Synthesis and evaluation of radioactive nanometallic agents that specifically recognize pancreatic cancer cells

• Project/Area Number: 18K07281
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Institutes for Quantum Science and Technology
• Principal Investigator: HANYU Masayuki 国立研究開発法人量子科学技術研究開発機構, 量子医科学研究所 先進核医学基盤研究部, 主任研究員 (80435552)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Cu-64 / At-211 / 標識方法 / ナノ粒子 / 銅-64 / 環状ペプチド / 放射性金属核種 / PET / PET核種 / 標識反応

Outline of Final Research Achievements

The aim of this study is to find a method to efficiently label nanoparticle systems with radionuclides and then introduce biological small molecules or biological macromolecules, which will be useful for the molecular design of future radiopharmaceuticals. The nanoparticulation was confirmed to be in progress with a yield of about 10%. PEG chains could be introduced into the nanoparticles by dispersing them with ultrasound. When isoDGR was labeled with Cu-64, it was found to accumulate in cancer cells but was quickly excreted into the kidney.

Academic Significance and Societal Importance of the Research Achievements

ナノ粒子化を利用した治療薬剤の開発は2000年代から研究報告が増大しており、その製剤は約30品目以上が市場にでている。すなわち今後さらに発展する可能性を秘めている。一般的に、ナノ粒子は大きな分子構造の変更なく複数の機能を組み込むことが可能であり治療と診断を融合させるには良好な素材である。そこでナノ粒子系中に効率よく放射性核種で位置特異的な標識を行い、放射性ナノ薬剤の分子設計の指標に大いに役立つことができると考えた。本研究ではCu-64とAt-211の放射性核種のナノ粒子が調製可能であることを見出したが、さらなる検討が必要であることも明らかとなった。

Research Products

• [Journal Article] Automated radiosynthesis of [11C]MTP38-a phosphodiesterase 7 imaging tracer using [11C]hydrogen cyanide for clinical applications (2022)
  • Author(s): Kawamura Kazunori、Hashimoto Hiroki、Ohkubo Takayuki、Hanyu Masayuki、Ogawa Masanao、Nengaki Nobuki、Arashi Daisuke、Kurihara Yusuke、Fujishiro Tomoya、Togashi Takahiro、Sakai Toshiyuki、Muto Masatoshi、Takei Makoto、Ishii Hideki、Saijo Takeaki、Matsumura Takehiko、Obokata Naoyuki、Zhang Ming‐Rong
  • Journal Title: Journal of Labelled Compounds and Radiopharmaceuticals Volume: 65 Issue: 5 Pages: 140-146
  • DOI: 10.1002/jlcr.3965
  • Peer Reviewed
• [Journal Article] Automated radiosynthesis of two 18F-labeled tracers containing 3-fluoro-2-hydroxypropyl moiety, [18F]FMISO and [18F]PM-PBB3, via [18F]epifluorohydrin (2021)
  • Author(s): Ohkubo Takayuki、Kurihara Yusuke、Ogawa Masanao、Nengaki Nobuki、Fujinaga Masayuki、Mori Wakana、Kumata Katsushi、Hanyu Masayuki、Furutsuka Kenji、Hashimoto Hiroki、Kawamura Kazunori、Zhang Ming-Rong
  • Journal Title: EJNMMI Radiopharmacy and Chemistry Volume: 6 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s41181-021-00138-9
  • Peer Reviewed / Open Access
• [Journal Article] ²¹¹At-Labeled Polymer Nanoparticles for Targeted Radionuclide Therapy of Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR)-Overexpressed Cancer (2021)
  • Author(s): Shi Xiumin、Li Qing、Zhang Lulu、Hanyu Masayuki、Xie Lin、Hu Kuan、Nagatsu Kotaro、Zhang Chuan、Wu Zhengcan、Wang Feng、Zhang Ming-Rong、Yang Kai、Zhu Ran
  • Journal Title: Bioconjugate Chemistry Volume: 32 Issue: 8 Pages: 1763-1772
  • DOI: 10.1021/acs.bioconjchem.1c00263
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Harnessing the PD-L1 interface peptide for positron emission tomography imaging of the PD-1 immune checkpoint (2020)
  • Author(s): Hu Kuan、Xie Lin、Hanyu Masayuki、Zhang Yiding、Li Lingyun、Ma Xiaohui、Nagatsu Kotaro、Suzuki Hisashi、Wang Weizhi、Zhang Ming-Rong
  • Journal Title: RSC Chemical Biology Volume: 1 Issue: 4 Pages: 214-224
  • DOI: 10.1039/d0cb00070a
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Marriage of black phosphorus and Cu2+ as effective photothermal agents for PET-guided combination cancer therapy (2020)
  • Author(s): Hu Kuan、Xie Lin、Zhang Yiding、Hanyu Masayuki、Yang Zhimin、Nagatsu Kotaro、Suzuki Hisashi、Ouyang Jiang、Ji Xiaoyuan、Wei Junjie、Xu Hao、Farokhzad Omid C.、Liang Steven H.、Wang Lu、Tao Wei、Zhang Ming-Rong
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 2778-2778
  • DOI: 10.1038/s41467-020-16513-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PET Imaging of VEGFR with a Novel 64Cu-Labeled Peptide (2020)
  • Author(s): Hu Kuan、Shang Jingjie、Xie Lin、Hanyu Masayuki、Zhang Yiding、Yang Zhimin、Xu Hao、Wang Lu、Zhang Ming-Rong
  • Journal Title: ACS Omega Volume: 5 Issue: 15 Pages: 8508-8514
  • DOI: 10.1021/acsomega.9b03953
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Radiosynthesis and evaluation of 4-(6-[18F]Fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine as a novel radiotracer candidate targeting leucine-rich repeat kinase 2 (2020)
  • Author(s): Mori Wakana、Yamasaki Tomoteru、Hattori Yasushi、Zhang Yiding、Kumata Katsushi、Fujinaga Masayuki、Hanyu Masayuki、Nengaki Nobuki、Zhang Hong、Zhang Ming-Rong
  • Journal Title: RSC Medicinal Chemistry Volume: 11 Issue: 6 Pages: 676-684
  • DOI: 10.1039/c9md00590k
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radiosynthesis of [thiocarbonyl-11C]disulfiram and its first PET study in mice (2020)
  • Author(s): Ishii Hideki、Yamasaki Tomoteru、Yui Joji、Zhang Yiding、Hanyu Masayuki、Ogawa Masanao、Nengaki Nobuki、Tsuji Atsushi B.、Terashima Yuya、Matsushima Kouji、Zhang Ming-Rong
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: - Issue: 6 Pages: 126998-126998
  • DOI: 10.1016/j.bmcl.2020.126998
  • Peer Reviewed
• [Journal Article] Simple separation of 67Cu from bulk zinc by coprecipitation using hydrogen sulfide gas and silver nitrate (2020)
  • Author(s): Tomoyuki Ohya, Kotaro Nagatsu, Masayuki Hanyu, Katsuyuki Minegishi, Ming-Rong Zhang
  • Journal Title: Radiochimica Acta Volume: - Issue: 6 Pages: 469-476
  • DOI: 10.1515/ract-2019-3168
  • Peer Reviewed
• [Journal Article] 131I-IITM and 211At-AITM: Two Novel Small-Molecule Radiopharmaceuticals Targeting Oncoprotein Metabotropic Glutamate Receptor 1 (2019)
  • Author(s): Xie Lin、Hanyu Masayuki、Fujinaga Masayuki、Zhang Yiding、Hu Kuan、Minegishi Katsuyuki、Jiang Cuiping、Kurosawa Fuki、Morokoshi Yukie、Li Huizi Keiko、Hasegawa Sumitaka、Nagatsu Kotaro、Zhang Ming-Rong
  • Journal Title: Journal of Nuclear Medicine Volume: 61 Issue: 2 Pages: 242-248
  • DOI: 10.2967/jnumed.119.230946
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of a remote purification apparatus with disposable evaporator for the routine production of high-quality 64Cu for clinical use (2019)
  • Author(s): Ohya Tomoyuki、Minegishi Katsuyuki、Suzuki Hisashi、Nagatsu Kotaro、Fukada Masami、Hanyu Masayuki、Zhang Ming-Rong
  • Journal Title: Applied Radiation and Isotopes Volume: 146 Pages: 127-132
  • DOI: 10.1016/j.apradiso.2019.01.024
  • Peer Reviewed
• [Journal Article] Developing native peptide-based radiotracers for PD-L1 PET imaging and improving imaging contrast by pegylation (2019)
  • Author(s): Kuan Hu、Masayuki Hanyu、Xie Lin、Zhang Yiding、Kotaro Nagatsu、Hisashi Suzuki、Zhang Ming-Rong
  • Journal Title: Chemical Communications Volume: 55 Issue: 29 Pages: 4162-4165
  • DOI: 10.1039/c9cc00445a
  • Peer Reviewed
• [Presentation] TRT薬剤「211At-AITM」合成法の改良 (2021)
  • Author(s): 破入 正行, 峯岸 克行, 門間 あゆみ, 謝 琳, Hu Kuan, 張 一鼎, 藤永 雅之, 永津 弘太郎, 張 明栄
  • Organizer: 第61回日本核医学会学術総会, 日本核医学会
• [Presentation] RADIOLABELLING AND PET IMAGING OF COPPER-64 LABELED ISODGR DERIVATIVE (2020)
  • Author(s): Masayuki Hanyu, Lin Xie, Hu Kuan, Yiding Zhang, Ming-Rong Zhang
  • Organizer: 第57回ペプチド討論会, 日本ペプチド学会
• [Presentation] 癌蛋白質mGluR1に基づくがん種横断的な211At-AITM標的アイソトープ治療法の開発 (2020)
  • Author(s): 謝 琳, 張 露露, 破入 正行, 藤永 雅之, 張 一鼎, 峯岸 克行, Hu Kuan, 李 惠子, 長谷川 純崇, 永津 弘太郎, 張 明栄
  • Organizer: 第60回日本核医学会学術総会, 日本核医学会
• [Presentation] Harnessing PD-L1 interface peptide for PET imaging of PD-1 immune checkpoint (2020)
  • Author(s): Hu Kuan, Lin Xie, Yiding Zhang, Masayuki Hanyu, Ming-Rong Zhang
  • Organizer: 第60回日本核医学会学術総会, 日本核医学会
• [Presentation] ET Imaging of VEGFR with a Novel 64Cu Labeled Peptide (2020)
  • Author(s): Hu Kuan, Lin Xie, Yiding Zhang, Masayuki Hanyu, Ming-Rong Zhang
  • Organizer: 第60回日本核医学会学術総会, 日本核医学会
• [Presentation] Positron Emission Tomography Imaging of Vascular Endothelial Growth Factor Receptor Expression with a new 64Cu labeled peptide (2020)
  • Author(s): Hu Kuan, Jingjie Shang, Lin Xie, Masayuki Hanyu, Yiding Zhang, Zhimin Yang, Hao Xu, Wang Lu, Ming-Rong Zhang
  • Organizer: SNMMI 2020 Annual Meeting, Society of Nuclear Medicine and Molecular Imaging
  • Int'l Joint Research
• [Presentation] HPLCポストカラム法を用いたPET薬剤中の金属不純物の定量 (2019)
  • Author(s): 破入正行, 石井英樹, 念垣信樹, 小川政直, 嵐大輔, 古塚賢士, 橋本裕輝, 河村和紀, 張明栄
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] 転移性メラノーマに対する211At-AITMによる標的アイソトープ治療薬としての実証 (2019)
  • Author(s): 謝琳, 破入正行, 藤永雅之, 張一鼎, 峯岸克行, 李惠子, 諸越幸恵, 長谷川純崇, 永津弘太郎, 張明栄
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] 承認申請を見据えた[64Cu]Cu-ATSM注射液の品質検査法の設定 (2019)
  • Author(s): 橋本裕輝, 破入正行, 大久保崇之, 河村和紀, 吉井幸恵, 脇厚生, 張明栄
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] 共沈を用いたバルクZnターゲットからの67Cu分離精製法 (2019)
  • Author(s): 大矢智幸, 永津弘太郎, 破入正行, 峯岸克行, 張明栄
  • Organizer: 第59回日本核医学会学術総会
• [Presentation] Effective therapy against melanoma using 211At labeled small-molecule radiopharmaceutical 211At-AITM by targeting oncoprotein metabotropic glutamate receptor 1 (2019)
  • Author(s): Lin Xie, Masayuki Hanyu, Masayuki Fujinaga, Yiding Zhang, Hu Kuan, Katsuyuki Minegishi, Cuiping Jiang, Fuki Kurosawa, Yukie Morokoshi, Huizi Li, Sumitaka Hasegawa, Kotaro Nagatsu, Ming-Rong Zhang
  • Organizer: World Molecular Imaging Society
  • Int'l Joint Research
• [Presentation] Radiolabeling and evaluation of isoDGR derivative using radioactive cooper (2019)
  • Author(s): Masayuki Hanyu, Lin Xie, Hu Kuan, Zhimin Yang, Yiding Zhang, Hisashi Suzuki, Ming-Rong Zhang
  • Organizer: 14th International Conference on Radiopharmaceutical Therapy
  • Int'l Joint Research
• [Presentation] Measurement of the metal impurity in PET probe using the HPLC post-column method (2019)
  • Author(s): Masayuki Hanyu, Hideki Ishii, Nobuki Nengaki, Masanao Ogawa, Daisuke Arashi, Kenji Furutsuka, Hiroki Hashimoto, Kazunori Kawamura, Ming-Rong Zhang
  • Organizer: 23nd International symposium on radiopharmaceutical science
  • Int'l Joint Research
• [Presentation] Separation study of silver radionuclides from a palladium target irradiated by cyclotron (2019)
  • Author(s): Tomoyuki Ohya, Kotaro Nagatsu, Masayuki Hanyu, Katsuyuki Minegishi, Ming-Rong Zhang
  • Organizer: 23nd International symposium on radiopharmaceutical science
  • Int'l Joint Research
• [Presentation] Develop a peptide-based PET radiotracer for imaging PD-L1 expression in cancer (2019)
  • Author(s): Kuan Hu, Lin Xie, Masayuki Hanyu, Yiding Zhang, Ming-Rong Zhang
  • Organizer: 23nd International symposium on radiopharmaceutical science
  • Int'l Joint Research
• [Presentation] Peptide modified and radiometals loaded BP quantum dots for targeted PET imaging-guided tumor photothermal and photodynamic therapy (2019)
  • Author(s): Kuan Hu, Lin Xie, Masayuki Hanyu, Yiding Zhang, Ming-Rong Zhang
  • Organizer: 23nd International symposium on radiopharmaceutical science
  • Int'l Joint Research
• [Presentation] 小分子放射性薬剤211At-AITMの合成と評価 (2018)
  • Author(s): 破入 正行, 謝 琳, 藤永 雅之, 張 一鼎, 羽鳥 晶子, 峯岸 克行, 李 惠子, 諸越 幸恵, 長谷川 純崇, 永津 弘太郎, 張 明栄
  • Organizer: 第58回日本核医学会学術総会