Liver targeting of interferon-beta with a liver-affinity polysaccharide based on metal coordination in mice.
Frequent and high-dose i.v. injections of interferon-beta (IFN-beta) have been used clinically to treat patients with viral hepatitis despite various side effects. Because side effects are caused by the systemic effects of IFN-beta, the purpose of this study was to target the drug specifically to the liver, thus reducing the adverse events. A chelating residue, diethylenetriaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity for the liver. Murine IFN-beta could be coordinately conjugated with the DTPA-pullulan by simple mixing in an aqueous solution containing zinc ion (Zn2+). Intravenous injection of the IFN-beta-DTPA-pullulan conjugate with Zn2+ coordination enhanced liver induction of an antiviral enzyme, 2',5'-oligoadenylate synthetase (2-5AS), to a greater extent than that by free IFN-beta, although the 2-5AS levels in the liver depended on the mixing ratio of the IFN-beta/DTPA residue of DTPA-pullulan/Zn2+. In addition, the duration of the liver 2-5AS induction by the IFN-beta-DTPA-pullulan conjugate with Zn2+ coordination was longer than that by free IFN-beta. The liver targeting of IFN-beta by DTPA-pullulan with Zn2+ coordination may be a promising IFN therapy.
Suginoshita
Y
Y
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tabata
Y
Y
Moriyasu
F
F
Ikada
Y
Y
Chiba
T
T
D000818:Animals; D015153:Blotting, Western; D002614:Chelating Agents / Q000737:chemistry*; D002850:Chromatography, Gel; D005936:Glucans / Q000737:chemistry*; D007275:Injections, Intravenous; D016899:Interferon-beta / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D004369:Pentetic Acid / Q000737:chemistry*; D014018:Tissue Distribution; D015032:Zinc / Q000737:chemistry*
D002614:Chelating Agents; D005936:Glucans; D016899:Interferon-beta; D004369:Pentetic Acid; C009109:pullulan; D015032:Zinc