脂質修飾c-di-GMP 封入MENDによるガン免疫治療

• Project/Area Number: 26830101
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Aichi Institute of Technology
• Principal Investigator: 兵藤 守 愛知工業大学, 工学部, 講師 (30548186)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: がん / 免疫 / DDS / リポソーム / 核酸 / ガン免疫療法 / アジュバント / ドラッグデリバリーシステム / c-di-GMP / YSK05

Outline of Annual Research Achievements

c-di-GMPを用いるガン免疫療法の確立を目指し、研究を行った。
申請者は前年度に c-di-GMP をYSK05リポソームに封入し、マウスに免疫することで癌細胞のマウスへの生着及び増殖を妨げる、すなわち、ガン治療効果があることをin vivoに置いて示すことに成功した。しかし、本方はovalbumin (以下 OVA) たんぱく質を抗原に、癌細胞表面にOVAを発現させたものを生着させようとしたため、成果が出やすい系であるという指摘はあった。
そこで本年は、より実際の薬として使用する条件、すなわち、このような抗原を使用せず、癌細胞増殖阻害効果を示すことができるかどうかについて検討を行った。
B16-F10 細胞を用い、マウス肺転移がんモデルを作成し、そこへc-di-GMP/YSK05 liposome を導入したところ、1型インターフェロンの誘導、NK細胞の活性化を経て、有意な癌細胞の増殖阻害効果を示すことが明らかになった。この成果はc-di-GMP が治療薬として免疫を活性化し、様々ながんを駆逐することができることを示唆する有益な成果であると言える。

Research Products

• [Journal Article] A lipid nanoparticle for the efficient delivery of siRNA to dendritic cells. (2016)
  • Author(s): Warashina S, Nakamura T, Sato Y, Fujiwara Y, Hyodo M, Hatakeyama H, Harashima H
  • Journal Title: J Control Release. Volume: 225 Pages: 183-191
  • DOI: 10.1016/j.jconrel.2016.01.042
  • NAID: 120005981350
  • Peer Reviewed
• [Journal Article] Relationship Between the Physicochemical Properties of Lipid Nanoparticles and the Quality of siRNA Delivery to Liver Cells (2016)
  • Author(s): Yusuke Sato, Hiroto Hatakeyama, Mamoru Hyodo, Hideyoshi Harashima
  • Journal Title: Molecular Therapy Volume: 24 Issue: 4 Pages: 788-795
  • DOI: 10.1038/mt.2015.222
  • NAID: 120005906929
  • Peer Reviewed
• [Journal Article] Novel pH-sensitive multifunctional envelope-type nanodevice for siRNA-based treatments for chronic HBV infection (2016)
  • Author(s): Yamamoto, N. Sato, Y. Munakata, T. Kakuni, M. Tateno, C. Sanada, T. Hirata, Y. Murakami, S. Tanaka, Y. Chayama, K. Hatakeyama, H. Hyodo, M. Harashima, H. Kohara, M.
  • Journal Title: Journal of hepatology Volume: 64 Issue: 3 Pages: 547-455
  • DOI: 10.1016/j.jhep.2015.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma. (2015)
  • Author(s): Nakamura T, Miyabe H, Hyodo M, Sato Y, Hayakawa Y, Harashima H.
  • Journal Title: J Control Release Volume: 216 Pages: 149-157
  • DOI: 10.1016/j.jconrel.2015.08.026
  • NAID: 120005853062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] New drug delivery system for liver sinusoidal endothelial cells for ischemia-reperfusion injury. (2015)
  • Author(s): Sano N, Tamura T, Toriyabe N, Nowatari T, Nakayama K, Tanoi T, Murata S, Sakurai Y, Hyodo M, Fukunaga K, Harashima H, Ohkohchi N.
  • Journal Title: World J Gastroenterol. Volume: 21 Issue: 45 Pages: 12778-12786
  • DOI: 10.3748/wjg.v21.i45.12778
  • Peer Reviewed
• [Journal Article] Mitochondrial delivery of Coenzyme Q via systemic administration using a MITO-Porter prevents ischemia/reperfusion injury in the mouse liver. (2015)
  • Author(s): Yamada Y, Nakamura K, Abe J, Hyodo M, Haga S, Ozaki M, Harashima H.
  • Journal Title: Journal of controlled release Volume: 10 Pages: 86-95
  • DOI: 10.1016/j.jconrel.2015.06.037
  • Peer Reviewed
• [Journal Article] RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system (2014)
  • Author(s): Yu Sakurai, Hiroto Hatakeyama, Yusuke Sato, Mamoru Hyodo, Hidetaka Akita, Noritaka Ohga, Kyoko Hida, Hideyoshi Harashima
  • Journal Title: J. Control. Release Volume: 173 Pages: 110-118
  • DOI: 10.1016/j.jconrel.2013.10.003
  • Peer Reviewed
• [Journal Article] A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy. (2014)
  • Author(s): Hiroko Miyabe, Mamoru Hyodo, Takashi Nakamura, Yusuke Sato, Yoshihiro Hayakawa, and Hideyoshi Harashima
  • Journal Title: J. Controlled Release Volume: 184 Pages: 20-27
  • DOI: 10.1016/j.jconrel.2014.04.004
  • NAID: 120005512017
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification and expression of troponin T, a new marker on the surface of cultured tumor endothelial cells by aptamer ligand (2014)
  • Author(s): Ara MN., Hyodo M., Ohga N., Akiyama K., Hida K., Hida Y., Shinohara N., Harashima H
  • Journal Title: Cancer Med Volume: 3 Issue: 4 Pages: 825-834
  • DOI: 10.1002/cam4.260
  • Peer Reviewed / Open Access
• [Journal Article] An aptamer ligand based liposomal nanocarrier system that targets tumor endothelial cells (2014)
  • Author(s): Ara MN, Matsuda T, Hyodo M, Sakurai Y, Hatakeyama H, Ohga N, Hida K, Harashima H
  • Journal Title: Biomaterials Volume: 35 Issue: 25 Pages: 7110-7120
  • DOI: 10.1016/j.biomaterials.2014.04.087
  • NAID: 120005512022
  • Peer Reviewed
• [Journal Article] RNA aptamers for targeting mitochondria using a mitochondria based SELEX method. (2014)
  • Author(s): Yuri Tawaraya, Mamoru Hyodo, Yuma Yamada, Hideyoshi Harashima
  • Journal Title: Biol. Pharm. Bull. Volume: 37 Pages: 1411-1415
  • NAID: 130004677537
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] c-di-GMP Enhances Protective Innate Immunity in a Murine Model of Pertussis. (2014)
  • Author(s): S. Elahi, J. Van Kessel, T. G. Kiros, S. Strom, Y Hayakawa, M.Hyodo, L. A. Babiuk, and V. Gerdts
  • Journal Title: PLOS ONE Volume: 9 Issue: 10 Pages: e109778-e109778
  • DOI: 10.1371/journal.pone.0109778
  • Peer Reviewed / Open Access / Acknowledgement Compliant