Development of Neutron Capture Therapy using intra-nucleus Gadolinium delivery to refractory scirrhous carcinoma

• Project/Area Number: 21K19520
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Yanagie Hironobu 東京大学, 大学院工学系研究科(工学部), 客員研究員 (30212278)
• Co-Investigator(Kenkyū-buntansha): 高橋 浩之 東京大学, 大学院工学系研究科(工学部), 教授 (70216753)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 中性子捕捉療法 / ガドリニウム化合物 / ボロン化合物 / Polyplex / エレクトロポレーション / 腫瘍内局所投与法 / ヒアルロン酸 / プロタミン / ガドリニウム中性子捕捉療法 / 157Gd-plex四元複合体 / 膵臓癌 / 腫瘍内局所注入法 / マイクロバブル/超音波刺激法 / 157Gd-plex混和複合体 / 陽荷電リポソーム / 核内デリバリー / 膜融合タンパク

Outline of Research at the Start

ガドリニウム中性子捕捉療法においては、ガドリニウム（157Gd）化合物に熱中性子照射することで発生する高Linear Energy TransferであるAuger電子とガンマ線を使用し癌制御を図る。157Gd原子を選択的に癌細胞の核内へ集積できれば、容易にDouble Strand Breakを生じ癌細胞死を誘導できる。
本研究では、157Gd化合物/トランスフェリンやヒアルロン酸/膜融合蛋白JTS-1やプロタミン等の複合体をよりサイズの小さいNanoDDS(20-50nm)に導入し、核内への選択的ターゲティングを施し、血管性に富まない硬癌への高機能性集学的中性子捕捉療法の開発を進める。

Outline of Final Research Achievements

Gadolinium neutron capture therapy (GdNCT) is one of the particle therapy by the reaction with gadolinium atom (Gd) and the thermal neutron. Gd induces cell cytotoxic effects by the Auger electron which is high LET of range 1μm and gamma rays of few mm ranges by reacting with a thermal neutron. We applied cationic liposome, and cationic polymer, as the Gd delivery system. We prepared Gadolinium-Polyplex; Gd-plex (Gd / hyaluronic acid / protamine-mixed with cationic liposome). The increase effect of AsPC-1 human pancreatic tumour growth suppression was recognized in the Gd-plex or Gd-PEI treated groups with thermal neutron irradiation.　Hyalinizations with significant degenerations were seen in the irradiation group, and apoptosis was thought as one of the mechanism of tumor growth suppression. We had the augumentation effect of tumour growth suppression by GdNCT using electroporation. We hope to apply to the intensive treatments for pancreatic cancers and hepatic cancers.

Academic Significance and Societal Importance of the Research Achievements

GdNCTの治療効果増強を目指して、Gd-polyplexを形成させ腫瘍内投与法を用いた、熱中性子照射による抗腫瘍効果を提唱している。
Gd-plexやBoro-plexを用いた中性子捕捉剤の癌細胞内デリバリーシステムの開発は、膵臓癌に対する超音波内視鏡下穿刺法や、肝臓癌に対するWOWエマルション封入肝動注法を用いての加速器中性子捕捉療法への応用が考えられ、集学的癌治療の新たな展開が期待できる。

Research Products

• [Journal Article] Metaplastic breast carcinoma producing prominent basal lamina with neuroendocrine differentiation (2023)
  • Author(s): Yoshitaka Furuya, Kenzo Hiroshima, Takashi Wakahara, Harutoshi Akimoto, Shigeo Kawai, Masayuki Ota, Yukio Nakatani, Akinori Furuya, Hironobu Yanagie
  • Journal Title: MOLECULAR AND CLINICAL ONCOLOGY Volume: 18, 36 Issue: 5 Pages: 1-6
  • DOI: 10.3892/mco.2023.2632
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rare combination of caecal volvulus with ileal intussusception after surgery (2022)
  • Author(s): Yoshitaka Furuya, Takashi Wakahara, Harutoshi Akimoto, Akinori Furuya, Hironobu Yanagie, Kenzo Hiroshima
  • Journal Title: ANZ Journal of Surgery Volume: 92 Issue: 12 Pages: 3395-3397
  • DOI: 10.1111/ans.17732
  • Peer Reviewed
• [Journal Article] Preliminary Experiment of Tumour Growth Suppression by Intra-Tumoral Injection of Boron-Polyplex/Polymer for Boron Neutron Capture Therapy to Pancreatic Cancer Model in vivo (2022)
  • Author(s): Hironobu Yanagie, Xuan Hou4, Masashi Yanagawa, Takehisa Matsukawa, Ayano Kubota, Minoru Suzuki, Yoshinori Sakurai, Hiroki Tanaka, Kazuhito Yokoyama, Masayuki Nashimoto, Jun Nakajima, Minoru Ono, Takumichi Sugihara, and Hiroyuki Takahashi
  • Journal Title: KURNS Reports 2022 Volume: 1
  • Open Access
• [Journal Article] Enhancement of Tumour Growth Suppression by Electroporation with Intra-Tumoural Injection of Gadolinium-Polyplex for Gadolinium-Neutron Capture Therapy to Pancreatic Cancer Model in vivo (2022)
  • Author(s): Hironobu Yanagie, Xuan Hou, Yoshiteru Yanagie, Takehisa Matsukawa, Ayano Kubota, Minoru Suzuki, Yoshinori Sakurai, Hiroki Tanaka, Takeshi Nagasaki, Takefumi Hirata, Masayuki Nashimoto, Minoru Ono, Takumichi Sugihara, and Hiroyuki Takahashi
  • Journal Title: KURNS Reports 2022 Volume: 1
  • Open Access
• [Journal Article] Pathological Findings of Tumor Growth Suppression of GdNCT with Intra-Tumoral Injec-tion of Gadolinium-Polyplex in Pancreatic Cancer Model in vivo (2022)
  • Author(s): Hironobu Yanagie, Yoshiteru Yanagie, Xuan Hou,Takehisa Matsukawa, Ayano Kubota, Minoru Suzuki, Yoshinori Sakurai, Hiroki Tanaka, Takeshi Nagasaki, Takefumi Hirata, Masayuki Nashimoto, Minoru Ono, Takumichi Sugihara, and Hiroyuki Takahashi
  • Journal Title: KURNS Reports 2022 Volume: 1
  • Open Access
• [Journal Article] Suppression of Tumor Growth in a Rabbit Hepatic Cancer Model by Boron Neutron Capture Therapy With Liposomal Boron Delivery Systems. (2021)
  • Author(s): Yanagie H, Yanagawa M, Morishita Y, Shinohara A, Dewi N, Nonaka Y, Furuya Y, Mizumachi R, Murata Y, Nakamura H, Suzuki M, Sakurai Y, Tanaka H, Masunaga S, Ono K, Sugihara T, Nashimoto M, Yamauchi H, Ono M, Nakajima J, Takahashi H.
  • Journal Title: In Vivo Volume: 35 Issue: 6 Pages: 3125-3135
  • DOI: 10.21873/invivo.12607
  • Peer Reviewed / Open Access
• [Presentation] Planning of Neutron Capture Therapy to Recurrent Hepatocellular Carcinoma using Water-in-Oil-in-Water Emulsion with DDS (2023)
  • Author(s): H. Yanagie, M. Fujiwara, H. Xuan, Y. Yanagie, K. Maruyama, S. Kageyama, T. Matsukawa, A. Kubota, A. Shinohara, T. Yamase, H. Nakamura, S. Higashi, K. Ono, M. Suzuki, T. Watanabe, N. Kondo, T. Kinashi, Y. Sakurai, H. Tanaka, M. Nashimoto, T. Sugihara, H. Yamauchi, M. Ono, J. Nakajima, and H. Takahashi, et. al.
  • Organizer: 2023 4th Japan-Taiwan Neutron Capture Therapy Academic Conference of Elites
  • Int'l Joint Research
• [Presentation] 膵臓癌に対する中性子捕捉療法へ向けたボロンポリ酸の中性子捕捉剤への基礎的検討 (2022)
  • Author(s): 柳衛 宏宣， 候 鉱， 篠原 厚子， 松川 岳久， 久保田 章乃， 櫻井 良憲， 田中 浩基， 鈴木 実， 山内 治雄， 小野 稔， 中島 淳， 梨本 正之， 杉原 多公通， 山瀬 利博， 高橋 浩之
  • Organizer: 第60回日本癌治療学会学術集会
• [Presentation] Inhibition of Human Pancreatic Cancer Cell Growth using Liposomal Gene Delivery of A Tumor Suppressing Gene, Tob, In Vitro (2022)
  • Author(s): Hironobu Yanagie, Yasumasa Nonaka, Kazuo Maruyama, & Hiroyuku Takahashi
  • Organizer: 7th JCA-AACR Special Joint Conference “The Latest Advances in Pancreatic Cancer Research: From Basic Science to Therapeutics”
  • Int'l Joint Research
• [Presentation] Augmentation of Neutron Capture Therapy by Intra-Tumoral Injection of Mixed Complexes with Neutron Capture Agents and Electroporation in Pancreatic Cancer Model. (2022)
  • Author(s): Hironobu Yanagie, Hou Xuan, Masashi Yanagawa, Takehisa Matsukawa, Ayano Kubota, Yoshiteru Yanagie, Minoru Suzuki, Shin-Ichiro Masunaga, Yoshinori Sakurai, Hiroki Tanaka, Minoru Ono, Jun Nakajima, Masayuki Nashimoto, Takumichi Sugihara, and Hiroyuki Takahashi
  • Organizer: The 18th JSNCT
• [Presentation] Enhancement of tumor growth suppression by Gd2O3 incorporated nanomicelle in Gadolinium Neutron Capture Therapy (2022)
  • Author(s): Xuan Hou, Changyuan Qin, Hironobu Yanagie, Horacio Cabral, Minoru Suzuki, Shinichiro Masunaga, Yoshinori Sakurai, Hiroki Tanaka, Takeshi Nagasaki, Hiroyuki Takahashi
  • Organizer: The 18th JSNCT
• [Presentation] ガドリニウム混和陽荷電複合体の腫瘍内投与法を用いた中性子捕捉療法におけるヒト膵臓癌AsPC-1腫瘍増殖抑制効果の検討 (2021)
  • Author(s): 柳衛宏宣、柳衛佳輝、Hou Xuan、柳川将志、石川達矢、森下保幸、Novriana Dewi、松川岳久、久保田章乃、鈴木実、増永慎一郎、桜井良憲、田中浩基、長崎健、高橋浩之
  • Organizer: 第17回日本中性子捕捉療法学会学術大会
• [Presentation] Application of Oxaliplatin Entrapped Stealth Liposome to Cancer Cell Cytotoxicity in Colon Cancer Model (2021)
  • Author(s): Hironobu Yanagie, Atsuko Shinohara, Yasuyuki Morishita, Yasumasa Nonaka, Yoshitaka Furuya, Kazuo Maruyama, Ryo Suzuki, Masazumi Eriguchi, Jun Nakajima, Minoru Ono, and Hiroyuki Takahashi
  • Organizer: 第59回日本癌治療学会学術集会
• [Presentation] Two case reports of QOL improvement by endoscopic stent placement to the intestinal obstruction caused by cancer invasion (2021)
  • Author(s): Hironobu Yanagie, Yasumasa Nonaka, Kazuko Umemura, Takako Kuji, Tsutomu Kikuchi, Naozumi Kuzuoka, Yoshinori Kano, Takahiro Nakamura, and Shin-ichiro Goto
  • Organizer: 第102回 日本消化器内視鏡学会総会
• [Presentation] Application of intra-tumoral injection of cationic polymers mixed with Gd compounds for Neutron Capture Therapy to pancreatic cancer model (2021)
  • Author(s): Yanagie H, Yanagawa M, Xuan H, Yanagie Y, Morishita Y, Dewi N, Nonaka Y, Furuya Y, Matsukawa T, Kubota A, Suzuki M, Masunaga S, Sakurai Y, Tanaka H, Shinohara A, Nashimoto M, Sugihara T, Yamauchi H, Nakajima J, Ono M, and Takahashi H
  • Organizer: 19th International Congess on Neutron Capture Therapy
  • Int'l Joint Research
• [Presentation] Tumor growth suppression by gadolinium-neutron capture therapy with intra-tumoral injection of gadolinium-liposome complex(Gd-plex) to pancreatic cancer model in vivo (2021)
  • Author(s): Yoshiteru Yanagie, Hironobu Yanagie, Xuan Hou, Masashi Yanagawa, Tatsuya Ishikawa, Novriana Dewi, Yasuyuki Morishita, Changyuan Qin, Takehisa Matsukawa, Ayano Kubota, Minoru Suzuki, Shi-ichiro Masunaga, Yoshinori Sakurai, Hiroki Tanaka, Takeshi Nagasaki, Masayuki Nashimoto, Takumichi Sugihara, and Hiroyuki Takahashi
  • Organizer: 19th International Congess on Neutron Capture Therapy
  • Int'l Joint Research
• [Presentation] The improvement of tumor accumulation by polymeric nanocarrieres on gadolinium neutron capture therapy (2021)
  • Author(s): Xuan Hou, Changyuan Qin, Hironobu Yanagie, Horacio Cabral, Hiroyuki Takahashi
  • Organizer: 19th International Congess on Neutron Capture Therapy
  • Int'l Joint Research