過酸化ナノチタン粒子の原子設計と新規ラジカル放射線増感療法の開発

2016 Fiscal Year Research-status Report

• Project/Area Number: 16K15581
• Research Institution: Kobe University
• Principal Investigator: 佐々木 良平 神戸大学, 医学部附属病院, 特命教授 (30346267)
• Co-Investigator(Kenkyū-buntansha): 荻野 千秋 神戸大学, 工学研究科, 教授 (00313693) ; 佐藤 和好 群馬大学, 大学院理工学府, 助教 (40437299) ; 沼子 千弥 千葉大学, 大学院理学研究科, 准教授 (80284280) ; 中山 雅央 神戸大学, 医学研究科, 医学研究員 (60582004) ; 赤坂 浩亮 神戸大学, 医学部附属病院, 特命助教 (20707161) ; 犬伏 祥子 (カリヤ) 神戸大学, 医学研究科, 特命助教 (60585959)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ナノ粒子 / 膵臓癌

Outline of Annual Research Achievements

我々は、二酸化チタンをナノ粒子化したチタン過酸化物が、X線照射によって大量のヒドロキシラジカルを発生することを発見し、国際調査を行った上で、新たな放射線増感剤として米国、欧州、中国等、世界5か国以上で国際特許（特許2010-032055、PCT/JP2011/　53348）を押さえたが、本申請では、更なる分子機序の解明を基に世界初のナノメタル放射線増感療法を開発し、膵臓癌などの難治癌に対する新たな治療戦略を提案事である。具体的には、① in vivo(細胞内、動物実験)での放射線増感を達成する最適メタルナノ粒子の原子構造設計の検討した結果、その作成法により、ラジカル発生の程度が異なることを見出した。その為異なる製造過程の数種の過酸化チタンナノ粒子を検討材料とした。② Reactive Oxygen Species（ROS）生成のメカニズムの探求とin vitro、 in vivoでの効率化の検討した結果、最終的に細胞内では過酸化水素が多量に発生することに着目できた。
本研究計画は、過酸化チタンナノ粒子による放射線増感効果を利用した抗腫瘍効果を明らかにするため、動物実験による放射線増感効果の評価をまず実施したが、再現性良く、過酸化チタンナノ粒子を局所注入した際に腫瘍増殖抑制効果を判定基準とした時の放射線増感効果が得られることを確認できた。さらに過酸化チタンナノ粒子に関して局所注入という投与経路において、同材料は小動物の生育に関して体重減少などの明らかな毒性は認めらておらず、今後長期間の毒性の有無などのさらなる検討は必要なものの、これまでの研究の成果の中では有効な併用療法であることが確認できた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

第一の目標である、過酸化チタンナノ粒子で放射線増感療法が確認できた。またその種類によって効果や分子機序が異なることを見出し、最適化への足掛かりを得た。細胞内でのROSの発生やその種類に関しても有用な実験結果を得ており、局所注入における毒性が想定範囲兄であることを確認できている。これらの結果を総合して計画としておおむね順調に経過していると判断できる。

Strategy for Future Research Activity

ナノ粒子の膵癌細胞などに対する選択性を向上させるために粒子の表面に抗原を付着させる方法を再検討中である。実際にはEGFレセプター抗体などを検討しているが、選択性向上に寄与するための設計を検討中である。

Causes of Carryover

過酸化チタンの製造方法によるROSの発生内容、発生程度が異なることに気付いたが、その評価方法の検討に一部時間を要したため、物品費を購入と使用が一部遅延した。現段階では一定の知見を得たので、次年度以降計画に組み込む予定である。

Expenditure Plan for Carryover Budget

ROSの判定方法などのIn vitroの検出キットなどを購入し、またフローサイトメーターでの識別化も予定している。

Research Products

• [Journal Article] Particle Therapy Using Protons or Carbon Ions for Unresectable or Incompletely Resected Bone and Soft Tissue Sarcomas of the Pelvis, (2017)
  • Author(s): Yusuke Demizu, Dongcun Jin, Nor Shazrina Sulaiman, Fumiko Nagano, Kazuki Terashima, Sunao Tokumaru, Takashi Akagi, Osamu Fujii, Takashi Daimon, Ryohei Sasaki, Nobukazu Fuwa, Tomoaki Okimoto,
  • Journal Title: Int J Radiat Oncol Biol Physc Volume: 98(2) Pages: 367-374
  • DOI: doi.org/10.1016/j. jrobp.2017.02.030
  • Peer Reviewed
• [Journal Article] Relationship between the uptake of 18F-borono-L-phenylalanine and L-[methyl-11C] methionine in head and neck tumors and normal organs, (2017)
  • Author(s): Yoshiaki Watanabe, Hiroaki Kurihara, Jun Itami, Ryohei Sasaki, Yasuaki Arai, Kazuro Sugimura,
  • Journal Title: Radiat Oncol. Volume: 12(1) Pages: 17
  • DOI: doi: 10.1186/s13014-017-0763-6.
  • Peer Reviewed / Open Access
• [Journal Article] [18F]Fluorodeoxyglucose uptake by positron emission tomography predicts outcomes for oropharyngeal and hypopharyngeal cancer treated with definitive radiotherapy. (2017)
  • Author(s): Takeaki Ishihara, Kazuhiro Kitajima, Yuko Suenaga, Yasuyuki Shimizu, Saki Osuga, Yasuo Ejima, Hirokazu Komatsu, Naoki Otsuki, Kenichi Nibu, Naomi kiyota, Satoru Takahashi, and Ryohei Sasaki,
  • Journal Title: Nagoya Journal of Medical Science, Volume: 79(1) Pages: 27-36
  • DOI: doi: 10.18999/nagjms.79.1.27.
  • Peer Reviewed
• [Journal Article] Sparing of tissue by using micro-slit-beam radiation therapy reduces neurotoxicity compared with broad-beam radiation therapy. (2017)
  • Author(s): Naritoshi Mukumoto, Masao Nakayama, Hiroaki Akasaka, Yasuyuki Shimizu, Saki Osuga, Daisuke Miyawaki, Kenji Yoshida, Yasuo Ejima, Yasushi Miura, Keiji Umetani, Takeshi Kondoh, Ryohei Sasaki,
  • Journal Title: J Radiat Res Volume: 58(1) Pages: 17-23
  • DOI: doi: 10.1093/jrr/rrw065.
  • Peer Reviewed / Open Access
• [Journal Article] MGDG extracted from spinach enhances the cytotoxicity of radiation in pancreatic cancer cells. (2017)
  • Author(s): Akasaka H, Mizushina Y, Yoshida K, Ejima Y, Mukumoto N, Wang T, Inubushi S, Nakayama M, Wakahara Y, Sasaki R.
  • Journal Title: Radiat Oncol. Volume: 11(1) Pages: 153.
  • DOI: DOI 10.1186/s13014-016-0729-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Radiotherapy for brainstem gliomas in children and adults: A single-institution experience and literature review. (2017)
  • Author(s): Yoshida K, Sulaiman NS, Miyawaki D, Ejima Y, Nishimura H, Ishihara T, Matsuo Y, Nishikawa R, Sasayama T, Hayakawa A, Kohmura E, Sasaki R.
  • Journal Title: Asia Pac J Clin Oncol. Volume: 13(2) Pages: e153-e160
  • DOI: doi: 10.1111/ajco.12451
  • Peer Reviewed
• [Journal Article] Dosimetric factors predicting radiation pneumonitis after CyberKnife stereotactic body radiotherapy for peripheral lung cancer (2016)
  • Author(s): Nakamura M, Nishimura H, Nakayama M, Mayahara H, Uezono H, Harada A, Hashimoto N, Ejima Y, Ishihara T, Sasaki R
  • Journal Title: Br J Radiol. Volume: 89(1068) Pages: 20160560
  • DOI: doi.org/10.1259/bjr.20160560
  • Peer Reviewed
• [Journal Article] Characterization of titanium dioxide nanoparticles modified with polyacrylic acid and H2O2 for use as a novel Radiosensitizer, (2016)
  • Author(s): Morita K, Miyazaki S, Numaki C, Ikeno S, Sasaki R, Nishimura Y, Ogino C, Kondo A,
  • Journal Title: Free Radical Research Volume: 50(12) Pages: 1319-1328
  • DOI: DOI:10.1080/10715762.2016.1241879
  • Peer Reviewed
• [Journal Article] The current status of space modulated radiotherapy. (2016)
  • Author(s): Ryohei Sasaki, Tianyuan Wang, Hiroaki Akasaka, Sachiko Inubushi, Kenji Yoshida, Shohei Komatsu, Yusuke Demizu, Takumi Fukumoto
  • Journal Title: Internal Medicine Review Volume: 2(9) Pages: 1
  • Peer Reviewed
• [Journal Article] Prospective Cohort Study of Performance Status and Activities of Daily Living after Surgery for Spinal Metastasis, (2016)
  • Author(s): Kakutani K, Sakai Y, Maeno Y, Takada T, Yurube T, Kurakawa T, Miyazaki S, Terashima Y, Ito M, Hara H, Kawamoto T, Ejima Y, Sakashita A, Kizawa Y, Sasaki R, Akisue T, Minami H, Kuroda R, Kurosaka R, Nishida K,
  • Journal Title: Clinical Spine Surgery Volume: - Pages: -
  • DOI: DOI:10.1097/BSD.0000000000000456
  • Peer Reviewed
• [Journal Article] Cause and occurrence timing of osteoradionecrosis of the jaw: a retrospective study focusing on prophylactic tooth extraction, (2016)
  • Author(s): Satoshi Wanifuchi, Masaya Akashi, Yasuo Ejima, Hirotaka Shinomiya, Tsutomu Minamikawa, Shungo Furudoi, Naoki Otsuki, Ryohei Sasaki, Ken-ichi Nibu, Takahide Komori,
  • Journal Title: Oral and Maxillofacial Surgery, Volume: 20(4) Pages: 337-342
  • DOI: DOI: 10.1007/s10006-016-0570-5
  • Peer Reviewed
• [Journal Article] Titanium peroxide nanoparticles enhanced cytotoxic effects of X-ray irradiation against pancreatic cancer model through reactive oxygen species generation in vitro and in vivo, (2016)
  • Author(s): Masao Nakayama, Ryohei Sasaki, Chiaki Ogino, Tsutomu Tanaka, Kenta Morita, Mitsuo Umetsu, Satoshi Ohara, Zhenquan Tan, Yuya Nishimura, Hiroaki Akasaka, Kazuyoshi Sato, Chiya Numako, Seiichi Takami, Akihiko Kondo,
  • Journal Title: Radiat Oncol. Volume: 11(1) Pages: 91
  • DOI: doi: 10.1186/s13014-016-0666-y.
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. (2016)
  • Author(s): Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, Kyotani K, Mukasa A, Mizukawa K, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E.
  • Journal Title: Neuro Oncol Volume: 18(11) Pages: 1559-1568
  • DOI: DOI:10.1093/neuonc/now090
  • Peer Reviewed
• [Journal Article] Hypofractionated stereotactic radiotherapy for brain metastases from lung cancer : Evaluation of indications and predictors of local control. (2016)
  • Author(s): Ishihara T, Yamada K, Harada A, Isogai K, Tonosaki Y, Demizu Y, Miyawaki D, Yoshida K, Ejima Y, Sasaki R.
  • Journal Title: Strahlenther Onkol. Volume: 192(6) Pages: 386-393
  • DOI: doi: 10.1007/s00066-016-0963-2.
  • Peer Reviewed
• [Journal Article] Efficacy of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis / Inferior Vena Cava Tumor Thrombosis: Evaluation by Comparison with Conventional Three-Dimensional Conformal Radiotherapy (2016)
  • Author(s): Yoshiro Matsuo, Kenji Yoshida, Hideki, Nishimura, Yasuo Ejima, Daisuke Miyawaki, Haruka Uezono, Takeaki Ishihara, Hiroshi Mayahara, Takumi Fukumoto, Yonson Ku, Masato Yamaguchi, Koji Sugimoto, and Ryohei Sasaki,
  • Journal Title: J Radiat Res, Volume: 57(5) Pages: 512-523
  • DOI: doi.org/10.1093/jrr/rrw028
  • Peer Reviewed / Open Access
• [Journal Article] Randomized Trial of Standard Pain Control with or without Gabapentin for Pain Related to Radiation-induced Mucositis in Head and Neck Cancer. (2016)
  • Author(s): Tomoko Kataoka, Naomi Kiyota, Takanobu Shimada, Yohei Funakoshi, Naoko Chayahara, Masanori Toyoda, Yutaka Fujiwara, Kenichi Nibu, Takahide Komori, Ryohei Sasaki, Toru Mukohara, and Hironobu Minami,
  • Journal Title: Auris Nasus Larynx, Volume: 43(6) Pages: 677-684
  • DOI: doi: 10.1016/j.anl.2016.02.012.
  • Peer Reviewed
• [Journal Article] A Dosimetric Comparison of Volumetric Modulated Arc Therapy (VMAT) with Unflattened Beams to VMAT with Flattened Beams and TomoTherapy for Head and Neck Cancer. (2016)
  • Author(s): Toshiyuki Ogata, Hideki Nishimura, Hiroshi Mayahara, Aya Harada, Yoshiro Matsuo, Masao Nakayama, Kazuyuki Uehara, Shinji Tsudou, Yasuo Ejima, Ryohei Sasaki, Takanobu Okayama,
  • Journal Title: J Nucl Med Radiat Ther Volume: 7 Pages: 274
  • DOI: 10.4172/2155-9619.1000274
  • Peer Reviewed
• [Journal Article] FDG-PET/contrast-enhanced CT as a post-treatment tool in head and neck squamous cell carcinoma: comparison with FDG-PET/non-contrast-enhanced CT and contrast-enhanced CT. (2016)
  • Author(s): uenaga Y, Kitajima K, Ishihara T, Sasaki R, Otsuki N, Nibu KI, Minamikawa T, Kiyota N, Sugimura K.
  • Journal Title: Eur Radiol. Volume: 26(4) Pages: 1018-1030
  • DOI: doi: 10.1007/s00330-015-3902-1.
  • Peer Reviewed
• [Journal Article] [18F]-FDG PET/CT imaging for detection of nodal metastases in patients with squamous cell carcinoma of the pharynx and larynx: comparison with CT. (2016)
  • Author(s): Suenaga Y, Kitajima K, Kanda T, Otsuki N, Nibu KI, Sasaki R, Itoh T, Sugimura K.
  • Journal Title: Jpn J Radiol. Volume: 34(3) Pages: 203-210
  • DOI: doi: 10.1007/s11604-015-0510-6.
  • Peer Reviewed
• [Journal Article] Concomitant chemoradiotherapy for advanced squamous cell carcinoma of the temporal bone. (2016)
  • Author(s): Shinomiya H, Hasegawa S, Yamashita D, Ejima Y, Kenji Y, Otsuki N, Kiyota N, Sakakibara S, Nomura T, Hashikawa K, Kohmura E, Sasaki R, Nibu KI.
  • Journal Title: Head Neck. Volume: 38 Suppl 1 Pages: E949-53.
  • DOI: DOI: 10.1002/hed.24133
  • Peer Reviewed
• [Presentation] 73.Assessment of the threshold dose for radiation fibrosis in thoracic esophageal cancer patients. (2016)
  • Author(s): Yasuo Ejima, Kenji Yoshida, Daisuke Miyawaki, Takeaki Ishihara, Ryo Nishikawa, Hiroki Kawaguchi, Yoshiro Matsuo, Atsuki Ikeda, Masanori Toyoda, Tetsu Nakamura, Ryohei Sasaki,
  • Organizer: The 1st Meeting of the Federation of Asisan Organizations for Radiation Oncology (FARO),
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2016-11-25 – 2016-11-27
  • Int'l Joint Research
• [Presentation] Space Modulated Particle Therapy with Newly Invented Bio-absorbable Spacer. (2016)
  • Author(s): Ryohei Sasaki, Hiroaki Akasaka, Sachiko Inubushi, Tianyuan Wang, Yasuyuki Shimizu, Saki Osuga, Yusuke Demizu, Takumi Fukumoto,
  • Organizer: the 4th Taiwan-Japan Radiation Oncology Symposium
  • Place of Presentation: Taipei Taiwan
  • Year and Date: 2016-06-04 – 2016-06-05
  • Int'l Joint Research / Invited
• [Presentation] 76.Assessment of Parametrial Response in stage IIB/IIIB Cervical Cancer Patients from EMBRACE (2016)
  • Author(s): Kenji Yoshida, Ryohei Sasaki
  • Organizer: the 4th Taiwan-Japan Radiation Oncology Symposium
  • Place of Presentation: Taipei Taiwan
  • Year and Date: 2016-06-04 – 2016-06-05
  • Int'l Joint Research
• [Book] Non-woven Fabrics (2016)
  • Author(s): Ryohei Sasaki, Hiroaki Akasaka, Yusuke Demizu, Sachiko Inubushi, Tianyuan Wang, Takumi Fukumoto
  • Total Pages: 324
  • Publisher: Intech
• [Book] Radiotherapy (2016)
  • Author(s): Yasuo Ejima, Takeaki Ishihara, Daisuke Miyawaki, Kenichiro Kakutani, Kotaro Nishida, Junichiro Inoue, Yoshitada Sakai, Tianyuan Wang, Ryohei Sasaki,
  • Total Pages: -
  • Publisher: Intech
• [Book] 耳鼻咽喉科・頭頸部外科研修ノート 改訂第2版 (2016)
  • Author(s): 佐々木良平、永井良三（監修）
  • Total Pages: 644 (475-480)
  • Publisher: 診断と治療社