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Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe

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    Two-Chain Mature Hepatocyte Growth Factor-Specific Positron Emission Tomography Imaging in Tumors Using 64Cu-Labeled HiP-8, a Nonstandard Macrocyclic Peptide Probe
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    • Shota Warashina
      Shota Warashina
      Laboratory for Molecular Delivery and Imaging Technology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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    • Hiroki Sato
      Hiroki Sato
      Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
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    • Maki Zouda
      Maki Zouda
      Laboratory for Molecular Delivery and Imaging Technology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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    • Maiko Takahashi
      Maiko Takahashi
      Laboratory for Molecular Delivery and Imaging Technology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
      More by Maiko Takahashi
    • Yasuhiro Wada
      Yasuhiro Wada
      Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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    • Toby Passioura
      Toby Passioura
      Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-0033, Japan
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      Orcidhttps://orcid.org/0000-0002-6089-5067
    • Hiroaki Suga
      Hiroaki Suga
      Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-0033, Japan
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      Orcidhttps://orcid.org/0000-0002-5298-9186
    • Yasuyoshi Watanabe
      Yasuyoshi Watanabe
      Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
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    • Kunio Matsumoto*
      Kunio Matsumoto
      Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
      WPI-Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan
      *Tel: +81-76-264-6747. Fax: +81-76-234-4513. Email: [email protected]
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    • Hidefumi Mukai*
      Hidefumi Mukai
      Laboratory for Molecular Delivery and Imaging Technology, RIKEN Center for Biosystems Dynamics Research, 6-7-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
      Department of Pharmaceutical Informatics, Graduate School of Biomedical Science, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8588, Japan
      *Tel: +81-78-304-7173. Fax: +81-78-304-7191. Email: [email protected]
      More by Hidefumi Mukai
      Orcidhttps://orcid.org/0000-0002-0749-8783
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 4, 2029–2038
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.2c01020
    Published March 2, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Two-chain hepatocyte growth factor (tcHGF), the mature form of HGF, is associated with malignancy and anticancer drug resistance; therefore, its quantification is an important indicator for cancer diagnosis. In tumors, activated tcHGF hardly discharges into the systemic circulation, indicating that tcHGF is an excellent target for molecular imaging using positron emission tomography (PET). We recently discovered HGF-inhibitory peptide-8 (HiP-8) that binds specifically to human tcHGF with nanomolar affinity. The purpose of this study was to investigate the usefulness of HiP-8-based PET probes in human HGF knock-in humanized mice. 64Cu-labeled HiP-8 molecules were synthesized using a cross-bridged cyclam chelator, CB-TE1K1P. Radio-high-performance liquid chromatography-based metabolic stability analyses showed that more than 90% of the probes existed in intact form in blood at least for 15 min. In PET studies, significantly selective visualization of hHGF-overexpressing tumors versus hHGF-negative tumors was observed in double-tumor-bearing mice. The accumulation of labeled HiP-8 into the hHGF-overexpressing tumors was significantly reduced by competitive inhibition. In addition, the radioactivity and distribution of phosphorylated MET/HGF receptor were colocalized in tissues. These results demonstrate that the 64Cu-labeled HiP-8 probes are suitable for tcHGF imaging in vivo, and secretory proteins like tcHGF can be a target for PET imaging.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.2c01020.

    • HPLC chromatograms and chemical structures of CB-TE1K1P-modified HiP-8 molecules, HPLC chromatograms of 64Cu-labeled HiP-8 probes after incubation in blood, and MIP PET images and radioactivity biodistribution data of 64Cu-labeled HiP-8 probes (PDF)

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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2023, 20, 4, 2029–2038
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.2c01020
    Published March 2, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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