Development of liposomal plastic antibody for novelDDS and applicaion for sepsis treatment

• Project/Area Number: 16K15111
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Physical pharmacy
• Research Institution: University of Shizuoka
• Principal Investigator: Oku Naoto 静岡県立大学, 薬学部, 教授 (10167322)
• Co-Investigator(Kenkyū-buntansha): 浅井 知浩 静岡県立大学, 薬学部, 准教授 (00381731) ; 清水 広介 浜松医科大学, 学内共同利用施設等, 准教授 (30423841) ; 小出 裕之 静岡県立大学, 薬学部, 助教 (60729177)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: リポソーム / ノンインプリント人工抗体 / プラスチック抗体 / 敗血症 / ヒストン / 毒素の中和 / 膜流動性 / ポリマー粒子 / ポリマーリガンド / 毒素 / 中和活性 / 薬物送達 / 人工抗体 / 解毒

Outline of Final Research Achievements

Neutralization of toxins which entered into bloodstream, is important for curing several disorders. The gold standard to neutralize macromolecular toxins is antibodies, even though they have several problems such as high cost for preparation, and biological and chemical instability. On the other hand, plastic antibodies synthesized with monomers having appropriate functional groups may substitute with antibodies. Although they also have sereral problems such as short blood circulation time and not so high target-neutralizing activity.
By the way, decoration with polymer ligands (PLs) on liposomal membrane, enables appropriate interaction between PLs and target toxins through the lateral diffusion of PLs on the membrane. For obtaining the proof of concept, we used histones, major mediators of sepsis, as model toxins in the present study, and the results of our study suggested that abiotic PLs on the lipid nanoparticles can be useful for capturing and neutralizing target toxins.

Research Products

• [Int'l Joint Research] University of California Irvine(U.S.A.)
• [Journal Article] Rational designing of an antidote nanoparticle decorated with abiotic polymer ligands for capturing and neutralizing target toxins. (2017)
  • Author(s): Koide H, Tsuchida H, Nakamoto M, Okishima A, Ariizumi S, Kiyokawa C, Asai T, Hoshino Y, Oku N
  • Journal Title: J. Control. Release. Volume: 68 Pages: 335-342
  • DOI: 10.1016/j.jconrel.2017.10.028
  • Peer Reviewed
• [Journal Article] A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165) (2017)
  • Author(s): Hiroyuki Koide,Keiichi Yoshimatsu,Yu Hoshino,Shih-Hui Lee,Ai Okajima,Saki Ariizumi, Yudai Narita,Yusuke Yonamine,Adam C. Weisman,Yuri Nishimura,Naoto Oku,Yoshiko Miura,Kenneth J. Shea
  • Journal Title: Nature Chemistry Volume: 9 Issue: 7 Pages: 715-722
  • DOI: 10.1038/nchem.2749
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] がん治療に向けたプラスチック人工抗体の開発 (2017)
  • Author(s): 小出裕之、有泉早紀、星野友、三浦佳子、Kenneth J. Shea、奥直人：
  • Organizer: 第81回日本生化学会中部支部例会・シンポジウム
• [Presentation] 生体内で標的生体高分子を吸着するPEG修飾ポリマーナノ粒子の設計 (2017)
  • Author(s): 林直希、小出裕之、有泉早紀、清川千秋、土田大貴、沖嶋杏奈、香門悠里、星野友、Kenneth J. Shea、奥直人
  • Organizer: 第33回日本DDS学会学術集会
• [Presentation] VEGFを吸着し中和する多官能性合成ポリマーナノ粒子を用いたがん治療 (2017)
  • Author(s): 小出裕之、有泉早紀、沖嶋杏奈、星野友、三浦佳子、Kenneth J. Shea、奥直人
  • Organizer: 第33回日本DDS学会学術集会
• [Presentation] 標的高分子を吸着しその機能を中和する合成ポリマーナノ粒子の開発と難治性疾患治療への応用 (2017)
  • Author(s): 小出裕之
  • Organizer: 第11回QCM研究会
• [Presentation] VEGFと結合して中和する多官能性ポリマーナノ粒子の開発とがん治療へ応用 (2017)
  • Author(s): 小出裕之、有泉早紀、星野友、三浦佳子、シェアケネス、奥直人
  • Organizer: 第66回高分子討論会
• [Presentation] 敗血症治療に向けたPEG含有ポリマーナノ粒子の開発 (2017)
  • Author(s): 林直希、小出裕之、沖島杏奈、星野友、シェアケネスジェイ、奥直人
  • Organizer: 第66回高分子討論会
• [Presentation] Development of long-circulating polymer nanoparticles for sepsis treatment. (2017)
  • Author(s): N. Hayashi, H. Koide, A. Okishima, Y. Kamon, Y. Hoshino, K.J. Shea, N. Oku
  • Organizer: American Association of Pharmaceutical Scientists Meeting and Exposition
• [Presentation] Development of polymer nanoparticles with affinity to a vascular endothlial growth factor for cancer therapy (2017)
  • Author(s): H. Koide, S. Ariizumi, Y. Hoshino, Y. Miura, S.J. Kenneth, N. Oku
  • Organizer: American Association of Pharmaceutical Scientists Meeting and Exposition
• [Presentation] 生体内で標的毒素を中和するポリマーリガンド修飾脂質ナノ粒子の開発 (2016)
  • Author(s): 59.土田大貴、小出裕之、仲本正彦、沖嶋杏奈、有泉早紀、清川千秋、浅井知浩、星野 友、奥 直人
  • Organizer: 第38回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2016-11-17
• [Presentation] Multifunctional polymer-modified liposomes that capture and neutralize toxic protein, histones. (2016)
  • Author(s): 48.Hiroki Tsuchida, Hiroyuki Koide, Masahiko Nakamoto, Anna Okishima, Saki Ariizumi, Chiaki Kiyokawa, Tomohiro Asai, Yu Hoshino, Naoto Oku
  • Organizer: International Conference on Nanomedicine and Nanobiotechnoloty
  • Place of Presentation: Paris, France
  • Year and Date: 2016-09-29
• [Presentation] 生体内で標的毒素を中和する脂質ナノ粒子解毒剤“Nano-dotes”の開発 (2016)
  • Author(s): 45.土田大貴、小出裕之、仲本正彦、沖嶋杏奈、有泉早紀、清川千秋、星野 友、奥 直人
  • Organizer: 第25回DDSカンファランス
  • Place of Presentation: 静岡
  • Year and Date: 2016-09-02
• [Presentation] 生体内で標的毒素を中和する“リポソーム解毒剤”の開発 (2016)
  • Author(s): 43.土田大貴、小出裕之、仲本正彦、沖嶋杏奈、有泉早紀、清川千秋、星野 友、奥 直人
  • Organizer: 第10回QCM研究会
  • Place of Presentation: 東京
  • Year and Date: 2016-08-26