Photo-immune therapy with liposomally formulated phospholipid-conjugated indocyanine green for glioblastoma

• Project/Area Number: 25462244
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Chiba University
• Principal Investigator: IWADATE Yasuo 千葉大学, 医学(系)研究科(研究院), 准教授 (70272309)
• Co-Investigator(Kenkyū-buntansha): TAMURA Yutaka 千葉大学, 大学院医学研究院, 准教授 (50263174)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 脳腫瘍 / グリオーマ / 光線力学療法 / 抗腫瘍免疫 / ICG / リポソーム / CD8 / 温熱療法 / ICG-Liposome / glioma / 抗原提示 / CTL

Outline of Final Research Achievements

We developed a clinically translatable nanoparticle that is liposomally formulated phospholipid-conjugated indocyanine green (LP-iDOPE) which accumulates in tumor tissues. This is near infrared (NIR) fluorescent liposomes for optical imaging and nanoparticle drug carrier as well as a photosensitizer which releases heat and singlet oxygen to kill cancer cells. A significant tumor growth retardation and a significant survival prolongation were observed in a rat glioma model. Histopathological examination showed inductions of both apoptosis and necrosis, and also accumulations of CD8 T-cell and macrophage/microglia. This efficacy was not observed in immunocompromised nude rats, and a mild hyperthermia alone at 45 degree did not show any therapeutic effects. These results collectively showed that the new nanoparticle LP-iDOPE combined with NIR irradiation can efficiently induce tumor-specific immune reaction, and is a promising therapeutic agent for malignant gliomas.

Research Products

• [Journal Article] Molecular imaging of 1p/19q deletion in oligodendroglial tumor with 11C-Methionine positron emission tomography. (2016)
  • Author(s): Iwadate Y, Shinozaki N (Co-first), Matsutani T, Uchino Y, Saeki N.
  • Journal Title: J Neurl Neurosurg Psy Volume: 印刷中 Issue: 9 Pages: 1016-1021
  • DOI: 10.1136/jnnp-2015-311516
  • Peer Reviewed / Open Access
• [Journal Article] Liposomally formulated phospholipid-conjugated indocyanine green for intra-operative brain tumor detection and resection. (2015)
  • Author(s): Suganami A, Iwadate Y, Shibata S, Yamashita M, Tanaka T, Shinozaki N, Aoki I, Saeki N, Shirasawa H, Okamoto Y, Tamura Y.
  • Journal Title: Int J Pharm. Volume: 496 Issue: 2 Pages: 401-406
  • DOI: 10.1016/j.ijpharm.2015.10.001
  • Peer Reviewed / Open Access
• [Journal Article] IDH1 mutation is prognostic for diffuse astrocytoma but not low-grade oligodendrogliomas in patients not treated with early radiotherapy. (2015)
  • Author(s): Iwadate Y, Matsutani T, Hirono S, Ikegami S, Shinozaki N, Saeki N.
  • Journal Title: J Neurooncol Volume: 124 Issue: 3 Pages: 493-500
  • DOI: 10.1007/s11060-015-1863-5
  • Peer Reviewed
• [Journal Article] Near-infrared-fluorescence imaging of lymph nodes by using liposomally formulated indocyanine green derivatives (2014)
  • Author(s): Taro Toyota, Hiromichi Fujito, Akiko Suganami, Tomoki Ouchi, Aki Ooishi, Akira Aoki, Kazutaka Onoue, Yutaka Muraki, Tomoyuki Madono, Masanori Fujinami, Yutaka Tamura, Hideki Hayashi
  • Journal Title: Bioorganic & Medical Chemistry Volume: 22 Issue: 2 Pages: 721-727
  • DOI: 10.1016/j.bmc.2013.12.026
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of the interaction between spermidine and G-G mismatch containing acceptor stemin tRNAIle: Molecular modeling, density functional theory, and molecular dynamics study. (2013)
  • Author(s): Hayashi, Y. et al.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 441 Issue: 4 Pages: 999-1004
  • DOI: 10.1016/j.bbrc.2013.11.016
  • Peer Reviewed
• [Journal Article] Effectiveness of deep vein thrombosis screening on admission to a rehabilitation hospital: a prospective study in 1043 consecutive patients (2013)
  • Author(s): Wada M, Iizuka M, Iwadate Y, et al.
  • Journal Title: Thromb Res Volume: 131 Issue: 6 Pages: 487-492
  • DOI: 10.1016/j.thromres.2013.04.022
  • Peer Reviewed
• [Presentation] 11C-methionine PETとglioma予後予測因子の相関について (2015)
  • Author(s): 篠崎夏樹、岩立康男、内野福生、吉川京燦、佐伯直勝
  • Organizer: 第74回日本脳神経外科学会学術総会
  • Place of Presentation: ロイトンホテル（北海道、札幌市））
  • Year and Date: 2015-10-14
• [Presentation] 膠芽腫における低酸素環境によるゲノムDNAの脱メチル化 (2015)
  • Author(s): 岩立康男、松谷智郎、廣野誠一郎、篠崎夏樹、菅波晃子、田村 裕、佐伯直勝
  • Organizer: 第74回日本脳神経外科学会学術総会
  • Place of Presentation: ロイトンホテル（北海道、札幌市）
  • Year and Date: 2015-10-14
• [Presentation] 血清抗グリオーマ抗原自己抗体によるグリオーマ早期診断の可能性 (2015)
  • Author(s): 岩立康男、松谷智郎、篠崎夏樹、葉山順代、足立明彦、日和佐隆樹、佐伯直勝
  • Organizer: 第18回日本分子脳神経外科学会
  • Place of Presentation: アクトシティ浜松コングレスセンター（静岡県、浜松市）
  • Year and Date: 2015-08-28
• [Presentation] Logical refinement of therapeutic targets for glioblastoma based on multidisciplinary proteomic approaches (2015)
  • Author(s): Iwadate Y, Matsutani T, Hiwasa T, Saeki N
  • Organizer: Drug Discovery and Therapy World Conference
  • Place of Presentation: Boston, USA
  • Year and Date: 2015-07-22
  • Int'l Joint Research / Invited
• [Presentation] 5-aminolevulinic acid (5-ALA) contributes to precise histopathological diagnosis in gliomas (2015)
  • Author(s): 松谷智郎、廣野誠一郎、岩立康男、佐伯直勝
  • Organizer: 第33回日本脳腫瘍病理学会
  • Place of Presentation: JRホテルクレメント高松（香川県、高松市）
  • Year and Date: 2015-05-29
• [Presentation] インドシアニングリーンを組み込んだ新たなナノ粒子によるラットグリオーマモデルの光線力学療法 (2013)
  • Author(s): 篠崎夏樹、岩立康男、田村裕、他
  • Organizer: 第72回日本脳神経外科学会学術総会
  • Place of Presentation: 横浜
• [Presentation] リポソーム化したリン脂質修飾型インドシアニングリーンによるラット神経膠腫の光線力学療法 (2013)
  • Author(s): 篠崎夏樹、岩立康男、田村裕、他
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] ICGを組み込んだnano-particleであるLP-iDOPEを用いたrat glioma modelの治療 (2013)
  • Author(s): 篠崎夏樹、岩立康男、田村裕、他
  • Organizer: 第9回日本脳神経光線力学学会
  • Place of Presentation: 仙台