Development of novel supramolecular drug for the treatments of neointimal lesions and aortic aneurysm

• Project/Area Number: 16H05422
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: The University of Tokyo
• Principal Investigator: Miura Yutaka 東京大学, 大学院工学系研究科(工学部), 客員研究員 (40557980)
• Co-Investigator(Kenkyū-buntansha): Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911) ; 小山 博之 東京大学, 医学部附属病院, 登録研究員 (10241994)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: 超分子化学 / ナノ材料 / 超分子

Outline of Final Research Achievements

This work deals with the development of novel supramolecular drug for the treatments of neointimal lesions and aortic aneurysm in rats. Moreover, to evaluate the potentials in supramolecular drug as an anti-cancer agent, drug-effect tests were performed against a head and neck tumor model. Our findings suggest that the novel supramolecular drug achieves specific delivery of rapamycin to the rat abdominal aortic aneurysm, neointimal lesions, and solid tumor, and might contribute to establishing a drug therapy approach targeting both aortic diseases and malignant cancers.

Academic Significance and Societal Importance of the Research Achievements

現在、血管内膜肥厚や動脈硬化症などの脈管系疾患を根治に至らしめる薬剤で上市されたものは存在しない。そのため、同疾患の治療に於いては、低侵襲かつ継続的な薬物治療が可能な新規治療法の確立が求められていた。本研究では超分子化学の側面から新たに脈管系疾患を対象とした薬剤の開発を行い、血管内膜肥厚ならびに動脈瘤の進行を抑制する成果を得ている。日本における死亡原因の上位は心臓・血管に由来する疾病であり、これに対する革新的な治療戦略の開発は我が国の将来にとって最も重要な基盤研究の一つと位置づけられ、本研究の成果が今後の医療に役立つことが期待されている。

Research Products

• [Journal Article] Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors (2019)
  • Author(s): Suzuki Kazumi、Miura Yutaka、Mochida Yuki、Miyazaki Takuya、Toh Kazuko、Anraku Yasutaka、Melo Vinicio、Liu Xueying、Ishii Takehiko、Nagano Osamu、Saya Hideyuki、Cabral Horacio、Kataoka Kazunori
  • Journal Title: Journal of Controlled Release Volume: 301 Pages: 28-41
  • DOI: 10.1016/j.jconrel.2019.02.021
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epirubicin-loaded polymeric micelles effectively treat axillary lymph nodes metastasis of breast cancer through selective accumulation and pH-triggered drug release (2018)
  • Author(s): Chida Tsukasa、Miura Yutaka、Cabral Horacio、Nomoto Takahiro、Kataoka Kazunori、Nishiyama Nobuhiro
  • Journal Title: Journal of Controlled Release Volume: 292 Pages: 130-140
  • DOI: 10.1016/j.jconrel.2018.10.035
  • Peer Reviewed
• [Journal Article] Targeting ability of self-assembled nanomedicines in rat acute limb ischemia model is affected by size (2018)
  • Author(s): Suhara Masamitsu、Miura Yutaka、Cabral Horacio、Akagi Daisuke、Anraku Yasutaka、Kishimura Akihiro、Sano Masaya、Miyazaki Takuya、Nakamura Noriko、Nishiyama Ayako、Kataoka Kazunori、Koyama Hiroyuki、Hoshina Katsuyuki
  • Journal Title: Journal of Controlled Release Volume: 286 Pages: 394-401
  • DOI: 10.1016/j.jconrel.2018.07.049
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition" (2017)
  • Author(s): Hailiang Wu, Anqi Tao, John D. Martin, Sabina Quader, Xueying Liu, Kei Takahashi, Louise Hespel, Yutaka Miura, Yoshihiro Hayakawa, Tatsuro Irimura, Horacio Cabral, Kazunori Kataoka
  • Journal Title: J. Pharm. Sci, Volume: - Issue: 9 Pages: 30217-30224
  • DOI: 10.1016/j.xphs.2017.03.031
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells (2017)
  • Author(s): Miyano Kazuki、Cabral Horacio、Miura Yutaka、Matsumoto Yu、Mochida Yuki、Kinoh Hiroaki、Iwata Caname、Nagano Osamu、Saya Hideyuki、Nishiyama Nobuhiro、Kataoka Kazunori、Yamasoba Tatsuya
  • Journal Title: J Control Release Volume: 261 Pages: 275-286
  • DOI: 10.1016/j.jconrel.2017.06.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adequately-sized nanocarriers allow sustained targeted drug delivery to neointimal lesions in rat arteries (2016)
  • Author(s): R. Taniguchi, Y. Miura, H. Koyama, T. Chida, Y. Anraku, A. Kishimura, K. Shigematsu, K. Kataoka, T. Watanabe
  • Journal Title: Molecular Pharmaceutics Volume: 13 Issue: 6 Pages: 2108-2116
  • DOI: 10.1021/acs.molpharmaceut.6b00219
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nanoparticles effectively target rapamycin delivery to sites of experimental aortic aneurysm in rats (2016)
  • Author(s): T. Shirasu, H. Koyama, Y. Miura, K. Hoshina, K. Kataoka, T. Watanabe
  • Journal Title: PLOS ONE Volume: 11 Issue: 6 Pages: e0157813-e0157813
  • DOI: 10.1371/journal.pone.0157813
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 急性下肢虚血に対する高分子ナノ粒子を用いたドラッグデリバリー (2018)
  • Author(s): 三浦裕、須原正光、安楽泰孝、保科克行、カブラル オラシオ
  • Organizer: 第67回高分子討論会
• [Presentation] Helical polymer structure provides platinum-loaded polymeric micelles with favorable size and stability for effective tumor-targeting (2018)
  • Author(s): Y. Mochida, H. Cabral, Y. Miura, K. Osada, N. Nishiyama, K. Kataoka
  • Organizer: 256th ACS National Meeting & Exposition
• [Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition (2017)
  • Author(s): J. D. Martin, H. Wu, A. Tao, S. Quader, X. Liu, K. Takahashi, L. Hespel, Y. Miura, Y. Hayakawa, T. Irimura, H. Cabral, K. Kataoka
  • Organizer: 11th Annual Symposium on Nanobiotechnology 2017
  • Place of Presentation: Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] Safe cancer therapy during pregnancy by using drug-loaded polymeric micelles (2017)
  • Author(s): J. Wan, K. Mizuno, B. Xiong, Y. Mochida, Y. Miura, K. Kataoka, H. Cabral
  • Organizer: 11th Annual Symposium on Nanobiotechnology 2017
  • Place of Presentation: Kawasaki City Industrial Promotion Hall, Kawasaki, Kanagawa
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming by NF-kB inhibition (2017)
  • Author(s): J. D. Martin, H. Wu, A. Tao, S. Quader, X. Liu, K. Takahashi, L. Hespel, Y. Miura, Y. Hayakawa, T. Irimura, H. Cabral, K. Kataoka
  • Organizer: Cancer Nanotechnology Gordon Research Conference Multimodal Nano-Therapies Against Cancer
  • Int'l Joint Research
• [Presentation] An active targeting strategy against locally advanced head and neck squamous cell carcinoma harboring cancer stem-like cells via cRGD peptide-installed cisplatin-loaded nanomedicines (2017)
  • Author(s): K. Miyano, H. Cabral, Y. Miura, Y. Matsumoto, Y. Mochida, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka
  • Organizer: The 14th US-Japan Symposium on Drug Delivery Systems Conference
  • Int'l Joint Research
• [Presentation] 高分子ミセル型DDSの構造と機能に及ぼす内核構造の影響 (2017)
  • 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33回DDS学会学術大会
• [Presentation] PEG-ポリグルタミン酸の立体構造に着目した白金錯体超分子ミセルの粒径及び腫瘍標的性の制御 (2017)
  • 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66回高分子討論会
• [Presentation] Development of staurosporine/epirubicin-loaded polymeric micelles as a robust in vivo therapy against differentiated cells and cancer stem-like cells (2016)
  • Author(s): J. Zhang, H. Kinoh, T. Chida, X. Liu, Y. Miura, H. Cabral, K. Kataoka
  • Organizer: The 11th SPSJ International Polymer Conference (IPC2016)
  • Place of Presentation: Fukuoka International Confress Center, Fukuoka
  • Year and Date: 2016-12-13
  • Int'l Joint Research
• [Presentation] Nanomedicine strategies for enhancing efficacy against head and neck squamous cell carcinoma bearing cancer stem-like cells (2016)
  • Author(s): H. Cabral, K. Miyano, M. Wang, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka
  • Organizer: Frontiers2016 - Joint Symposium of the EPFL and the University of Tokyo
  • Place of Presentation: Swiss Federal Institute of Technology(EPFL), Lausanne, Switzerland
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [Presentation] Size-modulated polymeric micelles for cancer therapy during pregnancy (2016)
  • Author(s): J. Wan, K. Mizuno, B. Xiong, Y. Mochida, Y. Miura, K. Kataoka, H. Cabral
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] Assembly of α-helical polymer chains plays a key role in tumor-targeting performance of platinum-loaded polymeric micelles (2016)
  • Author(s): Y. Mochida, H. Cabral, Y. Miura, K. Osada, N. Nishiyama, K. Kataoka
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] pH-Activatable targeted nanomedicine eradicates orthotopic mesothelioma bearing recalcitrant cancer stem cell sub-population (2016)
  • Author(s): H. Kinoh, Y. Miura, S. Fukushima, H. Cabral, K. Kataoka
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] Brain tumor targeting by cRGD peptide encircled polymeric micelles loaded with potent antiglioblastoma agent epirubicin (2016)
  • Author(s): S. Quader, X. Liu, Y. Chen, P. Mi, T. Chida, T. Ishii, Y. Miura, N. Nishiyama, H. Cabral, K. Kataoka
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] Effective treatment of locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells by cRGD peptide-installed cisplatin-loaded micelles (2016)
  • Author(s): K. Miyano, H. Cabral, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] Messenger RNA-based therapeutics for the treatment of Fas-ligand induced fulminant hepatitis mouse model (2016)
  • Author(s): A. Matsui, H. Cabral, Y. Miura, Y. Matsumoto, H. Kinoh, N. Nishiyama, T. Yamasoba, K. Kataoka
  • Organizer: 3rd Internatioal Conference on Biomaterials Science in Tokyo(ICBS2016)
  • Place of Presentation: Ito Hall located at The University of Tokyo, Tokyo, Japan
  • Year and Date: 2016-11-28
  • Int'l Joint Research
• [Presentation] 環状RGDペプチドを修飾した白金制がん剤内包高分子ミセルを用いたリンパ節転移／治療抵抗性がんの治療 (2016)
  • Author(s): 持田祐希、H. Cabral、牧野惇、三浦裕、M. Wang、西山伸宏、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
  • Year and Date: 2016-09-14
• [Presentation] 難治性頭頸部扁平上皮癌に対するリガンド搭載シスプラチンミセルによる治療戦略 (2016)
  • Author(s): 宮野一樹、三浦裕、松本有、岩田要、佐谷秀行、宮園浩平、西山伸宏、H. Cabral、山岨達也、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
  • Year and Date: 2016-06-30
• [Presentation] cRGD-PICsome及びMRI脳腫瘍イメージングの研究 (2016)
  • Author(s): 川村渉、三浦裕、國領大介、青木伊知男、狩野光伸、西山伸宏、佐賀恒夫、岸村顕広、近藤史郎、片岡一則
  • Organizer: 日本分子イメージング学会第11回学会総会
  • Place of Presentation: 神戸国際会議場・展示場、神戸市、兵庫県
  • Year and Date: 2016-05-28
• [Presentation] フェニルボロン酸導入高分子ミセルによる扁平上皮がんの治療 (2016)
  • Author(s): 三浦裕、田辺亜弥、H. Cabral、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
  • Year and Date: 2016-05-25
• [Presentation] 環状RGDペプチドを修飾した白金制がん剤内包ミセルのがん幹細胞治療への応用 (2016)
  • Author(s): 持田祐希、M. Wang、H. Cabral、三浦裕、西山伸宏、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
  • Year and Date: 2016-05-25
• [Presentation] Highly ordered core structure enhances drug delivery performance of polymeric micelles incorporating platinum anticencer agents (2016)
  • Author(s): Y. Mochida, H. Cabral, Y. Miura, A. Francesco, K. Osada, N. Nishiyama, K. Kataoka
  • Organizer: 10th World Biomaterials Congress
  • Place of Presentation: Montreal Convention Center, Montreal, Canada
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] Inhibition of lymph node metastasis and effective treatment of head and neck squamous cell carcinoma via cyclic-RGD mediated delivery of cisplatin-loaded micelles (2016)
  • Author(s): 宮野一樹、三浦裕、松本有、岩田要、佐谷秀行、宮園浩平、西山伸宏、H. Cabral、山岨達也、片岡一則
  • Organizer: 第16回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学駒場キャンパス、目黒区、東京
• [Remarks] 東京大学カブラル研究室
  • URL: http://www.bmc.t.u-tokyo.ac.jp/