Development of smart MRI contrast agents based on polymeric micelles to detect tumor microenvironment

• Project/Area Number: 25670010
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: NISHIYAMA Nobuhiro 東京工業大学, 資源化学研究所, 教授 (10372385)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 高分子ミセル / がん / イメージング / MRI / 低酸素領域 / 微小転移 / 診断

Outline of Final Research Achievements

To improve the accuracy of MR imaging, the development of tumor-specific MRI contrast agents have been strongly demanded. In this study, we have developed polymeric micelles composed of calcium phosphate core, which can exhibit dissolution responding to acidic pH environment in the tumor tissue and incorporated Mn2+ ions, an MRI contrast agent, into the micelles. Polymeric micelles could release Mn2+ ions selectively under the acidic conditions mimicking the tumor microenvironments, and the released Mn2+ ions showed T1 shortening through the interaction with proteins. The in vivo experiments revealed that Mn2+ ions-loaded micelles displayed remarkably enhanced tumor-specific contrast enhancement compared with clinically used MRI contrast agents. Also, the Mn2+ ions-loaded micelles have been demonstrated to be useful for MR imaging of tumor hypoxia and small metastases in the liver.

Research Products

• [Journal Article] Antibody fragment-conjugated polymeric micelles incorporating platinum drugs for targeted therapy of pancreatic cancer (2015)
  • Author(s): J. -Y. Ahn, Y. Miura, N. Yamada, T. Chida, X. Liu, A. Kim, R. Sato, R. Tsumura, Y. Koga, M. Yasunaga, N. Nishiyama, Y. Matsumura, H. Cabral, K. Kataoka
  • Journal Title: Biomaterials Volume: 39 Pages: 23-30
  • DOI: 10.1016/j.biomaterials.2014.10.069
  • Peer Reviewed
• [Journal Article] Light-induced cytosolic activation of reduction-sensitive camptothecin-loaded polymeric micelles for spatiotemporally controlled in vivo chemotherapy (2014)
  • Author(s): H.-C. Yen, H. Cabral, P. Mi, K. Toh, Y. Matsumoto, X. Liu, H. Koori, A. Kim, K. Miyazaki, Y. Miura, N. Nishiyama, K. Kataoka
  • Journal Title: ACS Nano Volume: 8 Issue: 11 Pages: 11591-11602
  • DOI: 10.1021/nn504836s
  • Peer Reviewed
• [Journal Article] Polymeric micelles loaded with platinum anticancer drugs target preangiogenic micrometastatic niches associated with inflammation (2014)
  • Author(s): H. Wu, H. Cabral, K. Toh, P. Mi, Y.-C. Chen, Y. Matsumoto, N. Yamada, X. Liu, H. Kinoh, Y. Miura, M. R. Kano, H. Nishihara, N. Nishiyama, K. Kataoka
  • Journal Title: J. Control. Release Volume: 189 Pages: 1-10
  • DOI: 10.1016/j.jconrel.2014.06.018
  • Peer Reviewed
• [Journal Article] Bundled assembly of helical nanostructures in polymeric micelles loaded with platinum drugs enhancing therapeutic efficiency against pancreatic tumor (2014)
  • Author(s): Y. Mochida, H. Cabral, Y. Miura, F. Albertini, S. Fukushima, K. Osada, N. Nishiyama, K. Kataoka
  • Journal Title: ACS Nano Volume: 8 Issue: 7 Pages: 6724-6738
  • DOI: 10.1021/nn500498t
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Three-layered polyplex micelle as a multifunctional nanocarrier platform for light-induced systemic gene transfer (2014)
  • Author(s): T. Nomoto, S. Fukushima, M. Kumagai, K. Machitani, Arnida, Y. Matsumoto, M. Oba, K. Miyata, K. Osada, N. Nishiyama, K. Kataoka
  • Journal Title: Nature Communications Volume: 5 Issue: 1 Pages: 3545-3545
  • DOI: 10.1038/ncomms4545
  • Peer Reviewed / Open Access
• [Journal Article] Hydrothermally synthesized PEGylated calcium phosphate nanoparticles incorporating Gd-DTPA for contrast enhanced MRI diagnosis of solid tumors (2014)
  • Author(s): P. Mi, D. Kokuryo, H. Cabral, M. Kumagai, T. Nomoto, I. Aoki, Y. Terada, A. Kishimura, N. Nishiyama, K. Kataoka
  • Journal Title: J. Control. Release Volume: 174 Pages: 63-71
  • DOI: 10.1016/j.jconrel.2013.10.038
  • Peer Reviewed
• [Journal Article] siRNA delivery from triblock copolymer micelles with spatially-ordered compartmants of PEG shell, siRNA-loaded intermediate layer, and hydrophobic core (2014)
  • Author(s): Hyun Jin Kim, Kanjiro Miyata, Takahiro Nomoto, Meng Zheng, Ahram Kim, Xueying Liu, Horacio Cabral, R. James Christie, Nobuhiro Nishiyama, Kazunori Kataoka
  • Journal Title: Biomaterials Volume: 35 Issue: 15 Pages: 4548-4556
  • DOI: 10.1016/j.biomaterials.2014.02.016
  • Peer Reviewed
• [Journal Article] Multicompartment micelles with adjustable poly (ethylene glycol) shell for efficient in vivo photodynamic therapy (2014)
  • Author(s): C. V. Synatschke, N. Nishiyama, et al.
  • Journal Title: ACS Nano Volume: (in press)(印刷中)(掲載確定) Issue: 2 Pages: 1161-1172
  • DOI: 10.1021/nn4028294
  • Peer Reviewed
• [Journal Article] Systemic siRNA delivery to a spontaneous pancreatic tumor model in transgenic mice by PEGylated calcium phosphate hybrid micelles (2014)
  • Author(s): F. Pittella, N. Nishiyama, et al.
  • Journal Title: J. Control. Release Volume: 178 Pages: 18-24
  • DOI: 10.1016/j.jconrel.2014.01.008
  • Peer Reviewed / Open Access
• [Journal Article] Elucidating the molecular mechanism for the intracellular trafficking and fate of block copolymer micelles and their components (2014)
  • Author(s): K. -S. Kato, N. Nishiyama, et al.
  • Journal Title: Biomaterials Volume: 35 Issue: 5 Pages: 1347-1358
  • DOI: 10.1016/j.biomaterials.2013.11.027
  • Peer Reviewed
• [Journal Article] Hydrothermally synthesized PEGylated calcium phosphate nanoparticles incorporating Gd-DTPA for contrast enhanced MRI diagnosis of solid tumors (2014)
  • Author(s): P. Mi, N. Nishiyama, et al.
  • Journal Title: J. Control. Release Volume: 136 Issue: 1 Pages: 157-163
  • DOI: 10.1021/ja406992w
  • Peer Reviewed
• [Journal Article] Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier (2013)
  • Author(s): Y. Miura, N. Nishiyama, et al.
  • Journal Title: ACS Nano Volume: 7 Issue: 10 Pages: 8583-8592
  • DOI: 10.1021/nn402662d
  • Peer Reviewed
• [Journal Article] Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. (2013)
  • Author(s): S. Deshayes, N. Nishiyama, et al.
  • Journal Title: J. Am. Chem. Soc. Volume: 135 Issue: 41 Pages: 15501-15507
  • DOI: 10.1021/ja406406h
  • Peer Reviewed
• [Journal Article] Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis (2013)
  • Author(s): H. Cabral, N. Nishiyama, et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 110 Issue: 28 Pages: 11397-11402
  • DOI: 10.1073/pnas.1301348110
  • Peer Reviewed
• [Journal Article] SPIO-PlCsome : Development of a highly sensitive and stealth-capable MRI nano-agent for tumor detection using SPIO-loaded unilamellar polyion complex vesicles (PICsomes) (2013)
  • Author(s): D. Kokuryo, N. Nishiyama, et al.
  • Journal Title: J. Control. Release Volume: 169 Issue: 3 Pages: 220-227
  • DOI: 10.1016/j.jconrel.2013.03.016
  • Peer Reviewed
• [Journal Article] Gd-DTPA-loaded polymer-metal complex micelles with high relaxivity for MR cancer imaging (2013)
  • Author(s): P. Mi, H. Cabrala, D. Kokuryo, M. Rafi, Y. Terada, I. Aoki, T. Saga, T. Ishii, N. Nishiyama, K. Kataoka
  • Journal Title: Biomaterials Volume: 34 Issue: 2 Pages: 492-500
  • DOI: 10.1016/j.biomaterials.2012.09.030
  • Peer Reviewed
• [Presentation] 生体イメージングを活用したナノDDS設計 (2014)
  • Author(s): 西山伸宏
  • Organizer: 疾患克服を目指したケミカルバイオフォトニクス技術 第87回日本生化学会大会
  • Place of Presentation: 京都国際会館, 京都市, 京都府
  • Year and Date: 2014-10-17
  • Invited
• [Presentation] 高分子ミセル型ナノ医薬品の研究開発 (2014)
  • Author(s): 西山伸宏
  • Organizer: 新製剤技術とエンジニアリングを考える会 第12回技術講演会
  • Place of Presentation: 京都国際会館, 京都市, 京都府
  • Year and Date: 2014-07-16
  • Invited
• [Presentation] Biological functionalities of polymeric micelle systems for targeting cancer (2014)
  • Author(s): N. Nishiyama
  • Organizer: The European Summit for Clinical Nanomedicine 2014 (6th CLINAM 2014)
  • Place of Presentation: Congress Center Basel, Basel, Switzerland
  • Year and Date: 2014-06-23
  • Invited
• [Presentation] 高分子ナノテクノロジーを基盤とするナノ医薬品の開発 (2014)
  • Author(s): 西山伸宏
  • Organizer: 第10回つくばがん遺伝子治療研究会
  • Place of Presentation: ステーションコンファレンス東京, 東京
  • Year and Date: 2014-06-20
  • Invited
• [Presentation] がんの診断・治療のための高分子ミセル型DDSの開発 (2014)
  • Author(s): 西山伸宏
  • Organizer: 本病院薬剤師会東北ブロック第４回学術大会
  • Place of Presentation: 仙台国際センター, 仙台市, 宮城県
  • Year and Date: 2014-05-31
  • Invited
• [Presentation] Development of supramolecular nanocarriers for cancer diagnosis and therapy (2014)
  • Author(s): N. Nishiyama
  • Organizer: Emerging Biomaterials 2014
  • Place of Presentation: KAIST Institute, Seoul, Korea
  • Year and Date: 2014-05-23
  • Invited
• [Presentation] がんの診断・治療のための高分子ミセル型DDSの開発 (2013)
  • Author(s): 西山 伸宏
  • Organizer: 製剤機械技術学会 第23回大会
  • Place of Presentation: ニッショーホール （東京都、港区）
  • Invited
• [Presentation] がんの革新的診断・治療のためのスマート機能型高分子ミセルの開発 (2013)
  • Author(s): 西山 伸宏
  • Organizer: BioJapan 2013
  • Place of Presentation: パシフィコ横浜 （神奈川県、横浜市）
  • Invited
• [Presentation] 高分子ナノテクノロジーによるがんの診断・治療システムの創製 (2013)
  • Author(s): 西山 伸宏
  • Organizer: 東京工業大学 バイオマテリアルシンポジウム
  • Place of Presentation: 東京工業大学すずかけホール （神奈川県、横浜市）
  • Invited
• [Presentation] Development of polymeric micellar nanocarriers for cancer diagnosis and therapy (2013)
  • Author(s): N. Nishiyama
  • Organizer: The 4th Asian Biomaterials Congress
  • Place of Presentation: The Hong Kong University of Science and Technology (Hong Kong, China)
  • Invited
• [Presentation] Development of supramolecular nanocarriers for cancer diagnosis and therapy (2013)
  • Author(s): N. Nishiyama
  • Organizer: 2013 International Advanced Drug Delivery Symposium
  • Place of Presentation: ITRI （Taiwan）
  • Invited
• [Book] ナノメディシン-副作用のない理想的な医薬品の実現に向けて (2015)
  • Author(s): 西山伸宏
  • Publisher: 現代化学 東京化学同人
• [Book] ナノメディシンによる革新的医薬品の実現に向けて (2014)
  • Author(s): 西山伸宏
  • Publisher: BIO Clinica 北隆館／ニューサイエンス社
• [Book] 高分子ナノテクノロジーを利用したナノメディシンの開発 (2014)
  • Author(s): 西山伸宏
  • Publisher: 最新医学 最新医学社
• [Book] 高分子ナノパーティクルを用いたDDSの展開 (2014)
  • Author(s): 西山伸宏
  • Publisher: 医薬ジャーナル 医薬ジャーナル社
• [Book] 標的指向性DDS開発の新展開 メディカルサイエンスダイジェスト(Vol.40 No.2)「DDS技術の進歩と医療応用」 (2014)
  • Author(s): 西山 伸宏
  • Total Pages: 106
  • Publisher: ニューサイエンス社
• [Remarks] 東京工業大学 資源化学研究所 西山研究室ホームページ
  • URL: http://www.res.titech.ac.jp
• [Remarks] 東京工業大学 資源化学研究所 西山研究室ホームページ
  • URL: http://www.bmw.res.titech.ac.jp