type / Q000008:administration & dosage* / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood; D047071:beta-Glucans / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D016376:Oligonucleotides, Antisense; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D047071:beta-Glucans; D000099181:Dectin-1; C033363:beta-1,3-glucan