Development of Innovative Anticancer Drug Delivery System for Malignant Glioma

• Project/Area Number: 18K08942
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Shiino Akihiko 滋賀医科大学, 神経難病研究センター, 准教授 (50215935)
• Co-Investigator(Kenkyū-buntansha): 田村 類 京都大学, 人間・環境学研究科, 名誉教授 (60207256) ; 谷垣 健二 滋賀県立総合病院(研究所), 神経病態研究部門, 専門研究員 (70362473)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 悪性神経膠腫 / 分子標的 / 抗癌剤 / drug delivery system / がん幹細胞 / ファージディスプレイ / 血液脳関門 / 分子標的抗癌剤 / ファージディスプレイ法 / ナノエマルジョン / 悪性神経厚種 / 分子標的薬 / DDS / MRI

Outline of Final Research Achievements

We developped two molecularly targeted peptide probes using a phage display method. The probes pass through the blood brain barrier (BBB) and are specifically incorporated into malignant glioma (GBM) cells when administered intravenously. The peptides were attached to the surface of nanoemulsions (NEs), and the NEs were encapsulated with anticancer agents to create molecularly targeted anticancer agents for GBM. The antitumor effect was confirmed in the patient-derived xenograft (PDX) model, in which human-derived GBM stem cells are transplanted into the mouse brain.

Academic Significance and Societal Importance of the Research Achievements

GBMの5年生存率は10%以下、平均余命は1～1.5年と予後不良である。この腫瘍は、浸潤性に進展するため切除範囲と脳の機能温存が対立し、手術で完全に摘出できない。血液脳関門(BBB)に守られ抗癌剤が届きにくい、という特徴があり、 ヒトのがんで最も治療が困難な疾患の1つである。研究者らは、頸静脈経由で腫瘍に特異的に輸送できるdrug delivery system(DDS)であるNEを開発した。本研究の特徴は、NE内に任意の抗癌剤を包埋できるので、多様な遺伝子変化をもつGBMに最も有効な抗癌剤カクテルを輸送できることにある。これまでに、このようなDDSの開発事例の報告はない。

Research Products

• [Journal Article] The Association Between Coronary Artery Calcification and Subclinical Cerebrovascular Diseases in Men: An Observational Study (2020)
  • Author(s): Khan Md Maruf Haque、Fujiyoshi Akira、Shiino Akihiko、Hisamatsu Takashi、Torii Sayuki、Suzuki Sentaro、Kunimura Ayako、Segawa Hiroyoshi、Kadota Aya、Ohkubo Takayoshi、Nozaki Kazuhiko、Miura Katsuyuki、Ueshima Hirotsugu、for the SESSA Research Group
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 27 Issue: 9 Pages: 995-1009
  • DOI: 10.5551/jat.51284
  • NAID: 130007894637
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2020-09-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteinuria and Reduced Estimated Glomerular Filtration Rate are Independently Associated With Lower Cognitive Abilities in Apparently Healthy Community-Dwelling Elderly Men in Japan: A Cross-sectional Study (2020)
  • Author(s): Fujiyoshi Akira、Miura Katsuyuki、Ohkubo Takayoshi、Miyagawa Naoko、Saito Yoshino、Miyazawa Itsuko、Shiino Akihiko、Kadota Aya、Kadowaki Sayaka、Hisamatsu Takashi、Torii Sayuki、Takashima Naoyuki、Tooyama Ikuo、Ueshima Hirotsugu
  • Journal Title: Journal of Epidemiology Volume: 30 Issue: 6 Pages: 244-252
  • DOI: 10.2188/jea.JE20180258
  • NAID: 130007852129
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2020-06-05
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation between musculoskeletal structure of the hand and primate locomotion: Morphometric and mechanical analysis in prehension using the cross- and triple-ratios (2020)
  • Author(s): Tamagawa Toshihiro、Lundh Torbjorn、Shigetoshi Kenji、Nitta Norihisa、Ushio Noritoshi、Inubushi Toshiro、Shiino Akihiko、Karlsson Anders、Inoue Takayuki、Mera Yutaka、Hino Kodai、Komori Masaru、Morikawa Shigehiro、Sawajiri Shuji、Naka Shigeyuki、Honma Satoru、Kimura Tomoko、Uchimura Yasuhiro、et al.
  • Journal Title: PLOS ONE Volume: 15 Issue: 5 Pages: 0232397-0232397
  • DOI: 10.1371/journal.pone.0232397
  • NAID: 120006797552
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 増大特集 人工知能と神経科学 人工知能を用いた神経画像診断 (2019)
  • Author(s): 椎野 顯彦
  • Journal Title: BRAIN and NERVE Volume: 71 Issue: 7 Pages: 733-748
  • DOI: 10.11477/mf.1416201345
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2019-07-01
• [Journal Article] Intracranial Artery Stenosis and Its Association With Conventional Risk Factors in a General Population of Japanese Men (2019)
  • Author(s): Shitara Satoshi、Fujiyoshi Akira、Hisamatsu Takashi、Torii Sayuki、Suzuki Sentarou、Ito Takahiro、Arima Hisatomi、Shiino Akihiko、Nozaki Kazuhiko、Miura Katsuyuki、Ueshima Hirotsugu、for the SESSA Research group
  • Journal Title: Stroke Volume: 50 Issue: 10 Pages: 2967-2969
  • DOI: 10.1161/strokeaha.119.025964
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association between excessive supraventricular ectopy and subclinical cerebrovascular disease: a population‐based study (2019)
  • Author(s): Hisamatsu T.、Miura K.、Fujiyoshi A.、Kunimura A.、Ito T.、Miyazawa I.、Torii S.、Shiino A.、Nozaki K.、Kanda H.、Arima H.、Ohkubo T.、Ueshima H.、on behalf of the Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) Research Group
  • Journal Title: European Journal of Neurology Volume: [Epub ahead of print] Issue: 9 Pages: 1219-1225
  • DOI: 10.1111/ene.13970
  • Peer Reviewed / Open Access
• [Journal Article] Magnetic Mixed Micelles Composed of a Non-Ionic Surfactant and Nitroxide Radicals Containing a D-Glucosamine Unit: Preparation, Stability, and Biomedical Application (2019)
  • Author(s): Nagura Kota、Takemoto Yusa、Yoshino Fumi、Bogdanov Alexey、Chumakova Natalia、Vorobiev Andrey、Imai Hirohiko、Matsuda Tetsuya、Shimono Satoshi、Kato Tatsuhisa、Komatsu Naoki、Tamura Rui
  • Journal Title: Pharmaceutics Volume: 11 Issue: 1 Pages: 42-42
  • DOI: 10.3390/pharmaceutics11010042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique Suerparamagnetic-like Behavior Observed in Non-pi-delocalized Nitroxide Diradical Compounds Showing Discotic Liquid Crystalline Phase. (2018)
  • Author(s): Takemoto, Y., Zaytseva, E., Suzuki, K., Yoshioka, N., Takanishi, Y., Funahashi, M., Uchida, Y., Akita, T., Park, J., Sato, S. Clevers, S., Coquerel, G., Mazhukin, D. G., Shimono, S., Sugiyama, M., Takahashi, H.,Yamauchi, J., Tamura, R.
  • Journal Title: Chemistry A European Journal Volume: 24 Issue: 65 Pages: 17293-17302
  • DOI: 10.1002/chem.201803534
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecuoar Mobility Effect on Magnetic Interactions in All-Organic Paramagnetic Liquid Crystal with Nitroxide Radical as a Hydrogen-Bonding Acceptor. (2018)
  • Author(s): Nakagami, S., Akita, T., Kiyohara, D., Uchida, Y., Tamura, R., Nishiyama, N.
  • Journal Title: The Journal of Physical Chemistry B Volume: 122 Issue: 29 Pages: 7409-7415
  • DOI: 10.1021/acs.jpcb.8b03839
  • Peer Reviewed
• [Presentation] ナノエマルジョンを用いた悪性神経膠腫の分子標的治療薬の開発 (2021)
  • Author(s): 椎野顯彦
  • Organizer: 第20回日本再生医療学会総会
• [Presentation] 統合失調症における脳形状の解析 (2019)
  • Author(s): 椎野顯彦
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] Hippocampal sparing ADの画像の特徴とAIによる診断 (2019)
  • Author(s): 椎野顯彦
  • Organizer: 第78回日本脳神経外科学会総会
• [Presentation] シンポジウム 2「最新のイメージング:脳循環の「今」を見る」人工知能を用いた画像解析技術による AD スペクトラムの予測 (2019)
  • Author(s): 椎野顯彦
  • Organizer: 日本脳循環代謝学会学術集会
• [Presentation] Hippocampal sparing ADのAIによる画像診断 (2019)
  • Author(s): 椎野顯彦
  • Organizer: 第38回日本認知症学会学術集会
• [Presentation] 治療継続中の認知症診療の注意点・問題点:再検査はどんな場合に必要か? (2019)
  • Author(s): 椎野顯彦
  • Organizer: 第３回日本脳神経外科認知症学会学術総会
  • Invited
• [Presentation] Preparation of Robust Metal-Free Magnetic Nanoemulsions Encapsulating Low-Molecular-Weight Nitroxide Radicals and Hydrophobic Drugs Directed Toward MRI-Visible Targeted Delivery System. (2018)
  • Author(s): K. Nagura, Y. Takemoto, S. Moronaga, Y. Uchida, S. Shimono, A. Shiino, K. Tanigaki, T. Amano, F. Yoshino, Y. Noda, S. Koizumi, N. Komatsu, T. Kato, J. Yamauchi, R. Tamura
  • Organizer: 27th International Liquid Crystal Conference
  • Int'l Joint Research
• [Presentation] Origin and Application of Unique Magnetic Properties of All-Organic Liquid Crystalline Compounds with a Particular Radical Structure. (2018)
  • Author(s): R. Tamura
  • Organizer: 3rd International Conference of Spin Physics, Spin chemistry and Spin Technology
  • Int'l Joint Research / Invited
• [Presentation] Preparation and Characterization of MRI-Visible Nitroxide-Based Nanoemulsions Encapsulating Hydrophobic Fluorophores or Drugs. (2018)
  • Author(s): K. Nagura, K. Sakamoto, S. Moronaga, A. Bogdanov, N. Chumakova, A. Kh. Vorobiev, H. Imai, T. Matsuda, A. Shiino, T. Amano, F. Yoshino, Y. Noda, S. Koizumi, S. Shimono, Y. Uchida, T. Kato, N. Komatsu, R. Tamura
  • Organizer: 第八回ナノカーボンバイオシンポジウム
• [Presentation] Unique Magnetic Properties of Organic Radical Soft Materials. (2018)
  • Author(s): R. Tamura
  • Organizer: 5th International Conference: Current Problems of Chemical Physics
  • Int'l Joint Research / Invited
• [Book] 人工知能を活用した脳MRI画像解析の理論と実践 (2019)
  • Author(s): 椎野顯彦
  • Total Pages: 256
  • Publisher: IDP出版
  • ISBN: 9784905130291