Suginoshita Y, Tabata Y, Moriyasu F, Ikada Y, Chiba T
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Pharmacol Exp Ther. 2001 Aug;298(2):805-11.
Frequent and high-dose i.v. injections of interferon-beta (IFN-beta) 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-beta, 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-beta could be coordinately conjugated with the DTPA-pullulan by simple mixing in an aqueous solution containing zinc ion (Zn2+). Intravenous injection of the IFN-beta-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-beta, although the 2-5AS levels in the liver depended on the mixing ratio of the IFN-beta/DTPA residue of DTPA-pullulan/Zn2+. In addition, the duration of the liver 2-5AS induction by the IFN-beta-DTPA-pullulan conjugate with Zn2+ coordination was longer than that by free IFN-beta. The liver targeting of IFN-beta by DTPA-pullulan with Zn2+ coordination may be a promising IFN therapy.
尽管存在各种副作用，但临床上已使用频繁且大剂量的静脉注射干扰素-β（IFN-β）来治疗病毒性肝炎患者。由于副作用是由IFN-β的全身作用引起的，本研究的目的是将药物特异性靶向肝脏，从而减少不良事件。将螯合残基二亚乙基三胺五乙酸（DTPA）引入对肝脏具有高亲和力的水溶性多糖支链淀粉中。在含有锌离子（Zn2+）的水溶液中简单混合，鼠源IFN-β可与DTPA-支链淀粉配位结合。静脉注射具有Zn2+配位的IFN-β-DTPA-支链淀粉偶联物，与游离IFN-β相比，能更大程度地增强肝脏中抗病毒酶2',5'-寡腺苷酸合成酶（2-5AS）的诱导，尽管肝脏中的2-5AS水平取决于IFN-β/DTPA-支链淀粉的DTPA残基/Zn2+的混合比例。此外，具有Zn2+配位的IFN-β-DTPA-支链淀粉偶联物诱导肝脏2-5AS的持续时间比游离IFN-β更长。通过具有Zn2+配位的DTPA-支链淀粉对IFN-β进行肝脏靶向可能是一种有前景的IFN治疗方法。
