Ligand-Linked Polymeric Micelles for Targeted Delivery of Platinum Anti-Cancer Drug into Malignant Tumor

• Project/Area Number: 24659584
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: The University of Tokyo
• Principal Investigator: MIURA Yutaka 東京大学, 医学(系)研究科(研究院), 助教 (40557980)
• Project Period (FY): 2012-04-01 – 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: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ドラッグデリバリー / ナノ材料 / 脳腫瘍

Outline of Final Research Achievements

The installation of ligand molecules such as peptides onto nanocarriers is now considered an important strategy to improve the selectivity of drug delivery. Among these ligands, Arg-Gly-Asp (RGD) peptides are promising ligand molecules for targeting alpha v beta 3 integrins, which are overexpressed in angiogenic sites and tumors, such as human glioblastoma (U87MG). In this study, the cyclic RGD was introduced to the maleimide-surface functionalized dichloro(1,2-diamino-cyclohexane)platinum(II)-loaded micelles by Michael addition reaction. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma. It was confirmed that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant anti-tumor effects in an orthotopic mouse model of U87MG human glioblastoma.

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] 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] Selective intracellular delivery of proteasome inhibitors through pH-sensitive polymeric micelles directed to efficient 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.2014.05.048
  • 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: J. Control. Release Volume: 189 Pages: 1-10
  • DOI: 10.1016/j.jconrel.2014.06.018
  • Peer Reviewed
• [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] Actively-targeted polyion complex micelles stabilized by cholesterol and disulfide cross-linking for systemic delivery of siRNA to solid tumors (2014)
  • Author(s): Y. Oe, R. J. Christie, M. Naito, S. A. Low, S. Fukushima, K. Toh, Y. Miura, Y. Matsumoto, N. Nishiyama, K. Miyata, K. Kataoka
  • Journal Title: Biomaterials Volume: 35 Issue: 27 Pages: 7887-7895
  • DOI: 10.1016/j.biomaterials.2014.05.041
  • Peer Reviewed
• [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
• [Journal Article] Transcription factor YYI contributes to tumor growth by stabilizing hypoxia fact or HIF-lα in a p53-independent manner. (2013)
  • Author(s): S. Wu, N. Nishiyama, et al.
  • Journal Title: Cancer Res. Volume: 73 Issue: 6 Pages: 1787-1799
  • DOI: 10.1158/0008-5472.can-12-0366
  • Peer Reviewed
• [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] 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] 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] Efficient intracellular delivery of monoclonal antibodies into the living cells by charge-conversional polyionic complex micelles (2014)
  • Author(s): A. Kim, Y. Miura, T. Ishii, 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] Ligand-linked polymeric micelles for targeted delivery of platinum anti-cancer drug into malignant tumor (2014)
  • Author(s): Y. Miura, K. Kataoka
  • Organizer: The Drug Discovery & Therapy World Congress 2014
  • Place of Presentation: John B. Hynes Veterans Mmemorial Convention Center, Boston, Massachusetts, USA
  • Year and Date: 2014-06-16 – 2014-06-19
  • Invited
• [Presentation] Sub- 100 Nm size of polymeric micelles incorporating platinum anticancer drugs mediates the targeting to lymph node metastasis after systemic injection (2014)
  • Author(s): H. Cabral, P. Mi, H. Wu, J. Makino, Y. Matsumoto, Y. Miura, K. Toh, N. Nishiyama, N. Yamada, K. Kataoka
  • Organizer: FIRST合同国際シンポジウム 難治がんを克服する―次世代の診断、治療が描く未来 Overcoming Intractable Cancer- a new path to the future
  • Place of Presentation: 伊藤国際学術研究センター、文京区、東京都
• [Presentation] Growth inhibition of tumor by ligand-mediated drug delivery system (2014)
  • Author(s): Y. Miura, H. Cabral, N. Nishiyama, K. Kataoka
  • Organizer: FIRST合同国際シンポジウム 難治がんを克服する―次世代の診断、治療が描く未来 Overcoming Intractable Cancer- a new path to the future
  • Place of Presentation: 伊藤国際学術研究センター、文京区、東京都
• [Presentation] Systemically injected polymeric micelles can inhibit the growth of lymph node metastasis (2013)
  • Author(s): H. Cabral, J. Makino, Y. Matsumoto, Y. Miura, M. Kano, N. Nishiyama, K. Kataoka
  • Organizer: FRONTIERS2013 - Joint EPFL/University of Tokyo Symposium on "Frontiers in Nanomedicine and Imaging"
  • Place of Presentation: Swiss Federal Institute of Technology, Lausanne, Switzerland
• [Presentation] Development of platinum incorporated polymeric micelle with peptide-ligand (2013)
  • Author(s): Y. Miura, N. Yamada, N. Nishiyama, K. Kataoka
  • Organizer: FRONTIERS2013 - Joint EPFL/University of Tokyo Symposium on "Frontiers in Nanomedicine and Imaging"
  • Place of Presentation: Swiss Federal Institute of Technology, Lausanne, 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, H. Saya K. Kazunori
  • Organizer: European Cancer Congress 2013
  • Place of Presentation: Avenue E. Mounier 83 B-1200 Brussels, Belgium
• [Presentation] Optimization of c-RGD peptide on the surface of polymeric micelles, incorporating epirubicin, for superior antitumor efficacy (2013)
  • Author(s): S. Quader, J. Makino, H. Cabral, T. Ishii, Y. Miura, N. Nishiyama, K. Kataoka
  • Organizer: The 13th Pacific Polymer Conference
  • Place of Presentation: Grand Hi-Lai Hotel Arena Branch, Kaohsiung, Taiwan
• [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
  • Place of Presentation: Lahaina, Maui, Hawaii
• [Presentation] pH応答性エピルビシン内包高分子ミセル(K-912(NC-6300))のヒト乳がん移植モデルマウスに対する治療効果 (2013)
  • Author(s): 千田司、三浦裕、西山伸宏、片岡一則、加藤泰己、奥村睦男、稲木敏男
  • Organizer: 第28年会 日本薬剤学会
  • Place of Presentation: ウインクあいち、名古屋市、愛知県
• [Presentation] ペプチドリガンドを有するプラチナ制がん剤内包高分子型ミセルの開発と機能評価 (2013)
  • Author(s): 三浦裕、山田直生、西山伸宏、片岡一則
  • Organizer: 第62回高分子年次大会
  • Place of Presentation: 京都国際会館、京都市、京都府
• [Presentation] リガンド導入ミセルの粒径に依存した抗腫瘍効果の研究 (2013)
  • Author(s): 山田直生、三浦裕、アン ジュヨン、カブラル オラシオ、西山伸宏、片岡一則
  • Organizer: 第62回高分子年次大会
  • Place of Presentation: 京都国際会館、京都市、京都府
• [Presentation] Development of antibody conjugated polymeric micelle for enhanced targeting drug delivery system (2013)
  • Author(s): J. -Y. Ahn, Y. Miura, H. Uchida, N. Yamada, H. Cabral, N. Nishiyama, K. Kataoka
  • Organizer: 第62回高分子年次大会
  • Place of Presentation: 京都国際会館、京都市、京都府
• [Presentation] ポリイオンコンプレックス型ベシクルによる腹部大動脈瘤の蛍光イメージング (2013)
  • Author(s): 三浦裕、安楽泰孝、赤井淳、岸村顕広、西山伸宏、小山博之、片岡一則
  • Organizer: 第62回高分子年次大会
  • Place of Presentation: 京都国際会館、京都市、京都府
• [Presentation] pH応答性エピルビシン内包高分子ミセルの特性評価並びに制がん活性に関する検討 (2013)
  • Author(s): 千田司、三浦裕、西山伸宏、片岡一則、加藤泰己、奥村睦男、稲木敏男
  • Organizer: 第62回高分子年次大会
  • Place of Presentation: 京都国際会館、京都市、京都府
• [Presentation] Development of antibody conjugated polymeric micelle for targeted drug delivery system (2013)
  • Author(s): J. -Y. Ahn, Y. Miura, N. Yamada, A. Kim, H. Uchida, H. Cabral, N. Nishiyama, K. Kataoka
  • Organizer: 第13回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学本郷キャンパス伊藤国際学術研究センター、文京区、東京都
• [Presentation] Targeting cancer stem cells with platinum anti-cancer drug-incorporated polymeric micelles (2013)
  • Author(s): M. Wang, 三浦裕, H. Cabral, 西山伸宏、片岡一則
  • Organizer: 第29回日本DDS学会学術集会
  • Place of Presentation: 京都テルサ、京都市、京都府
• [Presentation] 下咽頭癌を標的としたDACHPt内包高分子ミセルを用いたドラッグデリバリーシステムの開発 (2013)
  • Author(s): 木村美和子, H. Cabral, 三浦裕, 狩野光伸, 西山伸宏, 片岡一則
  • Organizer: 第29回日本DDS学会学術集会
  • Place of Presentation: 京都テルサ、京都市、京都府
• [Presentation] 粒径を精密制御したリガンド導入高分子ミセルの開発および抗腫瘍効果の評価 (2013)
  • Author(s): 山田直生、三浦裕、アン ジュヨン、西山伸宏、片岡一則
  • Organizer: 第29回日本DDS学会学術集会
  • Place of Presentation: 京都テルサ、京都市、京都府
• [Presentation] サイズとリガンド導入率の調整が可能なポリイオンコンプレックス型ベシクル (PICsome) の構築と機能評価 (2013)
  • Author(s): 川村渉、安楽泰孝、岸村顕広、三浦裕、片岡一則
  • Organizer: 第62回高分子学会討論会
  • Place of Presentation: 金沢大学角間キャンパス、金沢、石川
• [Presentation] 粒径とリガンド導入率を精密制御した白金制がん剤内包ミセルの合成ならびに脳腫瘍に対する治療効果 (2013)
  • Author(s): 山田直生、三浦裕、J. -Y. Ahn、H. Cabral、西山伸宏、片岡一則
  • Organizer: 第62回高分子学会討論会
  • Place of Presentation: 金沢大学角間キャンパス、金沢、石川
• [Presentation] 治療抵抗性がん治療に向けたリガンド導入高分子ミセルの合成 (2013)
  • Author(s): 鈴木利洋、石井武彦、三浦裕、西山伸宏、片岡一則
  • Organizer: 第35回日本バイオマテリアル学会大会
  • Place of Presentation: タワーホール船堀、江戸川、東京
• [Presentation] 抗体結合高分子ミセルの開発とアクティブターゲティング DDS への応用 (2013)
  • Author(s): J. -Y. Ahn、三浦裕、山田直生、K. Ahram、松村保広、西山伸宏、片岡一則
  • Organizer: 第35回日本バイオマテリアル学会大会
  • Place of Presentation: タワーホール船堀、江戸川、東京
• [Presentation] Disulfide crosslinked charge-conversional polymeric micelles for the efficient intracellular delivery of monoclonal antibodies (2013)
  • Author(s): K. Ahram、三浦裕、石井武彦、西山伸宏、片岡一則
  • Organizer: 第35回日本バイオマテリアル学会大会
  • Place of Presentation: タワーホール船堀、江戸川、東京
• [Presentation] pH 応答性エピルビシン内包高分子ミセルの特性評価並びに制がん活性に関する検討 (2013)
  • Author(s): 千田司、三浦裕、西山伸宏、片岡一則、加藤泰己、奥村睦男、稲木敏男
  • Organizer: 第35回日本バイオマテリアル学会大会
  • Place of Presentation: タワーホール船堀、江戸川、東京
• [Presentation] 環状RGDリガンドを有するプラチナ制がん剤内包ミセルの開発と悪性腫瘍への展開 (2013)
  • Author(s): 三浦裕、山田直生、西山伸宏、片岡一則
  • Organizer: 第22回ポリマー材料フォーラム
  • Place of Presentation: タワーホール船堀、江戸川、東京
• [Presentation] Size effect on the antitumor efficacy of cRGD-installed polymeric micelles against brain tumor (2013)
  • Author(s): Naoki Yamada; Yutaka Miura 他3名
  • Organizer: ICBS2013 (2nd International Conference of Biomaterials Science in Tsukuba)
  • Place of Presentation: つくば国際会議場（茨城県）
• [Presentation] Secondary structure of PEG-b-poly(glutamic acid) copolymer determines the drug delivery efficiency of cisplatin-loaded polymeric micelles (2013)
  • Author(s): Yuki Mochida, Yutaka Miura 他5名
  • Organizer: 16th International Symposium on RECENT ADVANCES IN DRUG DELIVERY SYSTEMS
  • Place of Presentation: Salt Lake City (USA)
• [Presentation] Preparation of antibody introduced micelle consist of well defined end-functionalized poly(ethylene oxide)-b-poly(amino acid) (2012)
  • Author(s): Jooyeon Ahn; Yutaka Miura 他4名
  • Organizer: The 9th International Polymer Conference（IPC2012)
  • Place of Presentation: 神戸コンベンションセンター（兵庫県）
• [Presentation] Characterization and evaluation of the charge-conversional polyionic complexmicelles incorporating monoclonal antibodies (2012)
  • Author(s): Ahram Kim, Yutaka Miura 他5名
  • Organizer: The 9th International Polymer Conference（IPC2012)
  • Place of Presentation: 神戸コンベンションセンター（兵庫県）
• [Presentation] Preparation and pH-responsive property of the charge-conversional polyionic complex micelles incorporating immunoreactive monoclonal antibodies (2012)
  • Author(s): Ahram Kim, Yutaka Miura 他5名
  • Organizer: The 61st Symposium on Macromolecules
  • Place of Presentation: 名古屋工業大学（愛知県）
• [Presentation] Preparation and Evaluation of the Charge-Conversional Protein Incorporated Polyionic Complex Micelles (2012)
  • Author(s): Ahram Kim, Yutaka Miura 他5名
  • Organizer: SPSJ Annual meeting
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] Formation and sustained-dissociation of antitumor platinum-loaded micelles regulated by secondary structure of poly(amino acids) in their core (2012)
  • Author(s): Yuki Mochida, Yutaka Miura 他5名
  • Organizer: 9th World Biomaterials Congress
  • Place of Presentation: Chengdu (China)
• [Presentation] 白金錯体制がん剤内包ミセルのコア高次構造が形態及び薬剤機能に及ぼす影響 (2012)
  • Author(s): 持田祐希、三浦裕 他5名
  • Organizer: 第61回高分子学会年次大会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] αヘリックス構造形成に基づくPEG‐ポリグルタミン酸ブロック共重合体／制がん剤ダハプラチン内包高分子ミセルの機能向上 (2012)
  • Author(s): 持田祐希、三浦裕 他5名
  • Organizer: 第61回高分子討論会
  • Place of Presentation: 名古屋工業大学（愛知県）
• [Presentation] Structure and enhanced pharmacokinetics of antitumor platinum-loaded micelles regulated by secondary structure in their core (2012)
  • Author(s): Yuki Mochida, Yutaka Miura 他5名
  • Organizer: The 9th SPSJ International Polymer Conference
  • Place of Presentation: 神戸コンベンションセンター（兵庫県）
• [Presentation] 悪性脳腫瘍を標的としたリガンド介在型ドラッグデリバリーシステムの開発 (2012)
  • Author(s): 三浦裕、Horacio Cabral, 西山伸宏、片岡一則
  • Organizer: 第28回日本DDS学会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
• [Book] The Frontiers in Life Sciencesシリーズ 生命科学から創薬へのイノベーション 第18章 ドラッグデリバリー (2014)
  • Author(s): 三浦裕、片岡一則
  • Total Pages: 8
  • Publisher: 南山堂
• [Remarks] 東京大学片岡研究室
  • URL: http://www.bmw.t.u-tokyo.ac.jp/
• [Remarks] 東京大学片岡研究室
  • URL: http://www.bmw.t.u-tokyo.ac.jp/
• [Patent(Industrial Property Rights)] 抗Ｔｉｓｓｕｅ Ｆａｃｔｏｒモノクローナル抗体 (2014)
  • Inventor(s): 片岡 一則, 西山 伸宏, 三浦 裕, 他8名
  • Industrial Property Rights Holder: 片岡 一則, 西山 伸宏, 三浦 裕, 他8名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-018586
  • Filing Date: 2014-02-03
• [Patent(Industrial Property Rights)] 環状ＲＧＤ配列含有ペプチドを含む抗癌剤 (2013)
  • Inventor(s): 片岡 一則, 西山 伸宏, 三浦 裕
  • Industrial Property Rights Holder: 片岡 一則, 西山 伸宏, 三浦 裕
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-11-29
  • Overseas
• [Patent(Industrial Property Rights)] 高分子ナノ粒子複合体、及びそれを含むＭＲＩ造影用組成物 (2013)
  • Inventor(s): 片岡 一則, 西山 伸宏, 三浦 裕, 他6名
  • Industrial Property Rights Holder: 片岡 一則, 西山 伸宏, 三浦 裕, 他6名
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-173866
  • Filing Date: 2013-08-23
• [Patent(Industrial Property Rights)] 環状ＲＧＤ配列含有ペプチドを含む抗癌剤 (2012)
  • Inventor(s): 片岡一則、西山伸宏、三浦裕
  • Industrial Property Rights Holder: 片岡一則、西山伸宏、三浦裕
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-261225
  • Filing Date: 2012-11-29