Development of indocyanine green-binding anti-cancer drug with specific accumulation in hepatocellular carcinoma

• Project/Area Number: 17H03595
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: Hasegawa Kiyoshi 東京大学, 医学部附属病院, 教授 (20292906)
• Co-Investigator(Kenkyū-buntansha): 國土 典宏 国立研究開発法人国立国際医療研究センター, その他部局等, 理事長 (00205361) ; 浦野 泰照 東京大学, 大学院薬学系研究科(薬学部), 教授 (20292956) ; 稲垣 善則 東京大学, 医学部附属病院, 助教 (40733390)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 肝細胞癌 / 抗癌剤 / ドラッグデリバリーシステム / 物質代謝

Outline of Final Research Achievements

The present study aimed to develop the new anti-cancer drug for hepatocellular carcinoma (HCC) by utilizing indocyanine green (ICG) that has the characteristics of accumulating in HCC. The newly synthesized ICG-Gemcitabine (ICG-Gem) accumulated in HCC tissue as well as ICG. The cytotoxicity of ICG-Gem to normal cells was weaker than that of gemcitabine (Gem) while the cytotoxicity to HCC cells was comparable. The direct injection of ICG-Gem to mouse tumor xenograft had the effect to inhibit the tumor growth compared with that of Gem. These results suggest that ICG-Gem may be available for the new anti-cancer drug of hepatic arterial infusion chemotherapy.

Academic Significance and Societal Importance of the Research Achievements

本研究では、肝細胞癌（HCC）組織におけるインドシアニングリーン（ICG）の特異的滞留性がHCCへの抗癌剤の送達に有用であることを示唆した。この成果は、非特異的な毒性の発生という課題を抱えており、開発が立ち遅れているHCCに対する新規抗癌剤の開発に貢献するものと期待される。また、ICGの特異的滞留性機構の解明は、HCC細胞における特有の代謝機構の存在を立証することにつながり、学術的に意義深い。

Research Products

• [Journal Article] Albumin?Indocyanine Green Evaluation (ALICE) grade combined with portal hypertension to predict post‐hepatectomy liver failure (2019)
  • Author(s): Shirata Chikara、Kokudo Takashi、Arita Junichi、Akamatsu Nobuhisa、Kaneko Junichi、Sakamoto Yoshihiro、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 8 Pages: 942-949
  • DOI: 10.1111/hepr.13327
  • Peer Reviewed / Open Access
• [Journal Article] Albumin-indocyanine green evaluation model in Western population. (2019)
  • Author(s): Shirata C, Hasegawa K.
  • Journal Title: Journal of Hepatobiliary Pancreatic Science. Volume: 26 Issue: 9
  • DOI: 10.1002/jhbp.651
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Preoperative Liver Function for Surgical Decision Making in Patients with Hepatocellular Carcinoma (2019)
  • Author(s): Kokudo Takashi、Hasegawa Kiyoshi、Shirata Chikara、Tanimoto Meguri、Ishizawa Takeaki、Kaneko Junichi、Akamatsu Nobuhisa、Arita Junichi、Demartines Nicolas、Uldry Emilie、Kokudo Norihiro、Halkic Nermin
  • Journal Title: Liver Cancer Volume: 8 Issue: 6 Pages: 447-456
  • DOI: 10.1159/000501368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel liver-specific fluorescent anti-cancer drug delivery system using indocyanine green (2019)
  • Author(s): Inagaki Yoshinori、Kokudo Takashi、Kamiya Mako、Uno Shin-nosuke、Sato Masumitsu、Kaneko Junichi、Kokudo Norihiro、Urano Yasuteru、Hasegawa Kiyoshi
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3044-3044
  • DOI: 10.1038/s41598-019-39269-0
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of indocyanine green-fluorescence imaging for real-time visualization of pancreas neuroendocrine tumor and cystic neoplasm (2018)
  • Author(s): Shirata Chikara、Kawaguchi Yoshikuni、Kobayashi Kosuke、Kobayashi Yuta、Arita Junichi、Akamatsu Nobuhisa、Kaneko Junichi、Sakamoto Yoshihiro、Kokudo Norihiro、Hasegawa Kiyoshi
  • Journal Title: Journal of Surgical Oncology Volume: 118 Issue: 6 Pages: 1012-1020
  • DOI: 10.1002/jso.25231
  • Peer Reviewed
• [Journal Article] Innovative treatment for hepatocellular carcinoma (HCC) (2018)
  • Author(s): Kaneko Junichi、Kokudo Takashi、Inagaki Yoshinori、Hasegawa Kiyoshi
  • Journal Title: Translational Gastroenterology and Hepatology Volume: 3 Pages: 78-78
  • DOI: 10.21037/tgh.2018.10.04
  • Peer Reviewed / Open Access
• [Journal Article] Near-infrared photothermal/photodynamic therapy with indocyanine green induces apoptosis of hepatocellular carcinoma cells through oxidative stress (2017)
  • Author(s): Shirata Chikara、Kaneko Junichi、Inagaki Yoshinori、Kokudo Takashi、Sato Masumitsu、Kiritani Sho、Akamatsu Nobuhisa、Arita Junichi、Sakamoto Yoshihiro、Hasegawa Kiyoshi、Kokudo Norihiro
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 13958-13958
  • DOI: 10.1038/s41598-017-14401-0
  • Peer Reviewed / Open Access
• [Journal Article] Portal vein territory identification using indocyanine green fluorescence imaging: Technical details and short-term outcomes (2017)
  • Author(s): Kobayashi Yuta、Kawaguchi Yoshikuni、Kobayashi Kosuke、Mori Kazuhiro、Arita Junichi、Sakamoto Yoshihiro、Hasegawa Kiyoshi、Kokudo Norihiro
  • Journal Title: Journal of Surgical Oncology Volume: 116 Issue: 7 Pages: 921-931
  • DOI: 10.1002/jso.24752
  • Peer Reviewed / Open Access
• [Presentation] Mutation analysis of OATP1B3 in cases with indocyanine green excretory defect. (2019)
  • Author(s): Tanimoto M, Kokudo T, Arita J, Ishizawa T, Akamatsu N, Kaneko J, Hasegawa K.
  • Organizer: 第31回日本肝胆膵外科学会・学術集会
• [Presentation] Wide applications of intraoperative fluorescence imaging for prevention of complications after laparoscopic hepato-biliary-pancreatic surgery. (2019)
  • Author(s): Watanabe G, Ishizawa T, Hayasaka M, Morito M, Ito D, Kokudo T, Akamatsu N, Kaneko J, Arita J, Hasegawa K.
  • Organizer: 第31回日本肝胆膵外科学会・学術集会
• [Presentation] Roles of Indocyanine Green in Surgical Treatments for Hepatocellular Carcinoma. (2019)
  • Author(s): Ishizawa T, Ichida A, Akamatsu N, Kaneko J, Arita J, Hasegawa K.
  • Organizer: APPLE2019
  • Int'l Joint Research
• [Presentation] Near-Infrared Photothermal/Photodynamic Therapy with Indocyanine Green for Hepatocellular Carcinoma Cells. (2019)
  • Author(s): Shirata C, Kaneko J, Inagaki Y, Kokudo T, Ishizawa T, Akamatsu N, Arita J, Kokudo N.
  • Organizer: APPLE2019
  • Int'l Joint Research
• [Presentation] 肝細胞癌に対するICG蛍光法を用いた系統的肝切除術 (2019)
  • Author(s): 國土 貴嗣, 石沢 武彰, 渡邉 元己, 真木 治文, 市田 晃彦, 金子 順一, 赤松 延久, 有田 淳一, 長谷川 潔
  • Organizer: 第81回日本臨床外科学会総会
• [Presentation] 肝癌蛍光イメージング：肝切除への臨床応用と光線力学的治療の可能性 (2019)
  • Author(s): 石沢 武彰, 白田 力, 稲垣 善則, 國土 貴嗣, 廣吉 淳子, 市田 晃彦, 赤松 延久, 有田 淳一, 金子 順一, 神谷 真子, 浦野 泰照, 長谷川 潔
  • Organizer: 第81回日本臨床外科学会総会
• [Presentation] 肝胆膵外科における術中蛍光イメージングの現況と展望 (2019)
  • Author(s): 石沢 武彰, 有田 淳一, 長谷川 潔
  • Organizer: JDDW2019KOBE
• [Presentation] ICG不耐症を疑う症例におけるOATP1B3の発現解析 (2018)
  • Author(s): 谷本芽弘理、國土貴嗣、有田淳一、稲垣善則、赤松延久、金子順一、阪本良弘、長谷川潔
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] Expression of OATP1B3 in Cases with Indocyanine Green Excretory Defect (2018)
  • Author(s): Tanimoto M, Kokudo T, Arita J, Inagaki Y, Akamatsu N, Kaneko J, Sakamoto Y, Hasegawa K
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research
• [Presentation] Low Expression of OATP1B3 Causes Delay in Indocyanine Green Clearance (2018)
  • Author(s): Tanimoto M, Kokudo T, Arita J, Inagaki Y, Akamatsu N, Kaneko J, Sakamoto Y, Hasegawa K
  • Organizer: APASL(the Asian Pacific Association for the Study of the Liver) Single Topic Conference on HCC: Strategy in the New Era
  • Int'l Joint Research
• [Presentation] Clearance / Retention / Metabolism tests including ICG (2018)
  • Author(s): Hasegawa K
  • Organizer: 13th IHPBA World Congress
  • Int'l Joint Research / Invited
• [Presentation] ICGを中心とした肝細胞癌の新規術前肝機能評価指標の開発 (2018)
  • Author(s): 國土貴嗣、谷本芽弘理、白田力、有田淳一、金子順一、赤松延久、阪本良弘、長谷川潔
  • Organizer: 第54回日本肝癌研究会
• [Presentation] 肝細胞癌に対する新規治療としてのIndocyanine greenを用いた光線力学療法の作用メカニズムの検討 (2018)
  • Author(s): 早阪誠、金子順一、白田力、稲垣善則、國土貴嗣、有田淳一、赤松延久、阪本良弘、長谷川潔
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] ICG Navigation in HPB Surgery (2018)
  • Author(s): Hasegawa K
  • Organizer: IHPBA India 2018
  • Int'l Joint Research / Invited
• [Presentation] Surgical resection for HCC with macroscopic vascular invasion (2017)
  • Author(s): Hasegawa K
  • Organizer: IASGO 2017 (27th World Congress of the International Association of Surgeons)
  • Int'l Joint Research
• [Presentation] Assessment of preoperative liver function in patients with hepatocellular carcinoma - The ALICE Grade (2017)
  • Author(s): Kokudo T, Shirata C, Miyazaki Y, Amikura K, Yamaguchi T, Arita J, Kaneko J, Akamatsu N, Sakamoto Y, Takahashi A, Sakamoto H, Kokudo N, Hasegawa K
  • Organizer: IASGO 2017 (27th World Congress of the International Association of Surgeons)
  • Int'l Joint Research
• [Presentation] ICG-guided hepatectomy (2017)
  • Author(s): Hasegawa K, Kawaguchi Y, Yamashita S, Kokudo T, Togashi J, Arita J, Kaneko J, Akamatsu N, Sakamoto Y, Kokudo N.
  • Organizer: 11th International Minimal Invasive Surgery Symposium and 7th CME Course of IASGO
  • Int'l Joint Research / Invited
• [Presentation] Intraoperative use ICG in liver surgery (2017)
  • Author(s): Hasegawa K
  • Organizer: APDW2017 (Asian Pacific Digestive Week)
  • Int'l Joint Research / Invited