title: Liver targeting of human interferon-beta with pullulan based on metal coordination.
abstract: Although interferon (IFN)-beta is widely used for the elimination of hepatitis C virus in patients with chronic liver disease, its clinical efficacy is unsatisfactory. Targeting IFN-beta to the liver might enhance its efficacy without increasing its side effects. The objective of the present study was to target IFN-beta to the liver to enhance its biological activity and reduce its side effects. A chelating residue, diethylenetriaminepentaacetic acid (DTPA), was introduced to pullulan, a water-soluble polysaccharide with a high affinity to the liver (DTPA-pullulan) and natural human IFN-beta was coordinately conjugated with the DTPA-pullulan by mixing in an aqueous solution containing zinc ions (Zn(2+)). Intravenous injection of the IFN-beta-DTPA-pullulan conjugate with Zn(2+) coordination into mice enhanced induction of an antiviral enzyme, 2',5'-oligoadenylate synthetase (2-5AS), specifically in the liver to a significantly greater extent than free natural IFN-beta. The enhanced 2-5AS level in the liver depended on the molar mixing ratio of IFN-beta, DTPA residue of the DTPA-pullulan, and Zn(2+). Moreover, the duration of the liver 2-5AS induction by the IFN-beta-DTPA-pullulan conjugate was longer than that by free natural IFN-beta. Thus, human IFN-beta-DTPA-pullulan conjugate appears to be applicable for clinical use, which is promising for treatment of patients with chronic hepatitis C.
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Suginoshita
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumura
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Motoshige
authors.initials: M
authors.lastname: Nabeshima
authors.forename: Fuminori
authors.initials: F
authors.lastname: Moriyasu
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ikada
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005936:Glucans / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D016899:Interferon-beta / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008670:Metals / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D004369:Pentetic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D005936:Glucans; D008670:Metals; D016899:Interferon-beta; D004369:Pentetic Acid; C009109:pullulan