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 b een used clinically to treat patients with viral hepatitis despite various side effects. Because side effects are caused by the systemic effects of IF N-beta, the purpose of this study was to target the drug specifically to th e liver, thus reducing the adverse events. A chelating residue, diethylenet riaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity for the liver. Murine IFN-beta could b e coordinately conjugated with the DTPA-pullulan by simple mixing in an aqu eous solution containing zinc ion (Zn2+). Intravenous injection of the IFN- beta -DTPA-pullulan conjugate with Zn2+ coordination enhanced liver inducti on of an antiviral enzyme, 2',5'-oligoadenylate synthetase (2-5AS), to a gr eater extent than that by free IFN-beta, although the 2-5AS levels in the l iver depended on the mixing ratio of the IFN-beta /DTPA residue of DTPA-pul lulan/Zn2+. In addition, the duration of the liver 2-5AS induction by the I FN-beta -DTPA-pullulan conjugate with Zn2+ coordination was longer than tha t by free IFN-beta. The liver targeting of IFN-beta by DTPA-pullulan with Z n2+ coordination may be a promising IFN therapy.