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Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: poly C in a murine lung metastasis model

Cancer Gene Therapy volume 10, pages 661–668 (2003)Cite this article

Abstract

We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-β or IFN-γ, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IFN-γ, while injection of lipoplexes containing pI:pC led to a low level of TNF-α and undetectable IFN-γ production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-α and IFN-γ nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-β induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-β gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-β antibody treatment, indicating that IFN-β produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-β in the lung delivered by intravenous administration of lipoplex containing IFN-β gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.

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Acknowledgements

This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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  1. Fuminori Sakurai

    Present address: Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

Authors and Affiliations

  1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Fuminori Sakurai, Takeshi Terada, Fumiyoshi Yamashita & Mitsuru Hashida

  2. Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Masato Maruyama & Yoshinobu Takakura

  3. Molecular Microbiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Yoshihiko Watanabe

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Sakurai, F., Terada, T., Maruyama, M. et al. Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: poly C in a murine lung metastasis model. Cancer Gene Ther 10, 661–668 (2003). https://doi.org/10.1038/sj.cgt.7700617

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