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

• Project/Area Number: 25750172
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biomedical engineering/Biomaterial science and engineering
• 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
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ドラッグデリバリー / 環状RGDペプチド / ナノ粒子のサイズ / アクティブターゲティング / 高分子ミセル / グリオーマ / 腫瘍ターゲティング / 制がん剤

Outline of Final Research Achievements

The aim was to evaluate the size effect of ligand-installed nanomedicines in their ability to target solid tumors. Drug-loaded micelles having 30-, 50-, 70- and 100-nm diameter were prepared, and conjugated with cyclic-RGD (cRGD) peptide for targeting of tumors overexpressing avb3 and avb5 integrins. cRGD-installed micelles (cRGD/m) showed comparable stability and drug release rates. The in vitro activity of cRGD/m against monolayer culture of glioma U87-MG cells showed that all cRGD/m had comparable cytotoxicity. In vivo, 30- and 50-nm cRGD/m suppressed the growth of U87-MG xenografts, while larger cRGD/m failed to show antitumor activity. Tumor accumulation was around 8% of injected dose per gram of tissue for 30- and 50-nm cRGD/m, whereas larger cRGD/m were lower than 2%. In vivo CLSM showed cRGD/m with 30-nm penetrated into U87-MG tumors, whereas 70-nm cRGD/m did not extravasate, indicating a size-mediated active transport mechanism.

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
• [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 Issue: 5 Pages: 4957-67
  • 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 Issue: 11 Pages: 11591-11602
  • DOI: 10.1021/nn504836s
  • Peer Reviewed
• [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: J. Control. Release Volume: 189 Pages: 1-10
  • DOI: 10.1016/j.jconrel.2014.06.018
  • Peer Reviewed
• [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 Issue: 7 Pages: 6724-6738
  • DOI: 10.1021/nn500498t
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] siRNA delivery from triblock copolymer micelles with spatially-ordered compartmants of PEG shell, siRNA-loaded intermediate layer, and hydrophobic core (2014)
  • Author(s): Hyun Jin Kim, Kanjiro Miyata, Takahiro Nomoto, Meng Zheng, Ahram Kim, Xueying Liu, Horacio Cabral, R. James Christie, Nobuhiro Nishiyama, Kazunori Kataoka
  • Journal Title: Biomaterials Volume: 35 Issue: 15 Pages: 4548-4556
  • DOI: 10.1016/j.biomaterials.2014.02.016
  • Peer Reviewed
• [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, N. Nishiyama, et al.
  • Journal Title: J. Control. Release Volume: 178 Pages: 18-24
  • DOI: 10.1016/j.jconrel.2014.01.008
  • Peer Reviewed / Open Access
• [Journal Article] Multicompartment micelles with adjustable poly (ethylene glycol) shell for efficient in vivo photodynamic therapy (2014)
  • Author(s): C. V. Synatschke, N. Nishiyama, et al.
  • Journal Title: ACS Nano Volume: (in press)(印刷中)(掲載確定) Issue: 2 Pages: 1161-1172
  • DOI: 10.1021/nn4028294
  • Peer Reviewed
• [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: J. Control. Release Volume: 174 Pages: 63-71
  • DOI: 10.1016/j.jconrel.2013.10.038
  • Peer Reviewed
• [Journal Article] Hydrothermally synthesized PEGylated calcium phosphate nanoparticles incorporating Gd-DTPA for contrast enhanced MRI diagnosis of solid tumors (2014)
  • Author(s): P. Mi, N. Nishiyama, et al.
  • Journal Title: J. Control. Release Volume: 136 Issue: 1 Pages: 157-163
  • DOI: 10.1021/ja406992w
  • Peer Reviewed
• [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
• [Journal Article] Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. (2013)
  • Author(s): S. Deshayes, N. Nishiyama, et al.
  • Journal Title: J. Am. Chem. Soc. Volume: 135 Issue: 41 Pages: 15501-15507
  • DOI: 10.1021/ja406406h
  • Peer Reviewed
• [Journal Article] Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood-brain tumor barrier (2013)
  • Author(s): Y. Miura, N. Nishiyama, et al.
  • Journal Title: ACS Nano Volume: 7 Issue: 10 Pages: 8583-8592
  • DOI: 10.1021/nn402662d
  • Peer Reviewed
• [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
  • 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
• [Presentation] Optimization of c-RGD peptide on the surface of Polymeric micelles, incorporating Epirubicin, for superior antitumor efficacy. (2013)
  • Author(s): S. Quander, J. Makino, H. Cabral, T. Ishii, Y. Miura, N. Nishiyama, K. Kataoka
  • Organizer: The 13th Pacific Polymer Conference
  • Place of Presentation: Kaohsiung, Taiwan
• [Presentation] Systemically injected polymeric micelles can inhibit the growth of lymph node metastasis (2013)
  • Author(s): H. Cabral, Jun Makino, Yu Matsumoto, Yutaka Miura, Mitsunobu Kano, Nobuhiro Nishiyama, Kazunori Kataoka Frontiers 2013 (Lausanne, Switzerland)
  • Organizer: Frontiers 2013-Joint EPFL/University of Tokyo Symposium on "Frontiers in Nanomedicine and Imaging"
  • Place of Presentation: Laussane, Switzerland
• [Presentation] Targeting cancer stem cells with platinum anti-cancer drug-incorporated polymeric micelles (2013)
  • Author(s): M. Wang, Y. Miura, H. Cabral, N. Nishiyama, K. Kataoka
  • Organizer: European Cancer Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Intravital Microscopy for DDS Evaluation and Development (2013)
  • Author(s): Y. Matsumoto, T. Nomoto, K. Toh, K. Miyano, H. Cabral, M.Murakami, R. J. Christie, T. A. Tockary, K. Osada, Y. Miura, N. Nishiyama, T. Yamasoba, K. Kataoka
  • Organizer: The 12th US-Japan Symposium on Drug Delivery Systems (Hawaii, USA)
  • Place of Presentation: Hawaii, USA