Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen <i>in vivo</i>

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  • Fumitaka Takeshita
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Yoshiko Minakuchi
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Shunji Nagahara
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Kimi Honma
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Hideo Sasaki
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Kotaro Hirai
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Takumi Teratani
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Nachi Namatame
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Yusuke Yamamoto
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Koji Hanai
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Takashi Kato
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Akihiko Sano
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan
  • Takahiro Ochiya
    Section for Studies on Metastasis, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Formulation Research Laboratories, Sumitomo Pharmaceutical, Osaka 567-0878, Japan; Koken Bioscience Institute, Tokyo 115-0051, Japan; and Department of Biology, School of Education, Waseda University, Tokyo 169-0051, Japan

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<jats:p> Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery for siRNAs toward treatment of bone-metastatic cancer. Accordingly, we report here that i.v. injection of GL3 luciferase siRNA complexed with atelocollagen showed effective reduction of luciferase expression from bone-metastatic prostate tumor cells developed in mouse thorax, jaws, and/or legs. We also show that the siRNA/atelocollagen complex can be efficiently delivered to tumors 24 h after injection and can exist intact at least for 3 days. Furthermore, atelocollagen-mediated systemic administration of siRNAs such as enhancer of zeste homolog 2 and phosphoinositide 3′-hydroxykinase p110-α-subunit, which were selected as candidate targets for inhibition of bone metastasis, resulted in an efficient inhibition of metastatic tumor growth in bone tissues. In addition, upregulation of serum IL-12 and IFN-α levels was not associated with the <jats:italic>in vivo</jats:italic> administration of the siRNA/atelocollagen complex. Thus, for treatment of bone metastasis of prostate cancer, an atelocollagen-mediated systemic delivery method could be a reliable and safe approach to the achievement of maximal function of siRNA. </jats:p>

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