Vol. 298, Issue 2, 805-811, August 2001

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

Yoshiki Suginoshita, Yasuhiko Tabata, Fuminori Moriyasu, Yoshito Ikada and Tsutomu Chiba

Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan (Y.S., F.M., T.C.); Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan (Y.T.); and Faculty of Medical Engineering, Suzuka University of Medical Science, Mie, Japan (Y.I.)

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