Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), San 31, Hyoja-dong, Nam-gu, Pohang, Kyungbuk 790-784, Korea.
Biomaterials. 2011 Nov;32(33):8722-9. doi: 10.1016/j.biomaterials.2011.07.088. Epub 2011 Aug 26.
Interferon alpha (IFNα) conjugated with polyethylene glycol (PEG) has been widely used for the treatment of hepatitis C virus (HCV) infection as a once-a-week injection formulation. However, the PEGylated IFNα has a low efficacy of ca. 39% and a side effect after repeated injections possibly due to the non-specific delivery with PEGylation. In this work, target specific long-acting hyaluronic acid-interferon alpha (HA-IFNα) conjugate was successfully developed for the treatment of HCV infection. HA-IFNα conjugate was synthesized by coupling reaction between aldehyde modified HA and the N-terminal group of IFNα. The IFNα content could be controlled in the range of 2-9 molecules per single HA chain with a bioconjugation efficiency higher than 95%. According to in vitro anti-proliferation assay using Daudi cells, HA-IFNα conjugate showed a comparable biological activity to PEG-Intron. In vivo real-time bioimaging confirmed the target specific delivery of near-infrared fluorescence (NIRF) dye labeled HA-IFNα conjugate to the liver in mice. In addition, pharmacokinetic analysis revealed the enhanced residence time longer than 4 days. After tail-vein injection, HA-IFNα conjugate induced ca. 60% higher expression of 2',5'-oligoadenylate synthetase 1 (OAS 1) for innate immune responses to viral infection in the murine liver tissues than IFNα and PEG-Intron.
聚乙二醇（PEG）偶联干扰素 alpha（IFNα）已广泛用于丙型肝炎病毒（HCV）感染的治疗，作为每周一次的注射制剂。然而，PEG 化 IFNα 的疗效约为 39%，且由于 PEG 化的非特异性递送，重复注射后可能会产生副作用。在这项工作中，成功开发了用于 HCV 感染治疗的靶向特异性长效透明质酸-干扰素 alpha（HA-IFNα）缀合物。HA-IFNα 缀合物通过醛修饰的 HA 与 IFNα 的 N 端基团之间的偶联反应合成。IFNα 的含量可以控制在每个 HA 链 2-9 个分子的范围内，生物偶联效率高于 95%。根据用 Daudi 细胞进行的体外增殖抑制测定，HA-IFNα 缀合物表现出与 PEG-Intron 相当的生物活性。体内实时生物成像证实了近红外荧光（NIRF）染料标记的 HA-IFNα 缀合物在小鼠肝脏中的靶向特异性递送。此外，药代动力学分析显示，其在体内的停留时间延长至 4 天以上。尾静脉注射后，HA-IFNα 缀合物在小鼠肝组织中诱导的 2'，5'-寡腺苷酸合成酶 1（OAS 1）的表达比 IFNα 和 PEG-Intron 高约 60%，这是对病毒感染的先天免疫反应。
