Development of Hydrophilic Boron Cluster Containing Molecular-Targeted Drugs

• Project/Area Number: 20K05753
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Osaka Metropolitan University (2022); Osaka Prefecture University (2020-2021)
• Principal Investigator: Hattori Yoshihide 大阪公立大学, 研究推進機構, 特任講師 (50514460)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: BNCT / ホウ素クラスター / セラノスティック / ホウ素薬剤 / 蛍光標識 / ドデカボレート / 腫瘍集積性分子

Outline of Research at the Start

近年、診断と治療の両方に適用可能ないわゆる「セラノスティック」な薬剤の開発研究が進展し、特に新規ながん治療への適用をめざした研究が盛んに行われている。
本研究は、がんの診断だけではなく、低侵襲ながん治療として注目されているホウ素中性子捕捉療法（BNCT）に適用可能な多機能な薬剤の開発を目指すものである。このために、コア分子として、20面体のホウ素クラスター分子であるBSHを選択し、反応性に富むイオウ原子に「腫瘍集積性分子」とイメージングのためのポジトロン放出核種や蛍光性分子等の「標識化分子」を導入したホウ素薬剤の分子設計と合成を行い、セラノスティクなBNCT用薬剤としての有用性を評価する。

Outline of Final Research Achievements

Recently, research on the development of so-called "theranostic" agents applicable to both diagnosis and treatment has been progressing, especially with the aim of applying them to novel cancer therapies.
In this study, to develop multifunctional agents applicable not only to cancer diagnosis but also to boron neutron capture therapy (BNCT), which is attracting attention as a minimally invasive cancer therapy. For this purpose, we selected BSH, an icosahedral boron cluster molecule, as the core molecule, and designed and synthesized boron drugs by introducing "tumor targetting molecules" and "labeling molecules" such as fluorescent molecules for imaging into sulfur atoms, and evaluated their usefulness as theranostic BNCT drugs. The evaluation of the boron drug as a theranostic BNCT agent was elucidated.

Academic Significance and Societal Importance of the Research Achievements

本研究は、がんの診断だけではなく、低侵襲ながん治療として注目されているホウ素中性子捕捉療法（BNCT）に適用可能な薬剤の開発を目指すものである。このためにホウ素１２原子から構成されホウ素含有率の非常に高いスルホニオドデカボレートを用い、様々な腫瘍集積性分子へ多量のホウ素原子と蛍光分子を同時に導入する手法を確立した。さらに、本手法を用いて調製したホウ素化抗体は赤外蛍光を用いて薬剤分布を解析可能なセラノスティック型BNCT用薬剤として有望な化合物であるを明らかとした。
今後、本研究で開発された化合物群を活用することにより、有用なセラノスティック型BNCT用薬剤の開発につながると期待できる。

Research Products

• [Journal Article] Multi-Targeted Neutron Capture Therapy Combined with an 18 kDa Translocator Protein-Targeted Boron Compound Is an Effective Strategy in a Rat Brain Tumor Model (2023)
  • Author(s): Kashiwagi Hideki、Hattori Yoshihide、Kawabata Shinji、Kayama Ryo、Yoshimura Kohei、Fukuo Yusuke、Kanemitsu Takuya、Shiba Hiroyuki、Hiramatsu Ryo、Takami Toshihiro、Takata Takushi、Tanaka Hiroki、Watanabe Tsubasa、Suzuki Minoru、Hu Naonori、Miyatake Shin-Ichi、Kirihata Mitsunori、Wanibuchi Masahiko
  • Journal Title: Cancers Volume: 15 Issue: 4 Pages: 1034-1034
  • DOI: 10.3390/cancers15041034
  • Peer Reviewed / Open Access
• [Journal Article] Dodecaborate-Encapsulated Extracellular Vesicles with Modification of Cell-Penetrating Peptides for Enhancing Macropinocytotic Cellular Uptake and Biological Activity in Boron Neutron Capture Therapy (2022)
  • Author(s): Hirase Shiori、Aoki Ayako、Hattori Yoshihide、Morimoto Kenta、Noguchi Kosuke、Fujii Ikuo、Takatani-Nakase Tomoka、Futaki Shiroh、Kirihata Mitsunori、Nakase Ikuhiko
  • Journal Title: Molecular Pharmaceutics Volume: 19 Issue: 4 Pages: 1135-1145
  • DOI: 10.1021/acs.molpharmaceut.1c00882
  • Peer Reviewed / Open Access
• [Journal Article] Dodecaborate Conjugates Targeting Tumor Cell Overexpressing Translocator Protein for Boron Neutron Capture Therapy (2021)
  • Author(s): Hattori Yoshihide、Ishimura Miki、Ohta Youichirou、Takenaka Hiroshi、Kawabata Shinji、Kirihata Mitsunori
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 13 Issue: 1 Pages: 50-54
  • DOI: 10.1021/acsmedchemlett.1c00377
  • Peer Reviewed
• [Journal Article] Antibody-based receptor targeting using an Fc-binding peptide-dodecaborate conjugate and macropinocytosis induction for boron neutron capture therapy (BNCT) (2020)
  • Author(s): Ikuhiko Nakase, Ayako Aoki, Yuriko Sakai, Shiori Hirase, Miki Ishimura, Tomoka Takatani-Nakase, Yoshihide Hattori and Mitsunori Kirihata
  • Journal Title: ACS Omega Volume: 5 Issue: 36 Pages: 22731-22738
  • DOI: 10.1021/acsomega.0c01377
  • Peer Reviewed / Open Access
• [Journal Article] The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model (2020)
  • Author(s): Fukuo Yusuke、Hattori Yoshihide、Kawabata Shinji、Kashiwagi Hideki、Kanemitsu Takuya、Takeuchi Koji、Futamura Gen、Hiramatsu Ryo、Watanabe Tsubasa、Hu Naonori、Takata Takushi、Tanaka Hiroki、Suzuki Minoru、Miyatake Shin-Ichi、Kirihata Mitsunori、Wanibuchi Masahiko
  • Journal Title: Biology Volume: 9 Issue: 12 Pages: 437-437
  • DOI: 10.3390/biology9120437
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and evaluation of dodecaboranethiol containing kojic acid (KA-BSH) as a novel agent for boron neutron capture therapy. (2020)
  • Author(s): Takeuchi F, Hattori Y, Kawabata S, Futamura G, Hiramatsu R, Wanibuchi M, Tanaka H, Masunaga S, Ono K, Miyatake S, Kirihata M.
  • Journal Title: Cells Volume: 9 Issue: 6 Pages: 1551-1551
  • DOI: 10.3390/cells9061551
  • Peer Reviewed / Open Access
• [Presentation] セラノスティック型BNCT用薬剤開発のためのバイファクショナルなドデカボレート誘導体の合成 (2023)
  • Author(s): 服部 能英
  • Organizer: 第１４３回日本薬学会年会
• [Presentation] Synthesis and Biological Evaluation of S-Octylsulfoniododecaborate containing L-Amino Acids for Boron Neutron Capture Therapy (2022)
  • Author(s): Yoshihide Hattori
  • Organizer: 第５９回ペプチド討論会
• [Presentation] 蛍光型ホウ素センサーの開発とホウ素薬剤の動態解析 (2022)
  • Author(s): 服部 能英
  • Organizer: 第１３回日本中性子捕捉療法学術大会
• [Presentation] トランスロケータープロテイン（TSPO）を標的とした ドデカボレート含有化合物の BNCT用薬剤としての評価 (2022)
  • Author(s): 服部 能英，石村 美紀，大田 洋一郎，竹中 宏誌，上原 幸樹， 浅野 智之，切畑 光統
  • Organizer: 日本薬学会第142年会
• [Presentation] Development of Dodecaborate Containing Amino Acid Derivatives for BNCT (2020)
  • Author(s): Yoshihide Hattori
  • Organizer: 2020 Taiwan-Japan BNCT International Conference
  • Int'l Joint Research / Invited