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.
Footnotes
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This work was supported by a grant of Research for the Future Program from the Japan Society for the Promotion of Science (JSPS-RFTF 97I0201).
- Abbreviations:
- IFN
- interferon
- 2-5AS
- 2′,5′-oligoadenylate synthetase
- DTPA
- diethylenetriaminepentaacetic acid
- GFC
- gel filtration chromatography
- LD
- lethal dose
- PEG
- polyethylene glycol
- Received December 27, 2000.
- Accepted April 12, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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