Effect of the size of ligand-conjugated nanocarriers on their accumulation and therapeutic effect in solid tumors

2014 Fiscal Year Annual Research Report

• Project/Area Number: 25750172
• Research Institution: The University of Tokyo
• Principal Investigator: CABRAL Horacio 東京大学, 工学(系)研究科(研究院), 准教授 (10533911)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: ドラッグデリバリー / アクティブターゲティング / 高分子ミセル / 環状RGDペプチド / グリオーマ / ナノ粒子のサイズ

Outline of Annual Research Achievements

本研究の目標は、リガンドを導入した制がん剤内包高分子ミセルのサイズが、その固形がんへのターゲティング能に対して及ぼす影響を評価する事であった。このミセルはマレイミド官能基を有したPEG-b-ポリグルタミン酸(マレイミド-PEG-b-ポリグルタミン酸)ブロック共重合体と(1,2-diaminocyclohexane)platinum(II)を混ぜあわせる事によって調製し、ミセルのサイズはポリグルタミン酸ホモ重合体を加えることによって制御できる。このようにして、30、50、70、100nmの粒径をもつ高分子ミセルを調製するとともに、各ミセル表層にマレイミド基を介して環状RGD(cRGD)ペプチドを20%導入する事で、avb3・avb5インテグリンを過剰発現した腫瘍への標的化を可能にした。in vitroにおけるU87-MGグリオーマスフェロイド培養においては、50nm以下の粒径をもつcRGD/mは70nm以上の粒径をもつcRGD/mよりも効果的となる事が分かった。in vitro共焦点顕微鏡(CLSM)により、30・50nmのcRGD/mはスフェロイドの深部まで浸透するが、70・100nmのミセルは外縁に残る事が示された。in vivoでは、30・50nmのcRGD/mはU87-MGの異種移植において腫瘍の成長を抑制した一方で、リガンドの無いミセルや70nm・100nmのcRGD/mは抗腫瘍活性を示す事ができなかった。腫瘍への集積を調べると、30・50nmのcRGD/mは約8%ID/g tissueを示したが、リガンド無しのミセルや70nm以上のcRGD/mは2%に満たなかった。in vivoCLSMにより、50nm以下のcRGD/mのみU87-MG腫瘍内で血管から浸出し深部へ浸透しており、このアクティブトランスポートメカニズムはナノ粒子のサイズに依存することが分かった。

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 / Acknowledgement Compliant
• [Journal Article] Systemic Targeting of Lymph Node Metastasis through the Blood Vascular System by Using Size-Controlled Nanocarriers (2015)
  • Author(s): H. Cabral, J. Makino, Y. Matsumoto, P. Mi, H. Wu, T. Nomoto, K. Toh, N. Yamada, Y. Higuchi, S. Konishi, M.R. Kano, H. Nishihara, Y. Miura, N. Nishiyama, K. Kataoka
  • Journal Title: ACS Nano Volume: Article ASAP Pages: nn5070259
  • DOI: 10.1021/nn5070259
  • Peer Reviewed / Acknowledgement Compliant
• [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 Pages: 11591-11602
  • DOI: 10.1021/nn504836s
  • Peer Reviewed / Acknowledgement Compliant
• [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: Journal of Controlled Release Volume: 189 Pages: 110
  • DOI: 10.1016/j.jconrel.2014.06.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective intracellular delivery of proteasome inhibitors through pH-sensitive polymeric micelles directed to effcient antitumor therapy. (2014)
  • Author(s): S. Quader, H. Cabral, Y. Mochida, T. Ishii, X. Liu, K. Toh, H. Kinoh, Y. Miura, N. Nishiyama, K. Kataoka,
  • Journal Title: Journal of Controlled Release Volume: 188 Pages: 67-77
  • DOI: 10.1016/j.jconrel.2014.06.018
  • Peer Reviewed / Acknowledgement Compliant
• [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 Pages: 6724-6738
  • DOI: 10.1021/nn500498t
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] siRNA delivery from triblock copolymer micelles with spatially-ordered compartments of PEG shell, siRNA-loaded intermediate layer, and hydrophobic core. (2014)
  • Author(s): H. -J. Kim, K. Miyata, T. Nomoto, M. Zheng, A. Kim, X. Liu, H. Cabral, R. J. Christie, N. Nishiyama, K. Kataoka
  • Journal Title: Biomaterials Volume: 35 Pages: 4548-4556
  • DOI: 10.1016/j.biomaterials.2014.02.016
  • Peer Reviewed / Acknowledgement Compliant
• [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, H. Cabral, Y. Maeda, P. Mi, S. Watanabe, H. Takemoto, H. -J. Kim, N. Nishiyama, K. Miyata, K. Kataoka
  • Journal Title: Journal of Controlled Release Volume: 178 Pages: 18-24
  • DOI: 10.1016/j.jconrel.2014.01.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Multicompartment micelles with adjustable poly(ethylene glycol) shell for efficient in vivo photodynamic therapy. (2014)
  • Author(s): C. V. Synatschke, T. Nomoto, H. Cabral, M. Fortsch, K. Toh, Y. Matsumoto, K. Miyazaki, A. Hanisch, F. H. Schacher, A. Kishimura, N. Nishiyama, A. H. E. Mueller, K. Kataoka
  • Journal Title: ACS Nano Volume: 8 Pages: 1161-1172
  • DOI: 10.1021/nn4028294
  • Peer Reviewed / Acknowledgement Compliant
• [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: Journal of Controlled Release Volume: 174 Pages: 63-71
  • DOI: 10.1016/j.jconrel.2013.10.038
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Polyion complex vesicles for photo-induced intracellular delivery of amphiphilic photosensitizer. (2014)
  • Author(s): H. Chen, L. Xiao, Y. Anraku, P. Mi, X. Liu, H. Cabral, A. Inoue, T. Nomoto, A. Kishimura, N. Nishiyama, K. Kataoka
  • Journal Title: Journal of the American Chemical Society Volume: 136 Pages: 157-163
  • DOI: 10.1021/ja406992w
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Progress of drug-loaded polymeric micelles into clinical studies (2014)
  • Author(s): H. Cabral, K. Kataoka
  • Journal Title: Journal of Controlled Release Volume: 190 Pages: 465-476
  • DOI: 10.1016/j.jconrel.2014.06.042
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 22. The impact of "Development of the polymer micelles carrier system for doxorubicin" on the nanomedicine realm: Original Research Article: Development of the polymer micelle carrier system for doxorubicin, 2001 (2014)
  • Author(s): H. Cabral, K. Kataoka
  • Journal Title: Journal of Controlled Release Volume: 190 Pages: 70-72
  • DOI: 10.1016/j.jconrel.2014.07.034
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Supramolecular Nanosystem Design for Eradication of Cancer Stem Cells (2015)
  • Author(s): H. Cabral, K. Kataoka
  • Organizer: 2nd CMS International Symposium
  • Place of Presentation: Lecture room 305, Shiiki Hall, Ito Campus, Kyushu University
  • Year and Date: 2015-01-20 – 2015-01-20
  • Invited
• [Presentation] 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. Matsumoto, J. -Y. Ahn, H. Kinoh, N. Nishiyama, Y. Miura, K. Kataoka
  • Organizer: The 10th International Polymer Conference IPC2014
  • Place of Presentation: International Congress Center, Tsukuba, Ibaraki
  • Year and Date: 2014-12-02 – 2014-12-05
• [Presentation] シスプラチン内包PEG-ポリ(L-グルタミン酸)ブロック共重合体ミセルの制がん効果に及ぼす内核ヘリックスバンドル構造の影響 (2014)
  • Author(s): 持田祐希、H. Cabral、三浦裕、長田健介、西山伸宏、片岡一則
  • Organizer: 第23回ポリマー材料フォーラム
  • Place of Presentation: 奈良県新公会堂、奈良市、奈良県
  • Year and Date: 2014-11-06 – 2014-11-07
• [Presentation] Supramolecular nanodevices for cancer diagnosis and therapy (2014)
  • Author(s): H. Cabral
  • Organizer: Seminar at MedImmune
  • Place of Presentation: 1MedImmune Way, Gathersburg, Washington, USA
  • Year and Date: 2014-10-08 – 2014-10-10
  • Invited
• [Presentation] Targeting intractable tumors and metastasis by using supramolecular nanodevices (2014)
  • Author(s): H. Cabral
  • Organizer: 12th International Nanomedicine and Drug Delivery Symposium (NanoDDS'14)
  • Place of Presentation: UNC Eshelman School of Pharmacy and Duke University, North Carolina, USA
  • Year and Date: 2014-10-06 – 2014-10-08
  • Invited
• [Presentation] Systemic targeting of lymph node metastasis by controlled design of drug-loaded polymeric micelles (2014)
  • Author(s): J. Makino, H. Cabral, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, K. Kataoka
  • Organizer: 12th International Nanomedicine and Drug Delivery Symposium (NanoDDS'14)
  • Place of Presentation: UNC Eshelman School of Pharmacy and Duke University, North Carolina, USA
  • Year and Date: 2014-10-06 – 2014-10-08
• [Presentation] Metallosomes as bioactive polymersomes formed by supramolecular assembly of block copolymer-metal complexation (2014)
  • Author(s): K. Osada, H. Cabral, Y. Mochida, Y. Anraku, A. Kishimura, N. Nishiyama, K. Kataoka
  • Organizer: 248th American Chemical Society (ACS) National Meeting & Exposition
  • Place of Presentation: Moscone Center, San Francisco, California, USA
  • Year and Date: 2014-08-10 – 2014-08-14
• [Presentation] 白金錯体制がん剤を内包する高分子ミセルのin vivo抗腫瘍効果に与える高分子高次構造の影響 (2014)
  • Author(s): 持田祐希、H. Cabral、三浦裕、F. Albertini、長田健介、西山伸宏、片岡一則
  • Organizer: 第43回医用高分子シンポジウム
  • Place of Presentation: 産業技術総合研究所臨海副都心センター、江東区、東京都
  • Year and Date: 2014-07-28 – 2014-07-29
• [Presentation] 金属配位結合を駆動力とした中空ナノ粒子構築とDDSへの応用 (2014)
  • Author(s): 長田健介、H. Cabral、持田祐希、安楽泰孝、岸村顕広、西山伸宏、片岡一則
  • Organizer: 第24回バイオ・高分子シンポジウム
  • Place of Presentation: 東京工業大学大岡山キャンパス、目黒区、東京都
  • Year and Date: 2014-07-24 – 2014-07-25
• [Presentation] Development of a specific targeting system for pancreatic tumors utilizing antibody conjugated Pt-loaded micelles (2014)
  • Author(s): J. -Y. Ahn, N. Yamada, A. Kim, T. Chida, Y. Miura, H. Cabral, Y. Matsumura, N. Nishiyama, K. Kataoka
  • Organizer: 41st Annual Meeting & Exposition of the Controlled Release Society
  • Place of Presentation: The Hilton Chicago, Chicago, Illinois, USA
  • Year and Date: 2014-07-13 – 2014-07-16
• [Presentation] Development of a glutathione sensitive polymeric micelles for the delivery of campothecin to solid tumors (2014)
  • Author(s): H.-C. Yen, H. Cabral, H. Koori, Y. Miura, P. Mi, A. Kim, N. Nishiyama, K. Kataoka
  • Organizer: 41st Annual Meeting & Exposition of the Controlled Release Society
  • Place of Presentation: The Hilton Chicago, Chicago, Illinois, USA
  • Year and Date: 2014-07-13 – 2014-07-16
• [Presentation] αヘリックスを基盤とするコアの高次構造がシスプラチンを内包する高分子ミセルの制がん効果に及ぼす影響 (2014)
  • Author(s): 持田祐希、H. Cabral、三浦裕、F. Albertini、長田健介、西山伸宏、片岡一則
  • Organizer: 第63回高分子学会年次大会
  • Place of Presentation: 名古屋国際会議場、名古屋市、愛知県
  • Year and Date: 2014-05-28 – 2014-05-30
• [Presentation] Intracerebral drug delivery treatment using a regularly-structured biodegradable gel for slow-release of gadolinium-containing nano-micelles in a glioblastoma model (2014)
  • Author(s): D. Kokuryo, P. Mi, T. Kurita, T. Yatabe, H. Cabral, S. Shibata, Y. Muragaki, H. Iseki, T. Sakai, U. -I. Chung, N. Nishiyama, T. Saga, I. Aoki, K. Kataoka
  • Organizer: Joint Annual Meeting ISMRM-ESMRMB 2014
  • Place of Presentation: Milano Congressi, Milano, Italy
  • Year and Date: 2014-05-10 – 2014-05-16