Synthesis and evaluation of BSH-containing kojic acid (KA-BSH) as a novel agent for boron neutron capture therapy

• Project/Area Number: 26462192
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Osaka Medical College
• Principal Investigator: Kawabata Shinji 大阪医科大学, 医学部, 講師 (20340549)
• Co-Investigator(Kenkyū-buntansha): 平松 亮 大阪医科大学, 医学部, 助教 (40609707) ; 古瀬 元雅 大阪医科大学, 医学部, 講師 (70340560)
• Research Collaborator: Kirihata Mitsunori 大阪府立大学, BNCT研究センター, 教授 ; Hattori Yoshihide 大阪府立大学, BNCT研究センター, 助教 ; Barth Rolf F. The Ohio State University, Pathology, Academy Professor
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 悪性神経膠腫 / 放射線治療 / ホウ素化合物 / 中性子捕捉療法 / コウジ酸

Outline of Final Research Achievements

Boron neutron capture therapy (BNCT) is a form of tumor-cell selective particle irradiation using low-energy neutron irradiation of nonradioactive boron-10 (10B) to produce high-energy alpha particles (10B [n, alpha] 7Li). To develop practical materials utilizing 10B carriers, we designed and synthesized novel dodecaboranethiol (BSH)-containing kojic acid (KA-BSH). In the present study, we evaluated the effects of this novel 10B carrier on cytotoxicity, 10B concentrations in F98 rat glioma cells, and micro-distribution of KA-BSH in vitro. Furthermore, biodistribution studies were performed in a rat brain tumor model. Based on these results, neutron irradiation was evaluated at the Kyoto University Research Reactor Institute with KA-BSH. Based on these findings, KA-BSH is a promising new B compound for BNCT of brain tumors.

Research Products

• [Journal Article] Evaluation of a novel sodium borocaptate-containing unnatural amino acid as a boron delivery agent for neutron capture therapy of the F98 rat glioma (2017)
  • Author(s): Futamura G, Kawabata S, Nonoguchi N, Hiramatsu R, Toho T, Tanaka H, Masunaga SI, Hattori Y, Kirihata M, Ono K, Kuroiwa T, Miyatake SI
  • Journal Title: Radiat Oncol. Volume: 12 Issue: 1 Pages: 26-26
  • DOI: 10.1186/s13014-017-0765-4
  • NAID: 120005997769
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Boron Neutron Capture Therapy for Malignant Brain Tumors (2016)
  • Author(s): Shin-Ichi MIYATAKE, Shinji KAWABATA, Ryo HIRAMATSU, Toshihiko KUROIWA, Minoru SUZUKI, Natsuko KONDO, Koji ONO
  • Journal Title: Neurologia medico-chirurgica Volume: 56 Issue: 7 Pages: 361-371
  • DOI: 10.2176/nmc.ra.2015-0297
  • NAID: 130005165070
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Delayed brain radiation necrosis: pathological review and new molecular targets for treatment. (2015)
  • Author(s): Furuse M, Nonoguchi N, Kawabata S, Miyatake S, Kuroiwa T
  • Journal Title: Med Mol Morphol. Volume: 48 Pages: 183-190
  • Peer Reviewed
• [Journal Article] The Anti-Proliferative Effect of Boron Neutron Capture Therapy in Prostate Cancer Xenograft Model (2015)
  • Author(s): Takahara K, Inamoto T, Minami K, Yoshikawa Y, Takai T, Ibuki N, Hirano H, Nomi H, Kawabata S, Kiyama S, Miyatake S, Kuroiwa T, Suzuki M, Kirihata M, Azuma H.
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: 136981-2
  • DOI: 10.1371/journal.pone.0136981
  • NAID: 120005763435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intratumoral and peritumoral post-irradiation changes, but not viable tumor. (2015)
  • Author(s): Furuse M, Nonoguchi N, Kawabata S, Miyata T, Toho T, Kuroiwa T, Miyatake S.
  • Journal Title: Radiat Oncol. Volume: 10 Issue: 1 Pages: 156-156
  • DOI: 10.1186/s13014-015-0446-0
  • Peer Reviewed / Open Access
• [Journal Article] Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain (2015)
  • Author(s): Shin-Ichi Miyatake, Noasuke Nonoguchi, Motomasa Furuse, Erina Yoritsune, Tomo Miyata, Shinji Kawabata, and Toshihiko Kuroiwa
  • Journal Title: Neurologia medico-chirurgica Volume: 55 Issue: 1 Pages: 50-59
  • DOI: 10.2176/nmc.ra.2014-0188
  • NAID: 130004922267
  • ISSN: 0470-8105, 1349-8029
  • Peer Reviewed / Open Access
• [Journal Article] Effect of boron neutron capture therapy for recurrent anaplastic meningioma: an autopsy case report. (2015)
  • Author(s): Kawaji H, Miyatake SI, Shinmura K, Kawabata S, Tokuyama T, Namba H
  • Journal Title: Brain Tumor Pathol Volume: 32 Issue: 1 Pages: 61-65
  • DOI: 10.1007/s10014-014-0189-x
  • Peer Reviewed
• [Journal Article] Tetrakis(p-Carboranylthio-Tetrafluorophenyl)Chlorin (TPFC):Application for Photodynamic Therapy and Boron Neutron Capture Therapy (2014)
  • Author(s): Hiramatsu R, Kawabata S, Tanaka H, Sakurai Y, Suzuki M, Ono K, Miyatake SI, Kuroiwa T, Hao E, Vicente MG
  • Journal Title: Journal of Pharmaceutical Volume: Dec 26 Issue: 3 Pages: 0-0
  • DOI: 10.1002/jps.24317
  • Peer Reviewed
• [Journal Article] A case of radiation-induced osteosarcoma treated effectively by boron neutron capture therapy. (2014)
  • Author(s): Futamura G, Kawabata S, Siba H, Kuroiwa T, Suzuki M, Kondo N, Ono K, Sakurai Y, Tanaka M, Todo T, Miyatake S
  • Journal Title: Radiat Oncol. Volume: 9 Pages: 273-273
  • Peer Reviewed / Open Access
• [Journal Article] Inflammation as well as angiogenesis may participate in the pathophysiology of brain radiation necrosis. (2014)
  • Author(s): Yoritsune E, Furuse M, Kuwabara H, Miyata T, Nonoguchi N, Kawabata S, Hana Hayasaki H, Kuroiwa T, Ono K, Shibayama Y, and Miyatake S
  • Journal Title: J Radiat Res Volume: 55(4) Issue: 4 Pages: 803-11
  • DOI: 10.1093/jrr/rru017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The roles of platelet-derived growth factors and their receptors in brain radiation necrosis (2014)
  • Author(s): Miyata T, Toho T, Nonoguchi N, Furuse M, Kuwabara H, Yoritsune E, Kawabata S, Kuroiwa T, and Miyatake S
  • Journal Title: Radiation Oncology Volume: 9 Issue: 1 Pages: 51-59
  • DOI: 10.1186/1748-717x-9-51
  • Peer Reviewed / Open Access
• [Journal Article] The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating peptide. (2014)
  • Author(s): Michiue H, Sakurai Y, Kondo N, Kitamatsu M, Bin F, Nakajima K, Hirota Y, Kawabata S, Nishiki T, Ohmori I, Tomizawa K, Miyatake S, Ono K, Matsui H.
  • Journal Title: Biomaterials. Volume: 35 Issue: 10 Pages: 3396-3405
  • DOI: 10.1016/j.biomaterials.2013.12.055
  • Peer Reviewed
• [Journal Article] Boron neutron capture therapy with bevacizumab may prolong the survival of recurrent malignant glioma patients: four cases (2014)
  • Author(s): Miyatake SI, Kawabata S, Hiramatsu R, Furuse M, Kuroiwa T, Suzuki M.
  • Journal Title: Radiation Oncology Volume: 9 Issue: 1 Pages: 6-11
  • DOI: 10.1186/1748-717x-9-6
  • Peer Reviewed / Open Access
• [Journal Article] 悪性神経膠腫の放射線治療後再発例に対するホウ素中性子捕捉療法の成績 (2014)
  • Author(s): 川端信司、平松亮、古瀬元雅、松下葉子、二村元、大西宏之、黒岩敏彦、近藤夏子、鈴木実、櫻井良憲、田中浩基、小野公二、宮武伸一
  • Journal Title: 定位放射線治療 Volume: １８ Pages: 43-49
• [Presentation] 再発悪性神経膠腫に対する加速器BNCT第一相試験の結果 (2016)
  • Author(s): 川端信司，鈴木 実，田中浩基，平松 亮，上原幸樹，佐藤岳実，黒岩敏彦，小野公二，宮武伸一
  • Organizer: 第34回日本脳腫瘍学会学術集会
  • Place of Presentation: 甲府富士屋ホテル （山梨県甲府市）
  • Year and Date: 2016-12-04
• [Presentation] ホウ素中性子捕捉療法による再発悪性神経膠腫に対する臨床試験 (2016)
  • Author(s): 川端信司，平松 亮，松下葉子，古瀬元雅，鈴木 実，増永慎一郎，小野公二，宮武伸一，黒岩敏彦
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Evaluation of BSH containing Kojic acid (KA-BSH) as novel agents for boron neutron capture therapy (2016)
  • Author(s): Takeuchi K, Kawabata S, Futamura G, Hiramatsu R, Kuroiwa T, Hattori Y, Kirihata M, Tanaka H, Sakurai Y, Masunaga S, Ono K, Miyatake SI
  • Organizer: 17th International Congress on Neutron Capture Therapy
  • Place of Presentation: University of Missouri (Missouri, USA)
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] Clinical results of reactor-based BNCT using BPA for the patients with recurrent malignant glioma (2016)
  • Author(s): Kawabata S, Hiramatsu R, Takeuchi K, Shiba H, Matsushita Y, Kuroiwa T, Tanaka H, Sakurai Y, Suzuki M, Ono K, Miyatake SI
  • Organizer: 17th International Congress on Neutron Capture Therapy
  • Place of Presentation: University of Missouri (Missouri, USA)
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] BNCTにおけるコウジ酸修飾BSH(KA-BSH)の新規ホウ素化合物としての評価－脳腫瘍モデル動物を用いた治療効果検討－ (2016)
  • Author(s): 竹内孝治，川端信司，平松 亮，二村 元，服部能英，切畑光統，櫻井良憲，増永慎一郎，小野公二，宮武伸一，黒岩敏彦
  • Organizer: 第13回日本中性子捕捉療法学会学術大会
  • Place of Presentation: 東京大学 伊藤謝恩ホール（東京都文京区）
  • Year and Date: 2016-08-06
• [Presentation] 浸潤部と闘う悪性神経膠腫の治療 (2016)
  • Author(s): 川端信司
  • Organizer: 第36回日本脳神経外科コングレス総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2016-05-20
  • Invited
• [Presentation] ホウ素中性子捕捉療法(BNCT)による再発悪性神経膠腫の治療～現状と展望 (2015)
  • Author(s): 川端信司、宮武伸一、竹内孝治、平松 亮、松下葉子、野々口直助、古瀬元雅、鈴木 実、小野公二、黒岩敏彦
  • Organizer: 第33回日本脳腫瘍学会学術集会
  • Place of Presentation: 宝が池プリンスホテル（京都府京都市）
  • Year and Date: 2015-12-09
• [Presentation] 再発悪性神経膠腫に対するホウ素中性子捕捉療法の臨床試験 (2015)
  • Author(s): 川端信司，宮武伸一，平松 亮，松下葉子，古瀬元雅，黒岩敏彦，鈴木 実，小野公二
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-10-31
• [Presentation] 悪性神経膠腫に対するホウ素中性子捕捉療法を用いた新たな治療戦略 (2015)
  • Author(s): 川端信司、宮武伸一、竹内孝治、平松 亮、二村 元、松下葉子、池田直廉、野々口直助、古瀬元雅、鈴木 実、小野公二、黒岩敏彦
  • Organizer: 社団法人日本脳神経外科学会第74回学術総会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-10-16
• [Presentation] 悪性脳腫瘍患者に対するBNCTおよびFBPA-PETの有用性と実臨床への道のり (2015)
  • Author(s): 川端信司、宮武伸一、竹内孝治、二村 元、平松 亮、松下葉子、野々口直助、黒岩敏彦、鈴木 実、小野公二
  • Organizer: 第12回日本中性子捕捉療法学会学術大会
  • Place of Presentation: 神戸学院大学 ポートアイランドキャンパス（兵庫県神戸市）
  • Year and Date: 2015-09-08
• [Presentation] Boron Neutron Capture Therapy for Brain Tumor (2015)
  • Author(s): S Kawabata
  • Organizer: The 15th International Congress of Radiation Research (ICRR 2015)
  • Place of Presentation: Kyoto International Conference Centere (Kyoto, Japan)
  • Year and Date: 2015-05-28
  • Int'l Joint Research / Invited
• [Presentation] 原子炉を中性子源としたホウ素中性子捕捉療法による再発悪性神経膠腫の臨床試験成績 (2015)
  • Author(s): 川端信司、宮武伸一、平松 亮、松下葉子、野々口直助、古瀬元雅、黒岩敏彦、田中浩基、櫻井良憲、鈴木 実、小野公二
  • Organizer: 第24回定位放射線治療学会
  • Place of Presentation: 長崎ブリックホール（長崎県長崎市）
  • Year and Date: 2015-05-15
• [Presentation] Boron neutron capture therapy (BNCT) for the patients with brain tumor (2015)
  • Author(s): 川端信司
  • Organizer: 第74回 日本医学放射線学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2015-04-18
  • Invited
• [Presentation] 再発悪性神経膠腫に対するBNCTの臨床試験と画像診断 (2015)
  • Author(s): 川端信司、宮武伸一、平松亮、松下葉子、野々口直助、古瀬元雅、田中浩基、鈴木実、小野公二、黒岩敏彦
  • Organizer: 第38回日本脳神経CI学会総会
  • Place of Presentation: ウインクあいち（愛知県・名古屋市）
  • Year and Date: 2015-02-13 – 2015-02-14
• [Presentation] 脳腫瘍の新たな核医学イメージング（F-18 FBPA PETについて） (2015)
  • Author(s): 川端信司
  • Organizer: 第3回 New Clear Imaging Conference
  • Place of Presentation: 新大阪ワシントンプラザ（大阪府・大阪市）
  • Year and Date: 2015-01-24
  • Invited
• [Presentation] 新規ホウ素投薬プロトコールによる再発悪性神経膠腫に対するBNCT の臨床試験 (2014)
  • Author(s): 川端信司、宮武伸一、平松亮、二村元、松下葉子、野々口直助、古瀬元雅、黒岩敏彦、田中浩基、櫻井良憲、近藤夏子、鈴木実、小野公二
  • Organizer: 第32回日本脳腫瘍学会学術集会
  • Place of Presentation: シェラトン・グランデ・トーキョーベイ・ホテル（千葉県・浦安市）
  • Year and Date: 2014-11-30 – 2014-12-02
• [Presentation] 再発悪性神経膠腫に対するＢＰＡ単剤を用いたホウ素中性子捕捉療法の臨床試験～中間報告～ (2014)
  • Author(s): 川端信司、二村元、野々口直助、矢木亮吉、斯波宏行、松下 葉子、古瀬元雅、平松亮、黒岩敏彦、近藤夏子、鈴木実、小野公二、宮武伸一
  • Organizer: 日本脳神経外科学会第73回学術総会
  • Place of Presentation: グランドプリンス ホテル新高輪（東京都・港区）
  • Year and Date: 2014-10-09 – 2014-10-11
• [Presentation] ホウ素中性子捕捉療法による悪性髄膜腫の臨床研究 (2014)
  • Author(s): 川端信司、平松亮、古瀬元雅、松下 葉子、黒岩 敏彦、鈴木 実、増永慎一郎、小野 公二、宮武 伸一
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] PET検査と悪性髄膜腫に対するホウ素中性子捕捉療法の適応拡大 (2014)
  • Author(s): 川端信司、二村 元、平松亮、松下 葉子、野々口 直助、古瀬元雅、黒岩 敏彦、田中 浩基、櫻井 良憲、鈴木 実、小野 公二、宮武 伸一
  • Organizer: 第52回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2014-08-28 – 2014-08-30
• [Presentation] 再発悪性神経膠腫に対するホウ素中性子捕捉療法の臨床成績 (2014)
  • Author(s): 川端信司、二村元、松下葉子、古瀬元雅、野々口直助、黒岩敏彦、田中浩基、櫻井良憲、近藤夏子、鈴木実、小野公二、宮武伸一
  • Organizer: 第11 回日本中性子捕捉療法学会学術大会
  • Place of Presentation: 大阪大学吹田キャンパスコンベンションセンター（大阪府・吹田市）
  • Year and Date: 2014-07-05 – 2014-07-06
• [Presentation] 加速器BNCT時代に向けての共通言語（標準化）．BNCTにおける腫瘍線量～NCT主治医としての考え方 (2014)
  • Author(s): 川端信司
  • Organizer: 第11 回日本中性子捕捉療法学会学術大会
  • Place of Presentation: 大阪大学吹田キャンパスコンベンションセンター（大阪府・吹田市）
  • Year and Date: 2014-07-05 – 2014-07-06
  • Invited
• [Presentation] 再発悪性グリオーマに対するホウ素中性子捕捉療法 (2014)
  • Author(s): 川端信司、宮武伸一、二村元、平松亮、松下葉子、古瀬元雅、黒岩敏彦、櫻井良憲、鈴木 実、小野公二
  • Organizer: 第23回日本定位放射線治療学会
  • Place of Presentation: ナレッジキャピタルコングレコンベンションセンター（大阪府・大阪市）
  • Year and Date: 2014-06-27
• [Presentation] Clinical results of Boron neutron neutron capture therapy for the patients with malignant meningioma (2014)
  • Author(s): S. Kawabata, S-I. Miyatake, G. Futamura, R. Hiramatsu, Y. Matsushita, M. Furuse, Y. Tamura, T. Kuroiwa, H. Tanaka, Y. Sakurai, S-I. Masunaga, M. Suzuki, K. Ono
  • Organizer: The 16th International Congress on Neutron Capture Therapy
  • Place of Presentation: Helsinki (Finland)
  • Year and Date: 2014-06-14 – 2014-06-19
• [Presentation] Development of BNCT in 12 years at Osaka Medical College (2014)
  • Author(s): S. Miyatake, S. Kawabata, R. Hiramatsu, K. Yokoyama, A Doi, K Onishi, S. Miyata, Y. Kuroda, Y. Hirota1 G. Futamura, T. Kuroiwa, K. Ono
  • Organizer: The 16th International Congress on Neutron Capture Therapy
  • Place of Presentation: Helsinki (Finland)
  • Year and Date: 2014-06-14 – 2014-06-19
  • Invited
• [Presentation] Examination of the usefulness as the new boron compound of ACBC-BSH (2014)
  • Author(s): G Futamura, S. Kawabata, S-I. Miyatake, T. Kuroiwa, Y. Hattori, M. Kirihata, H. Tanaka, Y. Sakurai, S-I. Masunaga, K. Ono
  • Organizer: The 16th International Congress on Neutron Capture Therapy
  • Place of Presentation: Helsinki (Finland)
  • Year and Date: 2014-06-14 – 2014-06-19
• [Presentation] BNCT for recurrent malignant gliomas, with the special combination of bevacizumab (2014)
  • Author(s): S. Miyatake, S. Kawabata, R. Hiramatsu, N. Nonoguchi, M. Furuse, T. Kuroiwa, N. Kondo, M. Suzuki, K. Ono
  • Organizer: The 16th International Congress on Neutron Capture Therapy
  • Place of Presentation: Helsinki (Finland)
  • Year and Date: 2014-06-14 – 2014-06-19
• [Presentation] Novel multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating (2014)
  • Author(s): H. Michiue, Y. Sakurai, N. Kondo, M. Kitamatsu, F. Bin, K. Nakajima, Y. Hirota, S. Kawabata, T-I. Nishiki, I. Ohmon, K. Tomizawa, S-I. Miyatake, K. Ono, H. Matsui
  • Organizer: The 16th International Congress on Neutron Capture Therapy
  • Place of Presentation: Helsinki (Finland)
  • Year and Date: 2014-06-14 – 2014-06-19