高分子ミセルキャリヤーの免疫原性制御のためのインターフェース設計

• Project Area: Molecular Soft-Interface Science
• Project/Area Number: 21106524
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Jikei University School of Medicine
• Principal Investigator: 横山 昌幸 東京慈恵会医科大学, 医学部, 准教授 (20220577)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2010: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2009: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 免疫原性 / 高分子ミセル / リポソーム / 体内動態 / DDS / ABC現象 / ターゲティング / 固形がん

Research Abstract

本研究は、高分子ミセルのABC現象(Accelerated Blood Clearance)解析を通して、ソフト界面での免疫認識機構を検証し、がん診断・治療に有効なキャリヤーシステムを確立することを目的とする。ABC現象は、PEG修飾リポソームの2回目投与でクリアランスが顕著に増大する現象で、PEG鎖を有するキャリヤーを用いた診断と治療には重要な現象である。本研究の推進により、ソフト界面の生物的な機能の新たな解明に結びつくと共に、固形がんなどの診断・治療の応用に大きな貢献をする。
前年度までのPEG-修飾リポソームによってABC現象を検出する実験から今年度は条件を拡張して検討した。MRI造影剤キャリヤーシステムでは、1回目のどの投与量においても、2回目に投与した造影剤ミセルのマウスでの血中濃度に変化は観察されなかった。つまり、造影剤ミセルではABC現象を起こさない。一方、薬物キャリアーの高分子ミセルでは、PEG-修飾リポソームの2回目の投与で検出すると、PEG-PBLAミセルはABC現象を引き起こすが、2回目の投与を蛍光のFITCラベルした高分子ミセルで測定するとABC現象は検出されない。まとめると、内核が親水性の高分子ミセルMRI造影剤はABC現象引き起こさず、内核が疎水性のPEG-PBLAミセルではABC現象を引き起こすが、ABC現象では認識されないという、大変興味深い結果を得た。
以上の結果は、基礎的にはPEG外殻と内核のソフト界面が,ABC現象の誘導と認識に重要な役割を果たしていることを明らかにしたとともに、医療応用の側面では、高分子ミセルキャリヤーは造影剤としても薬物治療剤としてもABC現象に関わる問題をなにも起こさない重要な事実が判明した。

Research Products

• [Journal Article] Effects of organic solvents on drug incorporation into polymeric carriers and morphological analyses of drug-incorporated polymeric micelles. (2011)
  • Author(s): Yoshiko Harada, Tatsuhiro Yamamoto, Masaru Sakai, Toshiharu Saiki, Kumi Kawano, Yoshie Maitani, Masayuki Yokoyama
  • Journal Title: International Journal of Pharmaceutics Volume: 404 Pages: 271-280
  • Peer Reviewed
• [Journal Article] Accelerated Blood Clearance Was Not Induced for a Gadolinium-Containing PEG-poly(L-lysine)-Based Polymeric Micelle in Mice. (2010)
  • Author(s): Huili Ma, Kouichi Shiraishi, Takuya Minowa, Kumi Kawano, Masayuki Yokoyama, Yoshiyuki Hattori, Yoshie Maitani
  • Journal Title: Pharmaceutical Research Volume: 27 Pages: 296-302
  • Peer Reviewed
• [Journal Article] Vital microscopic analysis of polymeric micelle extravasation from tumor vessels : macromolecular delivery according to tumor vascular growth stage. (2010)
  • Author(s): Katsuyoshi Hori, Masamichi Nishihara, Masayuki Yokoyama
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 99 Pages: 549-562
  • Peer Reviewed
• [Journal Article] The Combretastatin Derivative Cderiv, a Vascular Disrupting Agent, Enables Polymeric Nanomicelles to Accumulate in Microtumors. (2010)
  • Author(s): Katsuyoshi Hori, Masamichi Nishihara, Masayuki Yokoyama
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 99 Pages: 2914-25
  • Peer Reviewed
• [Journal Article] Encapsulation of a Hydrophobic Drug into a Polymer-Micelle Core Explored with Synchrotron SAXS. (2010)
  • Author(s): Isamu Akiba, Naotaka Terada, Satoshi Hashida, Kazuo Sakurai, Taku Sato, Kouichi Shiraishi, Masayoshi, Yokoyama, Hiroyasu Masunaga, Hiroki Ogawa, Naoto Yagi
  • Journal Title: Langmuir Volume: 26 Pages: 7544-7551
  • Peer Reviewed
• [Journal Article] Synthesis of Poly(ethylene glycol)-b-Poly(L-lysine) Block Copolymers Having Gd-DOTA as MRI Contrast Agent and Their Polymeric Micelle Formation by Polyion Complexation. (2010)
  • Author(s): Kouichi Shiraishi, Kumi Kawano, Yoshie Maitani, Masayuki Yokoyama
  • Journal Title: Journal of Controlled Release Volume: 148 Pages: 160-167
  • Peer Reviewed
• [Journal Article] Convection-enhanced delivery of a synthetic retinoid Am80, loaded into polymeric micelles, prolongs the survival of rats bearing intracranial glioblastoma xenografts. (2010)
  • Author(s): Michiko Yokosawa, Yukihiko Sonoda, Shin-ichiro Sugiyama, Ryuta Saito, Yoji Yamashita, Masamichi Nishihara, Taku Satoh, Toshihiro kumabe, Masayuki Yokoyama, teiji Tominaga
  • Journal Title: Tohoku J.Exp.Med. Volume: 221 Pages: 257-64
  • NAID: 10027085245
  • Peer Reviewed
• [Journal Article] Polymeric micelles as a novel drug carrier system and their required considerations for clinical trials. (2010)
  • Author(s): Masayuki Yokoyama
  • Journal Title: Expert Opinion on Drug Delivery Volume: 7 Pages: 145-158
  • Peer Reviewed
• [Journal Article] 高分子ミセルの薬剤学分野への応用 (2010)
  • Author(s): 横山昌幸
  • Journal Title: 薬剤学 Volume: 70 Pages: 27-31
  • NAID: 10029100644
• [Journal Article] Vital microscopic analysis of polymeric micelle extravasation from tumor vessels : macromolecular delivery according to tumor vascular growth stage (2010)
  • Author(s): Katsuyoshi Hori, Masamichi Nishihara, Masayuki Yokoyama
  • Journal Title: Journal of Pharmaceutical Sciences 99 Pages: 549-562
  • Peer Reviewed
• [Journal Article] Polymeric micelles as a novel drug carrier system and their required considerations for clinical trials (2010)
  • Author(s): Masayuki Yokoyama
  • Journal Title: Expert Opinion on Drug Delivery 7 Pages: 145-58
  • Peer Reviewed
• [Journal Article] 高分子ミセルの薬剤学分野への応用 (2010)
  • Author(s): 横山昌幸
  • Journal Title: 薬剤学 70 Pages: 27-31
  • NAID: 10029100644
• [Journal Article] Therapeutic efficacy of a polymeric micellar doxorubicin infused by convection-enhanced delivery against intracranial 9L brain tumor models (2009)
  • Author(s): T.Inoue, Y.Yamashita, M.Nishihara, S.Sugiyama, Y.Sonoda, T.Kumabe, M.Yokoyama, T.Tominaga
  • Journal Title: Neuro-Oncology 11 Pages: 151-157
  • Peer Reviewed
• [Journal Article] Preparation and in vivo imaging of PEG-poly(L-lysine)-based polymeric micelle MRI contrast agents (2009)
  • Author(s): Kouichi Shiraishi, Kumi Kawano, Takuya Minowa, Yoshie Maitani, Masayuki Yokoyama
  • Journal Title: Journal of Controlled Release 136 Pages: 14-20
  • Peer Reviewed
• [Journal Article] Vital microscopic analysis of polymeric micelle's extravazation at solid tumors : What part of vasculature makes a main role for macromolecular delivery at tumors? (2009)
  • Author(s): Taku Satoh, Yuriko Higuchi, Shigeru Kawakami, Mitsuru Hashida, Hiroyuki Kagechika, Koichi Shudo, Masayuki Yokoyama
  • Journal Title: Journal of Controlled Release 136 Pages: 187-195
  • Peer Reviewed
• [Journal Article] Enhanced in vivo antitumor efficacy of fenretinide encapsulated in polymeric micelles (2009)
  • Author(s): Tomoyuki Okuda, Shigeru Kawakami, Yuriko Higuchi, Taku Satoh, Yoshimi Oka, Masayuki Yokoyama, Fumiyoshi Yamashita, Mitsuru Hashida
  • Journal Title: International Journal of Pharmaceutics 373 Pages: 100-106
  • Peer Reviewed
• [Journal Article] Histological study on side effects and tumor targeting of a block copolymer micelle on rats (2009)
  • Author(s): Takanori Kawaguchi, Takashi Honda, Masamichi Nishihara, Tatsuhiro Yamamoto, Masayuki Yokoyama
  • Journal Title: Journal of Controlled Release 136 Pages: 240-246
  • Peer Reviewed
• [Journal Article] Accelerated Blood Clearance Was Not Induced for a Gadolinium-Containing PEG-poly(L-lysine)-Based Polymeric Micelle in Mice (2009)
  • Author(s): Huili Ma, Kouichi Shiraishi, Takuya Minowa, Kumi Kawano, Masayuki Yokoyama, Yoshiyuki Hattori, Yoshie Maitani
  • Journal Title: Pharmaceutical Research 27 Pages: 296-302
  • Peer Reviewed
• [Journal Article] Increase in tumour permeability following TGF-b type I receptor inhibitor treatment observed by dynamic contrast-enhanced MRI (2009)
  • Author(s): T.Minowa, K.Kawano, H.Kuribayashi, K.Shiraishi, T.Sugino, Y.Hattori, M.Yokoyama, Y.Maitani
  • Journal Title: British Journal of Cancer 101 Pages: 1884-1890
  • Peer Reviewed
• [Journal Article] DDSと分子イメージング (2009)
  • Author(s): 横山昌幸
  • Journal Title: 血管医学 10 Pages: 97-104
• [Journal Article] DDSと分子イメージング:MRI造影剤を例にして (2009)
  • Author(s): 横山昌幸
  • Journal Title: JSMI Report 2 Pages: 9-11
  • Peer Reviewed
• [Journal Article] 自己組織化高分子のターゲティングへの応用 (2009)
  • Author(s): 横山昌幸
  • Journal Title: 高分子 58 Pages: 469-472
  • NAID: 10025093568
• [Journal Article] The Combretastatin Derivative Cderiv, a Vascular Disrupting Agent, Enables Polymeric Nanomicelles to Accumulate in Microtumors
  • Author(s): Katsuyoshi Hori, Masamichi Nishihara, Masayuki Yokoyama
  • Journal Title: Journal of Pharmaceutical Sciences (In press)
  • Peer Reviewed
• [Presentation] 高分子ミセルキャリヤーの免疫原性制御のためのインターフェース設計 (2011)
  • Author(s): 横山昌幸、白石貢一
  • Organizer: 「ソフトインターフェースの分子科学」第5回公開シンポジウム
  • Place of Presentation: 東京理科大学森戸記念館
  • Year and Date: 2011-02-03
• [Presentation] 薬物標的治療に求められる合成高分子 (2011)
  • Author(s): 横山昌幸
  • Organizer: 平成22年度東海シンポジウム
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2011-01-27
• [Presentation] ABC phenomenon of nanocarrier-based MRI contrast agents and their importance for tumor targeting by the EPR effect (2010)
  • Author(s): Kouichi Shiraishi, Huili Ma, Kumi Kawano, Yoshie Maitani, Masayuki Yokoyama
  • Organizer: PACIFICHEM2010
  • Place of Presentation: Hawaii Convention Center(Honolulu, Hawaii, USA)
  • Year and Date: 2010-12-18
• [Presentation] Combined diagnosis and chemotherapy of solid tumors using polymeric micelle carriers (2010)
  • Author(s): Masayuki Yokoyama
  • Organizer: PACIFICHEM2010
  • Place of Presentation: Hawaii Convention Center(Honolulu, Hawaii, USA)
  • Year and Date: 2010-12-16
• [Presentation] 高分子ミセル、リポソームの親水・疎水性界面のABC現象への影響 (2010)
  • Author(s): 白石貢一、馬会利、川野久美、米谷芳枝、横山昌幸
  • Organizer: 第59回高分子討論会
  • Place of Presentation: 北海道
  • Year and Date: 2010-09-15
• [Presentation] Effective tumor targeting of polymeric micelle MRI contrast agent by a tumor vascular disrupting agent. (2010)
  • Author(s): Kouichi Shiraishi, Kumi Kawano, Yoshie Maitani, Katsuyoshi Hori, Masayuki Yokoyama
  • Organizer: 2010WorldMolecularImagingCongress
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2010-09-11
• [Presentation] 急性脳梗塞診断と治療へのナノサイズキャリヤーの応用 (2010)
  • Author(s): 横山昌幸
  • Organizer: ナノメディシンフォーラム
  • Place of Presentation: 慈恵医科大学(東京)
  • Year and Date: 2010-09-04
• [Presentation] Does ABC phenomenon occur for polymeric micelle MRI contrast agents (2010)
  • Author(s): M.Yokoyama, K.Shiraishi, Huili Ma, T.Minowa 3, K.Kawano, Y.Hattori, Y.Maitani
  • Organizer: 37th Annual Meeting & Exposition of the Controlled Release Society
  • Place of Presentation: Portland Convention Center (Portland, Oregon, USA)
  • Year and Date: 2010-07-14
• [Presentation] Combretastatin derivative (Cderiv) as a vascular disrupting agent enhances tumor accumulation of polymeric micelle carrier system. (2010)
  • Author(s): Kouichi Shiraishi, Kumi Kawano, Yoshie Maitani, Katsuyoshi Hori, Masayuki Yokoyama
  • Organizer: 37th Annual Meeting & Exposition of the Controlled Release Society
  • Place of Presentation: Portland Convention Center (Portland, Oregon, USA)
  • Year and Date: 2010-07-13
• [Presentation] 高分子ミセルキャリア内核の影響によるABC現象の発現と回避 (2010)
  • Author(s): 白石貢一、馬会利、川野久美、米谷芳枝、横山昌幸
  • Organizer: 第26回日本DDS学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-06-18
• [Presentation] 高分子ミセルMRI造影剤の頻回投与によるABC現象への影響と診断への有用性 (2010)
  • Author(s): 白石貢一、馬会利、川野久美、米谷芳枝、横山昌幸
  • Organizer: 第26回日本DDS学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-06-18
• [Presentation] 臨床診断用超音波による各種相変化型ナノ液滴の気相化と圧壊の検討 (2010)
  • Author(s): 遠藤怜子、白石貢一、川畑健一、田畑泰彦、横山昌幸、古幡博
  • Organizer: 日本超音波医学会第83回学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2010-05-31
• [Presentation] 高分子ミセルMRI造影剤とABC現象の検証 (2010)
  • Author(s): 白石貢一, 川野久美, 米谷芳枝, 横山昌幸
  • Organizer: 第5回日本分子イメージング学会学術集会
  • Place of Presentation: 大津
  • Year and Date: 2010-05-22
• [Presentation] ポリエチレングリコール-ポリリシンからなる高分子ミセルのMRI造影剤への展開 (2009)
  • Author(s): 白石貢一, 川野久美, 箕輪卓也, 馬会利, 米谷芳枝, 横山昌幸
  • Organizer: 第58回高分子討論会
  • Place of Presentation: 熊本大学(熊本)
  • Year and Date: 2009-09-16
• [Presentation] 薬物及び造影剤キャリヤーとしての高分子ミセル (2009)
  • Author(s): 横山昌幸
  • Organizer: 第58回高分子討論会
  • Place of Presentation: 熊本大学(熊本)
  • Year and Date: 2009-09-16
• [Presentation] Accelerated blood clearance phenomenon was not induced by repeated injections of Gadrinium-containing Polymeric micelle (2009)
  • Author(s): 白石貢一, 馬会利, 箕輪卓也, 川野久美, 横山昌幸, 服部喜之, 米谷芳枝
  • Organizer: 第25回日本DDS学会
  • Place of Presentation: 東京ドームホテル(東京)
  • Year and Date: 2009-07-03
• [Presentation] 腫瘍血流遮断薬による変性領域形成と高分子ミセル集積挙動のMRIによる観察 (2009)
  • Author(s): 白石貢一, 川野久美, 箕輪卓也, 米谷芳枝, 堀勝義, 横山昌幸
  • Organizer: 第25回日本DDS学会
  • Place of Presentation: 東京ドームホテル(東京)
  • Year and Date: 2009-07-03
• [Book] 遺伝子医学 MOOK18:創薬研究への分子イメージング応用 (2010)
  • Author(s): 横山昌幸
  • Publisher: メデイカルドウ