Development of enzyme-loaded PIC-nanoreactor working under the blood circulation

• Project/Area Number: 15K12536
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biomedical engineering/Biomaterial science and engineering
• Research Institution: The University of Tokyo
• Principal Investigator: Anraku Yasutaka 東京大学, 大学院工学系研究科(工学部), 助教 (60581585)
• Project Period (FY): 2015-04-01 – 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 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 酵素 / 酵素補充療法 / 薬剤送達システム / 高分子ベシクル / 急性リンパ性白血病 / 高分子化学 / ナノリアクタ / 急性骨髄性白血病 / 急性白血病 / ドラッグデリバリーシステム / PICsome

Outline of Final Research Achievements

Enzyme-loaded synthetic vesicles have attracted great attention for their feasibility to exert the efficient and prolonged functionality of loaded enzymes in harsh environments. However, several issues remain regarding the optimization of their structures toward practical application. Herein, we fabricated polyion complex vesicles loaded with L-asparaginase (ASNase@PICsomes) and conducted a detailed characterization to ensure their utility as nanoreactors functioning under the harsh in vivo environment (bloodstream). ASNase@PICsomes showed 100 nm-sized monodispersed vesicular structures. Fluorescence cross-correlation spectroscopy revealed essentially no empty PICsome fraction in the product, indicating the quantitative formation of ASNase@PICsomes. Furthermore, ASNase@PICsomes exhibited significantly prolonged enzymatic reaction compared with free ASNase after systemic injection into mice, corroborating their functionality as in vivo nanoreactors working under the blood circulation.

Research Products

• [Journal Article] Therapeutic Vesicular Nanoreactors with Tumor-Specific Activation and Self-Destruction for Synergistic Tumor Ablation (2017)
  • Author(s): Li Junjie、Dirisala Anjaneyulu、Ge Zhishen、Wang Yuheng、Yin Wei、Ke Wendong、Toh Kazuko、Xie Jinbing、Matsumoto Yu、Anraku Yasutaka、Osada Kensuke、Kataoka Kazunori
  • Journal Title: Angew Chem Int Ed Engl Volume: 56 Issue: 45 Pages: 14025-14030
  • DOI: 10.1002/anie.201706964
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Facile Preparation of Delivery Platform of Water-Soluble Low-Molecular-Weight Drugs Based on Polyion Complex Vesicle (PICsome) Encapsulating Mesoporous Silica Nanoparticle (2017)
  • Author(s): 2.Akinori Goto, Hung-Chi Yen, Yasutaka Anraku, Shigeto Fukushima, Ping-Shan Lai, Masaru Kato, Akihiro Kishimura, and Kazunori Kataoka
  • Journal Title: ACS Biomater. Sci. Eng. Volume: 印刷中 Issue: 5 Pages: 807-815
  • DOI: 10.1021/acsbiomaterials.6b00562
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Enzyme-Loaded Polyion Complex Vesicles as in Vivo Nanoreactors Working Sustainably under the Blood Circulation: Characterization and Functional Evaluation (2017)
  • Author(s): Daiki Sueyoshi, Yasutaka Anraku, Toru Komatsu, Yasuteru Urano and Kazunori Kataoka
  • Journal Title: Biomacromolecules Volume: 18 Issue: 4 Pages: 1189-1196
  • DOI: 10.1021/acs.biomac.6b01870
  • Peer Reviewed
• [Journal Article] Systemically injectable enzyme-loaded polyion complex vesicles as in vivo nanoreactors functioning in tumors (2016)
  • Author(s): Y. Anraku, A. Kishimura, M. Kamiya, S. Tanaka, T. Nomoto, K. Toh, Y. Matsumoto, S. Fukushima, D. Sueyoshi, M. R. Kano, Y. Urano, N. Nishiyama, K. Kataoka
  • Journal Title: Angew. Chem. Int. Ed. Volume: 128 Issue: 2 Pages: 570-575
  • DOI: 10.1002/ange.201508339
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enhanced target recognition of nanoparticles by cocktail PEGylation with chains of varying lengths (2016)
  • Author(s): T. Ishii, K. Miyata, Y. Anraku, M. Naito, Y. Yi, T. Jinbo, S. Takae, Y. Fukusato, M. Hori, K. Osada, K. Kataoka
  • Journal Title: Chem. Commun. Volume: 52 Issue: 7 Pages: 1517-1519
  • DOI: 10.1039/c5cc06661a
  • Peer Reviewed
• [Presentation] Enzyme-loaded polyion complex vesicles as in vivo nanoreactors (2017)
  • Author(s): Y. Anraku
  • Organizer: 11th Annual Symposium on Nanobiotechnology 2017
  • Int'l Joint Research / Invited
• [Presentation] PIC vesicle-based enzymatic nanoreactors functioning in vivo under the blood circulation (2017)
  • Author(s): D. Sueyoshi, Y. Anraku, T. Komatsu, Y. Urano, K. Kataoka
  • Organizer: 11th Annual Symposium on Nanobiotechnology 2017
  • Int'l Joint Research
• [Presentation] Stabilization and application of polyion complex vesicles (PICsomes) with chemical modifications of polymer side-chain (2017)
  • Author(s): M. Hori, Y. Anraku, C. Horacio, A. Kishimura, K. Kataoka
  • Organizer: The 14th US-Japan Symposium on Drug Delivery Systems Conference
  • Int'l Joint Research
• [Presentation] 多点ではたらくイオン間相互作用と水素結合を利用した自己組織化によるポリマーソームの構築とその特性解析 (2017)
  • Author(s): 堀真緒、安楽泰孝、岸村顕広、片岡一則
  • Organizer: 第66回高分子討論会
• [Presentation] 血流中で機能するナノリアクターを指向した酵素封入ポリイオンコンプレックス型ベシクルの構築および機能評価 (2016)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第25回インテリジェント材料・システムシンポジウム
  • Place of Presentation: 東京女子医科大学、新宿区、東京都
  • Year and Date: 2016-01-08
• [Presentation] 生体内環境での安定性向上を目指したポリイオンコンプレックス型ベシクル(PICsome)の開発 (2016)
  • Author(s): 堀真緒、安楽泰孝、岸村顕広、片岡一則
  • Organizer: 遺伝子・デリバリー研究会第16回シンポジウム
  • Place of Presentation: 川崎生命科学・環境研究センター、川崎市、神奈川県
• [Presentation] 血中循環型ナノリアクターを指向した酵素封入PICsomeの開発 (2016)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 遺伝子・デリバリー研究会第16回シンポジウム
  • Place of Presentation: 川崎生命科学・環境研究センター、川崎市、神奈川県
• [Presentation] 血流中に持続的なナノ反応場を提供する酵素封入PIC型ベシクルの開発 (2016)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第65回高分子学会年次大会
  • Place of Presentation: 神戸国際会議場・展示場、神戸市、兵庫県
• [Presentation] 内水相に酵素を封入したPIC型ベシクルの血中循環型ナノリアクターとしての機能展開 (2016)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第32回DDS学会学術大会
  • Place of Presentation: グランシップ(静岡県コンベンションアーツセンター)、静岡市、静岡県
• [Presentation] ポリイオンコンプレックス型ベシクル（PICsome）の開発とその物性評価 (2016)
  • Author(s): 堀真緒、安楽泰孝、岸村顕広、片岡一則
  • Organizer: 西日本ナノシート研究会サマーキャンプ2016
  • Place of Presentation: シーサイドホテル屋久島、屋久島町、鹿児島県
• [Presentation] 血中循環型ナノリアクターを指向した酵素封入PIC型ベシクルの物性および機能評価 (2016)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第65回高分子討論会
  • Place of Presentation: 神奈川大学横浜キャンパス、横浜市、神奈川県
• [Presentation] Development of polyion complex vesicles (PICsomes) with various side-chain modifications for stability enhancement under the physiological salt condition (2016)
  • Author(s): M. Hori, Y. Anraku, A. Kishimura, K. Kataoka
  • Organizer: 2016 MRS Fall Meeting & Exhibit
  • Place of Presentation: Boston, Massachussets, USA
  • Int'l Joint Research
• [Presentation] Development of enzyme-loaded PIC vesicles for enzyme/prodrug therapy (2016)
  • Author(s): Y. Anraku, A. Kishimura, M. Kamiya, S. Tanaka, T. Nomoto, K. Toh, Y. Matsumoto, M. R. Kano, Y. Urano, N. Nishiyama, K. Kataoka
  • Organizer: Frontiers2016 Symposium of the EPFL
  • Place of Presentation: Swiss Federal Institute of Technology(EPFL), Lausanne, Switzerland
  • Int'l Joint Research
• [Presentation] Development of polyion complex vesicles (PICsomes) with side chain modification as new drug delivery carrier (2016)
  • Author(s): M. Hori, Y. Anraku, S. Chuanoi, A. Kishimura, K. Kataoka
  • Organizer: Frontiers2016 Symposium of the EPFL
  • Place of Presentation: Swiss Federal Institute of Technology(EPFL), Lausanne, Switzerland
  • Int'l Joint Research
• [Presentation] Enzyme-loaded polyion complex vesicles as nano-reactors functioning in the blood circulation (2016)
  • Author(s): D. Sueyoshi, Y. Anraku, K. Kataoka
  • Organizer: The 11th SPSJ International Polymer Conference (IPC2016)
  • Place of Presentation: Fukuoka International Confress Center, Fukuoka
  • Int'l Joint Research
• [Presentation] Development of polyion complex vesicle (PICsome) decorated with guanidinium groups as a new drug delivery carrier (2015)
  • Author(s): M. Hori, Y. Anraku, S. Chuanoi, A. Kishimura, K. Kataoka
  • Organizer: The 13th US-Japan Symposium on Drug Delivery Systems Conference
  • Place of Presentation: The Westin Maui Resort & Spa, Hawaii, USA
  • Year and Date: 2015-12-18
  • Int'l Joint Research
• [Presentation] Development of enzyme-loaded polyion complex vesicles for in vivo nanoreactor (2015)
  • Author(s): Y. Anraku, M. Kamiya, S. Tanaka, T. Nomoto, K. Toh, Y. Matsumoto, S. Fukushima, D. Sueyoshi, A. Kishimura, M. Kano, Y. Urano, N. Nishiyama, K. Kataoka
  • Organizer: THE INTERNATIONAL CHEMICAL CONGRESS OF PACIFIC BASIN SOCIETIES (PACIFICHEM2015)
  • Place of Presentation: Hawaii Convention Center, Hawaii, USA
  • Year and Date: 2015-12-16
  • Int'l Joint Research
• [Presentation] Stability enhancement of polyion complex vesicles (PICsomes) by polymer side-chain modification (2015)
  • Author(s): M. Hori, Y. Anraku, S. Chuanoi, A. Kishimura, K. Kataoka
  • Organizer: PPC-14 14th PACIFIC POLYMER CONFERENCE
  • Place of Presentation: Kauai, Hawaii, USA
  • Year and Date: 2015-12-10
  • Int'l Joint Research
• [Presentation] Development of enzyme-loaded PIC nanoreactor for enzyme/prodrug therapy (2015)
  • Author(s): Y. Anraku, A. Kishimura, M. Kamiya, S. Tanaka, T. Nomoto, K. Toh, Y. Matsumoto, S. Fukushima, D. Sueyoshi, M. R. Kano, Y. Urano, N. Nishiyama, K. Kataoka
  • Organizer: PPC-14 14th PACIFIC POLYMER CONFERENCE
  • Place of Presentation: Kauai, Hawaii, USA
  • Year and Date: 2015-12-10
  • Int'l Joint Research
• [Presentation] Development of enzyme-loaded polyion complex vesicles as versatile nano-reactors in blood circulation (2015)
  • Author(s): D. Sueyoshi, Y. Anraku, K. Kataoka
  • Organizer: 2015 MRS Fall Meeting & Exhibit
  • Place of Presentation: Boston, Massachussets, USA
  • Year and Date: 2015-12-02
  • Int'l Joint Research
• [Presentation] 生体内ナノリアクターとしての酵素封入PIC型ベシクルの構築および血流中における機能評価 (2015)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第37回日本バイオマテリアル学会大会
  • Place of Presentation: 京都テルサ、京都市、京都府
  • Year and Date: 2015-11-10
• [Presentation] Development of polyion complex vesicles (PICsomes) functionalized by guanidinium moieties (2015)
  • Author(s): M. Hori, Y. Anraku, A. Kishimura, K. Kataoka
  • Organizer: Core2Core LMU-UTokyo Symposium 2015
  • Place of Presentation: Innovation Center for Biotechnology (IZB), Planegg/Martinsried, Deutschland
  • Year and Date: 2015-10-28
  • Int'l Joint Research
• [Presentation] 血流中で機能するナノリアクターとしての酵素封入PIC型ベシクルの構築および機能評価 (2015)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第64回高分子討論会
  • Place of Presentation: 東北大学川内キャンパス、仙台市、宮城県
  • Year and Date: 2015-09-16
• [Presentation] Self-assembled nanostructures from block copolymers for biomedical application (2015)
  • Author(s): Y. Anraku
  • Organizer: 250th American Chemical Society (ACS) National Meeting & Exposition
  • Place of Presentation: Boston, Massachusetts, USA
  • Year and Date: 2015-08-18
  • Int'l Joint Research / Invited
• [Presentation] 血流中で機能する酵素封入PIC型ナノリアクターの開発 (2015)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第31回日本DDS学会学術集会
  • Place of Presentation: 京王プラザホテル、新宿区、東京都
  • Year and Date: 2015-07-02
• [Presentation] 血流中で機能するナノリアクターを指向した酵素封入PIC型ベシクルの構築 (2015)
  • Author(s): 末吉大輝、安楽泰孝、片岡一則
  • Organizer: 第64回高分子学会年次大会
  • Place of Presentation: 札幌コンベンションセンター、札幌市、北海道
  • Year and Date: 2015-05-27
• [Presentation] PIC型ベシクルの特異な物質透過性に関する機能評価 (2015)
  • Author(s): 安楽泰孝、O. Mutaf、岸村顕広、片岡一則
  • Organizer: 第64回高分子学会年次大会
  • Place of Presentation: 札幌コンベンションセンター、札幌市、北海道
  • Year and Date: 2015-05-27
• [Book] 分子マシンの科学 (2017)
  • Author(s): 安楽泰孝、片岡一則
  • Total Pages: 200
  • Publisher: 化学同人
  • ISBN: 9784759813869
• [Remarks] 東京大学大学院工学系研究科 カブラル研究室
  • URL: http://www.bmc.t.u-tokyo.ac.jp
• [Remarks] 東京大学大学院工学系研究科バイオエンジニアリング専攻カブラル研究室
  • URL: http://www.bmc.t.u-tokyo.ac.jp
• [Remarks] 片岡研究室ホームページ
  • URL: http://www.bmw.t.u-tokyo.ac.jp
• [Patent(Industrial Property Rights)] ポリイオンコンプレックス型ポリマーソームを用いたナノリアクタとその製造方法 (2016)
  • Inventor(s): 片岡一則、安楽泰孝、末吉大輝
  • Industrial Property Rights Holder: 片岡一則、安楽泰孝、末吉大輝
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-05-06
  • Overseas
• [Patent(Industrial Property Rights)] ポリイオンコンプレックス型ポリマーソームを用いたナノリアクタとその製造方法 (2015)
  • Inventor(s): 片岡一則、安楽泰孝、末吉大輝
  • Industrial Property Rights Holder: 国立大学法人東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-095278
  • Filing Date: 2015-05-07