Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1426571 | Journal of Controlled Release | 2008 | 7 Pages |
Human interferon-alpha (IFN-α), a 19.2 KD protein containing two disulfide bonds (cys1–cys98; cys29–cys138), was reduced and modified with a reversible lipidization agent. The product of the lipidization, PAL-IFN, was homogenous, with four palmitoyl moieties linked to the four Cys residues in the protein molecule via reversible disulfide linkages. The far-UV circular dichroism (CD) spectrum of PAL-IFN was virtually overlapped with that of IFN, indicating that the IFN structure was not altered by the modification. After iv injection in mice of 0.1 mg/kg of PAL-IFN, a low level of serum IFN activity was sustained for more than 8 h, while serum IFN activity was rapidly diminished to an undetectable level at 2 h post IFN injection at the same dose. Evidence suggested that IFN was slowly released from PAL-IFN into blood circulation upon reduction of the disulfide bonds in vivo. Furthermore, the liver-targeting effect of PAL-IFN was demonstrated by the observation that the level of 2′-5′ oligoadenylate synthetase (OAS) expressed in the liver of mice treated with PAL-IFN was significantly higher than that with IFN. In conclusion, reversible lipidization can potentially achieve both a prolonged plasma half-life and an enhanced liver-targeting effect of IFN in antiviral therapy.