Elucidation and evasion of the immunogenicity induced by the repeated administration of the PEGylated nanocarrier

• Project/Area Number: 24790530
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: TOH Kazuko 東京大学, 医学(系)研究科(研究院), 研究員 (90342732)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ドラッグデリバリーシステム / ポリエチレングリコール / ABC現象 / 生体内共焦点顕微鏡 / 生体内リアルタイム共焦点顕微鏡 / 生体内リアルタイム蛍光共焦点顕微鏡

Outline of Final Research Achievements

In drug delivery system (DDS), the modification of nanocarriers with polyethylene glycol (PEGylated nanocarrier) is commonly used technique to improve blood circulation time. However, it is reported that repeated injection of PEGylated carrier cause ‘accelerated blood clearance (ABC)’ phenomenon in animal experiments. The ABC phenomenon is one of the barriers in the DDS development. In this study, the convenient evaluation method using in vivo confocal microscopy was established. After the investigation of various nanocarrier, the structure avoiding the ABC phenomenon was examined. The evaluation method of siRNA intact ratio including the nanocarrier and the inhibition method of photobleaching in case of long time measurement were also established.

Research Products

• [Journal Article] Multicompartment Micelles with Adjustable Poly(ethylene glycol) Shell for Efficient in Vivo Photodynamic Therapy (2014)
  • Author(s): Christopher V. Synatschke, Takahiro Nomoto, Horacio Cabral, Melanie Förtsch, Kazuko Toh, Yu Matsumoto, Kozo Miyazaki, Andreas Hanisch, Felix H. Schacher, Akihiro Kishimura, Nobuhiro Nishiyama, Axel H. E. Müller, and Kazunori Kataoka
  • Journal Title: ACS NANO Volume: 8(2) Pages: 1161-1172
  • Peer Reviewed
• [Journal Article] Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors (2014)
  • Author(s): Z. Ge, Q. Chen, K. Osada, X. Liu, T. A. Tockary, S. Uchida, A. Dirisala, T. Ishii, T. Nomoto, K. Toh, Y. Matsumoto, M. Oba, M. R. Kano, K. Itaka, K. Kataoka
  • Journal Title: Biomaterials Volume: 35 Issue: 10 Pages: 3416-3426
  • DOI: 10.1016/j.biomaterials.2013.12.086
  • Peer Reviewed
• [Journal Article] Multifunctional polyion complex micelle featuring enhanced stability, targetability, and endosome escapability for systemic siRNA delivery to subcutaneous model of lung cancer (2014)
  • Author(s): Hyun Jin Kim, Takehiko Ishii, Meng Zheng, Sumiyo Watanabe, Kazuko Toh, Yu Matsumoto, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka
  • Journal Title: Drug Delivery and Translational Research Volume: 4 Issue: 1 Pages: 50-60
  • DOI: 10.1007/s13346-013-0175-6
  • Peer Reviewed / Open Access
• [Journal Article] Tethered PEG Crowdedness Determining Shape and Blood Circulation Profile of Polyplex Micelle Gene Carriers (2013)
  • Author(s): Theofilus A. Tockary, Kensuke Osada, Qixian Chen, Kaori Machitani, Anjaneyulu Dirisala, Satoshi Uchida, Takahiro Nomoto, Kazuko Toh, Yu Matsumoto, Keiji Itaka, Koji Nitta, Kuniaki Nagayama, and Kazunori Kataoka
  • Journal Title: Macromolecules Volume: 46 Issue: 16 Pages: 6585-6592
  • DOI: 10.1021/ma401093z
  • Peer Reviewed
• [Journal Article] Evaluation of the Dynamics of Drug Delivery Systems (DDS) Using Intravital Real-Time Confocal Laser Scanning Microscopy (2012)
  • Author(s): 野本貴大、松本 有、藤 加珠子、R. James Christie、宮田完二郎、大庭 誠、Horacio Cabral、村上真美、福島重人、西山伸宏、片岡一則
  • Journal Title: YAKUGAKU ZASSHI Volume: 132 Issue: 12 Pages: 1347-1354
  • DOI: 10.1248/yakushi.12-00234-1
  • NAID: 130002489530
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2012-12-01
  • Peer Reviewed
• [Presentation] Intravital confocal microscopy assay for the evaluation of antioxidant capacity (2014)
  • Author(s): Yu Matsumoto, Kazuko Toh, Kazunori Kataoka and Tatsuya Yamasoba
  • Organizer: 37th ARO MidWinter Meeting
  • Place of Presentation: San Diego, California, USA
• [Presentation] Intravital Monitoring of Intact siRNA Using Fluorescence Resonance Energy Transfer (2013)
  • Author(s): Kazuko Toh, Takahiro Nomoto, Yu Matsumoto, Sumiyo Watanabe, Shigeto Fukushima, Hiroyuki Chaya, R. James Christie, Kanjiro Miyata, Nobuhiro Nishiyama, Kazunori Kataoka
  • Organizer: 40th annual meeting & exposition of the Controlled Release Society
  • Place of Presentation: Honolulu, Hawaii, U. S. A.
• [Presentation] Förster Resonance Energy Transferと生体内顕微鏡を用いたintact siRNAの定量的評価法の開発 (2013)
  • Author(s): 藤 加珠子, 野本 貴大, 松本 有, 渡邉 秀美代, 福島 重人, 茶谷 洋行, R. James Christie, 宮田 完二郎, 西山 伸宏, 片岡 一則
  • Organizer: 第35回日本バイオマテリアル学会大会
  • Place of Presentation: 東京都江戸川区船堀4-1-1 タワーホール船堀