Liver Targeting of Interferon-β with a Liver-Affinity Polysaccharide Based on Metal Coordination in Mice

Abstract

Frequent and high-dose i.v. injections of interferon-β (IFN-β) 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-β, 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-β could be coordinately conjugated with the DTPA-pullulan by simple mixing in an aqueous solution containing zinc ion (Zn²⁺). Intravenous injection of the IFN-β-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-β, although the 2-5AS levels in the liver depended on the mixing ratio of the IFN-β/DTPA residue of DTPA-pullulan/Zn²⁺. In addition, the duration of the liver 2-5AS induction by the IFN-β-DTPA-pullulan conjugate with Zn²⁺ coordination was longer than that by free IFN-β. The liver targeting of IFN-β by DTPA-pullulan with Zn²⁺ coordination may be a promising IFN therapy.