<i>In Vivo</i> Imaging of Liposomal Small Interfering RNA (siRNA) Trafficking by Positron Emission Tomography

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  • Ando Hidenori
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Yonenaga Norihito
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Asai Tomohiro
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Hatanaka Kentaro
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Koide Hiroyuki
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Tsuzuku Takuma
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka
  • Harada Norihiro
    PET Center, Central Research Laboratory, Hamamatsu Photonics K.K.
  • Tsukada Hideo
    PET Center, Central Research Laboratory, Hamamatsu Photonics K.K.
  • Oku Naoto
    Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka

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Other Title
  • RNA創薬研究におけるポジトロン標識small interfering RNA (siRNA) の positron emission tomography (PET) 体内動態イメージング
  • RNAソウヤク ケンキュウ ニ オケル ポジトロン ヒョウシキ small interfering RNA (siRNA)ノ positron emission tomography (PET)タイナイ ドウタイ イメージング

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Description

In the development of nucleic acid medicines such as small interfering RNA (siRNA) drugs, one problem is how to study the pharmacokinetics and pharmacodynamics, since the precise in vivo behavior of siRNA is hard to detect. In this research, to establish a highly sensitive detection system of siRNA biodistribution in the whole body, the technology of positron imaging was applied. First, a one-step synthetic method in which double-stranded siRNA was directly labeled by a positron emitter, 18F, was developed. By using [18F]-labeled siRNA ([18F]-siRNA), the complex of siRNA and polycation liposomes (PCL) containing dicetylphosphate tetraethylenepentamine (TEPA-PCL) was prepared. Then, the biodistribution of the siRNA after intravenous administration to mice was analyzed by planar positron imaging system (PPIS). As a result, whereas naked [18F]-siRNA was immediately excreted in mouse bladder after administration, the complex with cationic liposome (CL) was trapped in the lungs. Furthermore, [18F]-siRNA carried with PEGylated CL (PL) was distributed throughout the body, suggesting that it circulated in the bloodstream for an extended period of time. Additionally, PET imaging revealed more detailed biodistribution of the siRNA than in vivo imaging system (IVIS) because PET imaging is not affected by the depth variation of target tissues. On the other hand, to induce high accumulation of siRNAs against c-myc, MDM2, and VEGF in tumor tissue, a tumor-targeting probe, RGD peptide, was grafted at the top of PEG chain in PEGylated TEPA-PCL and the effect of the complex on experimental lung metastasis of B16 melanoma was examined. The complex suppressed the progression of tumor. We believe that the positron imaging data would support the development of siRNA agent for clinical use.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 132 (12), 1373-1381, 2012-12-01

    The Pharmaceutical Society of Japan

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