Development of the next generation polymeric nano DDS for intractable head and neck cancer

• Project/Area Number: 16K11226
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: The University of Tokyo
• Principal Investigator: Matsumoto Yu 東京大学, 医学部附属病院, 助教 (80548553)
• Research Collaborator: Miyano Kazuki ; Horacio Cabral ; Inoue Yuta ; Igarashi Kazunori ; Toh Kazuko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 生体イメージング / ナノテクノロジー / 頭頚部外科学

Outline of Final Research Achievements

The study aims to incorporate multiple functions into the polymeric nano DDS. The intravital kinetics of the nano DDS were analyzed to optimize the molecular modification. The tongue carcinoma cells and oral carcinoma cells were used to analyze the antitumor activity of the nano DDS. The PEG length was determined as the molecular weight of 12000 according to the blood circulation assay. The tumor-targeting molecule was installed on the surface of nano DDS, and the linking ratio was optimized as 20%. IVIS imaging system and intravital confocal microscopy were used to analyze the intratumoral distribution of the nano DDS. Our results suggested that the installation of the cRGD peptide on the nano DDS promoted the targeting of tumor and metastatic lymph node, and improved antitumor efficacy and survival.

Academic Significance and Societal Importance of the Research Achievements

腫瘍組織の血管透過性に依存した「受動的ターゲティング」ナノDDSでは治療が難しいがんを克服したいと考えています。標的指向分子を搭載した次世代の高分子ナノDDSを開発しました。細胞実験や動物実験を行い、cRGDを搭載したナノDDSが腫瘍や転移性リンパ節に集積して治療効果を改善することを確認しました。今後も様々な分子修飾による作り込みと機能評価を行い、ナノDDSの開発を進めます。

Research Products

• [Journal Article] Pure Skin Perforator Flaps (2018)
  • Author(s): Narushima Mitsunaga、Yamasoba Tatsuya、Iida Takuya、Matsumoto Yu、Yamamoto Takumi、Yoshimatsu Hidehiko、Timothy Shim、Pafitanis Georgios、Yamashita Shuji、Koshima Isao
  • Journal Title: Plastic and Reconstructive Surgery Volume: 142
  • DOI: 10.1097/prs.0000000000004698
• [Journal Article] The adhesion molecule cadherin 11 is essential for acquisition of normal hearing ability through middle ear development in the mouse (2018)
  • Author(s): Kiyama Yuji、Kikkawa Yayoi S.、Kinoshita Makoto、Matsumoto Yu、Kondo Kenji、Fujimoto Chisato、Iwasaki Shinichi、Yamasoba Tatsuya、Manabe Toshiya
  • Journal Title: Lab Invest. Volume: 98 Pages: 1364-1374
  • DOI: 10.1038/s41374-018-0083-y
  • Peer Reviewed / Open Access
• [Journal Article] Glycaemic control boosts glucosylated nanocarrier crossing the BBB into the brain. (2018)
  • Author(s): Y. Anraku, H. Kuwahara, Y. Fukusato, A. Mizoguchi, T. Ishii, K. Nitta, Y. Matsumoto, K. Toh, K. Miyata, S. Uchida, K. Nishina, K. Osada, K. Itaka, N. Nishiyama, H. Mizusawa, T. Yamasoba, T. Yokota, K. Kataoka
  • Journal Title: Nat. Commun. Volume: 8 Pages: 1-001
  • DOI: 10.1038/s41467-017-00952-3
  • Peer Reviewed / Open Access
• [Journal Article] Polyplex micelle installing intracellular self-processing functionalities without free catiomers for safe and efficient systemic gene therapy through tumor vasculature targeting. (2017)
  • Author(s): Q. Chen, K. Osada, Z. Ge, S. Uchida, T. A. Tockary, A. Dirisala, A. Matsui, K. Toh, K. M. Takeda, X. Liu, T. Nomoto, T. Ishii, M. Oba, Y. Matsumoto, K. Kataoka
  • Journal Title: Biomaterials Volume: 113 Pages: 253-265
  • DOI: 10.1016/j.biomaterials.2016.10.042
  • Peer Reviewed
• [Journal Article] Therapeutic vesicular nanoreactors with tumor-specific activation and self-destruction for synergistic tumor ablation. (2017)
  • Author(s): J. Li, A. Dirisala, Z. Ge, Y. Wang, W. Yin, W. Ke, K. Toh, J. Xie, Y. Matsumoto, Y. Anraku, K. Osada, K. Kataoka
  • Journal Title: Angew. Chem. Int. Ed. Volume: 56 Pages: 14025-14030
  • DOI: 10.1002/anie.201706964
  • Peer Reviewed / Int'l Joint Research
• [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] Molecularly Imprinted Nanogels Acquire Stealth In Situ by Cloaking Themselves with Native Dysopsonic Proteins (2017)
  • Author(s): Takeuchi Toshifumi、Kitayama Yukiya、Sasao Reo、Yamada Takuya、Toh Kazuko、Matsumoto Yu、Kataoka Kazunori
  • Journal Title: Angewandte Chemie International Edition Volume: 56 Pages: 7088-7092
  • DOI: 10.1002/anie.201700647
  • Peer Reviewed
• [Journal Article] Systemically Injectable Enzyme-Loaded Polyion Complex Vesicles as In Vivo Nanoreactors Functioning in Tumors. (2016)
  • Author(s): Anraku Y, Kishimura A, Kamiya M, Tanaka S, Nomoto T, Toh K, Matsumoto Y, Fukushima S, Sueyoshi D, Kano MR, Urano Y, Nishiyama N, Kataoka K.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 55 Pages: 560-5
  • DOI: 10.1002/anie.201508339
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder. (2016)
  • Author(s): Kikuta S, Matsumoto Y, Kuboki A, Nakayama T, Asaka D, Otori N, Kojima H, Sakamoto T, Akinori K, Kanaya K, Ueha R, Kagoya R, Nishijima H, Toma-Hirano M, Kikkawa Y, Kondo K, Tsunoda K, Miyaji T, Yamaguchi T, Kataoka K, Mori K, Yamasoba T.
  • Journal Title: Sci Rep. Volume: 6 Pages: 35361-35361
  • DOI: 10.1038/srep35361
  • NAID: 130006708720
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Hearing Outcomes of Cochlear Implantation in Waardenburg Syndrome. (2016)
  • Author(s): Koyama H, Kashio A, Sakata A, Tsutsumiuchi K, Matsumoto Y, Karino S, Kakigi A, Iwasaki S, Yamasoba T.
  • Journal Title: Biomed Res Int Volume: なし Pages: 2854736-2854736
  • DOI: 10.1155/2016/2854736
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced Efficacy against Cervical Carcinomas through Polymeric Micelles Physically Incorporating the Proteasome Inhibitor MG132. (2016)
  • Author(s): Matsumoto Y, Miyamoto Y, Cabral H, Matsumoto Y, Nagasaka K, Nakagawa S, Yano T, Maeda D, Oda K, Kawana K, Nishiyama N, Kataoka K, Fujii T
  • Journal Title: Cancer Sci. Volume: in press Pages: 773-781
  • DOI: 10.1111/cas.12926
  • NAID: 120007089072
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery (2016)
  • Author(s): Yu Matsumoto, Joseph W. Nichols, Kazuko Toh, Takahiro Nomoto, Horacio Cabral, Yutaka Miura, R. James Christie, Naoki Yamada, Tadayoshi Ogura, Mitsunobu R. Kano, Yasuhiro Matsumura, Nobuhiro Nishiyama, Tatsuya Yamasoba, You Han Bae, Kazunori Kataoka
  • Journal Title: Nat. Nanotechnol. Volume: - Pages: 533-538
  • DOI: 10.1038/nnano.2015.342
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Systemic Delivery of Sirna by Actively Targeted Polyion Complex Micelles for Silencing the E6 and E7 Human Papillomavirus Oncogenes (2016)
  • Author(s): Nishida H, Matsumoto Y, Kawana K, Christie RJ, Naito M, Kim BS, Toh K, Min HS, Yi Y, Matsumoto Y, Kim HJ, Miyata K, Taguchi A, Tomio K, Yamashita A, Inoue T, Nakamura H, Fujimoto A, Sato M, Yoshida M, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Nishiyama N, Kataoka K, Osuga Y, Fujii T
  • Journal Title: Journal of Controlled Release Volume: in press Pages: 29-37
  • DOI: 10.1016/j.jconrel.2016.03.016
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Calcium phosphate-based organic-inorganic hybrid nanocarriers with pH-responsive on/off switch for photodynamic therapy (2016)
  • Author(s): T. Nomoto, S. Fukushima, M. Kumagai, K. Miyazaki, A. Inoue, P. Mi, Y. Maeda, K. Toh, Y. Matsumoto, Y. Morimoto, A. Kishimura, N. Nishiyama, K. Kataoka
  • Journal Title: Biomaterials Scinece Volume: 印刷中 Pages: 826-38
  • DOI: 10.1039/c6bm00011h
  • Peer Reviewed
• [Journal Article] Analyzing Spatiotemporal Distribution of Uniquely Fluorescent Nanoparticles in Xenograft Tumors (2016)
  • Author(s): Stirland DL, Matsumoto Y, Toh K, Kataoka K, Bae YH
  • Journal Title: J Control Release Volume: in press Pages: 38-44
  • DOI: 10.1016/j.jconrel.2016.02.016
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeted systemic delivery of siRNA to cervical cancer model using cyclic RGD-installed unimer polyion complex-assembled gold nanoparticles. (2016)
  • Author(s): Y. Yi, H. -J. Kim, P. Mi, M. Zheng, H. Takemoto, K. Toh, B. -S. Kim, K. Hayashi, M. Naito, Y. Matsumoto, K. Miyata, K. Kataoka
  • Journal Title: Journal of Controlled Release Volume: 244 Pages: 247-256
  • DOI: 10.1016/j.jconrel.2016.08.041
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 外科的治療で軽快した鼓膜炎の1例 (2016)
  • Author(s): 畑裕子, 奥野妙子, 竹内成夫, 吉田亜由, 松本有, 山崎葉子
  • Journal Title: Otology Japan Volume: 26 Pages: 639-643
  • NAID: 130007594903
  • Peer Reviewed
• [Presentation] 先天性外耳道閉鎖症における鼓索神経、顔面神経のCTによる評価 (2018)
  • Author(s): 星雄二郎、樫尾明憲、松本有、近藤健二、山岨達也
  • Organizer: 第41回日本顔面神経学会
• [Presentation] 鼓索神経の走行と分類 (2018)
  • Author(s): 松本有
  • Organizer: 第41回日本顔面神経学会
• [Presentation] In situステルス性獲得にもとづく長期血中滞留性金ナノ粒子内包分子インプリントナノゲルの創製 (2018)
  • Author(s): 北山雄己哉、山田託也、赤坂浩亮、西村勇哉、五十嵐一紀、松本有、佐々木良平、竹内俊文
  • Organizer: 第34回日本DDS学会学術集会
• [Presentation] pHおよびグルコースに応答してPEGが脱離する高分子ミセルの構築 (2018)
  • Author(s): 小路恭子、宮崎拓也、持田祐希、L. Hespel、籐加珠子、福島重人、松本有、松元亮、H. Cabral、片岡一則
  • Organizer: 第34回日本DDS学会学術集会
• [Presentation] 高速共焦点/二光子顕微鏡を用いた生体イメージング (2018)
  • Author(s): 松本有
  • Organizer: 金沢大学がん進展制御研究所「多光子顕微鏡セミナー」
  • Invited
• [Presentation] 浅在化鼓膜に対する修正手術後再浅在化のCT画像における予測因子 (2018)
  • Author(s): 寺村侑、樫尾明憲、星雄二郎、松本有、岩崎真一、山岨達也
  • Organizer: 第28回耳科学会
• [Presentation] 先天性外耳道閉鎖症・狭窄症における術中の鼓索神経出現を予測する因子についての検討 (2018)
  • Author(s): 星雄二郎、樫尾明憲、松本有、岩崎真一、山岨達也
  • Organizer: 第28回日本耳科学会
• [Presentation] 内耳病態研究の未来 組織透明化と機械学習を用いた蝸牛地図作成 (2018)
  • Author(s): 浦田真次、飯田忠恒、水嶋優、藤本千里、松本有、岡部繁男、山岨達也
  • Organizer: 第28回日本耳科学会
• [Presentation] CT画像による鼓室内の鼓索神経の走行パターンの解析 (2018)
  • Author(s): 浦中司、松本有、星雄二郎、樫尾明憲、岩崎真一、山岨達也
  • Organizer: 第28回日本耳科学会
• [Presentation] 低位中頭蓋窩症例のCTによる評価の検討 (2018)
  • Author(s): 中澤良太、樫尾明憲、星雄二郎、浦中司、松本有、岩崎真一、山岨達也
  • Organizer: 第28回日本耳科学会
• [Presentation] 放射線治療のための金ナノ粒子内包分子インプリントポリマーナノゲルの開発 (2018)
  • Author(s): 北山雄己哉、山田託也、木口健太朗、吉田碧衣、赤坂浩亮、西村勇哉、五十嵐一紀、松本有、佐々木良平、竹内俊文
  • Organizer: 第40回日本バイオマテリアル学会大会
• [Presentation] 血液脳関門を効率的に通過する脳へのドラッグデリバリーシステムの開発 (2018)
  • Author(s): 桑原宏哉、安楽泰孝、福里優、石井武彦、新田佳子、松本有、籐加珠子、宮田完二郎、内田智士、仁科一隆、長田健介、位高啓史、水澤英洋、片岡一則、横田隆徳
  • Organizer: 第36回日本神経治療学会学術集会
• [Presentation] Development of polymeric micelles for mitochondria targeting through Installation of phosphocoline ligands (2018)
  • Author(s): T. Miyazaki、K. Igarashi、Y. Matsumoto、K. Kataoka、H. Cabral
  • Organizer: 1st G'L'owing Polymer Symposium in KANTO
  • Int'l Joint Research
• [Presentation] Molecularly imprinted nanogels acquiring stealth capability in situ via controlling protein corona via molecular imprinting-based protein recognition (2017)
  • Author(s): Kitayama Y, Yamada T, Kuguchi K, Toh K, Matsumoto Y, Kataoka K, Takeuchi T
  • Organizer: The 15th International Conference on Advanced Materials (IUMRS-ICAM 2017)
  • Int'l Joint Research
• [Presentation] プロテインコロナ組成を制御してステルス性を獲得する分子認識ナノ粒子 (2017)
  • Author(s): 竹内俊文, 吉田碧衣, 木口健太朗, 山田託也, 藤加珠子, 松本有, 片岡一則, 北山雄己哉
  • Organizer: 第39回日本バイオマテリアル学会大会
• [Presentation] 耳科手術用骨鋭匙ハンドルの改良 (2017)
  • Author(s): 松本有, 柿木章伸, 星雄二郎, 樫尾明憲, 岩崎真一
  • Organizer: 第27回日本耳科学会総会・学術講演会
• [Presentation] アブミ骨陥入を伴う外傷性外リンパ瘻に対する内視鏡下内耳窓閉鎖術 (2017)
  • Author(s): 佐原利人, 松本有, 星雄二郎, 樫尾明憲, 岩崎真一, 山岨達也
  • Organizer: 第27回日本耳科学会総会・学術講演会
• [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): Miyano K, Cabral H, Miura Y, Matsumoto Y, Mochida Y, Kinoh H, Nishiyama N, Yamasoba T, Kataoka K
  • Organizer: The 14th US-Japan Symposium on Drug Delivery Systems Conference
  • Int'l Joint Research
• [Presentation] Elucidation and control of dynamic tumor vessel permeability: nano-eruption (2017)
  • Author(s): Inoue Y, Matsumoto Y, Toh K, Miyano K, Cabral H, Igarashi K, Iwasaki S, Yamasoba T, Kataoka K
  • Organizer: The 14th US-Japan Symposium on Drug Delivery Systems Conference
  • Int'l Joint Research
• [Presentation] 動的な腫瘍血管透過経路の発見 (2017)
  • Author(s): 松本有, 山岨達也
  • Organizer: 第118回日本耳鼻咽喉科学会・学術講演会
• [Presentation] 卵円窓閉鎖に対して伝音再建手術を施行した5症例の検討 (2017)
  • Author(s): 星雄二郎, 樫尾明憲, 松本有, 狩野章太郎, 柿木章伸, 岩崎真一, 山岨達也
  • Organizer: 第118回日本耳鼻咽喉科学会・学術講演会
• [Presentation] 内視鏡下内耳窓閉鎖術を行った外リンパ瘻の3症例 (2017)
  • Author(s): 勝然昌子, 松本有, 星雄二郎, 樫尾明憲, 狩野章太郎, 岩崎真一, 山岨達也
  • Organizer: 第118回日本耳鼻咽喉科学会・学術講演会
• [Presentation] 浅在化鼓膜の検討 (2017)
  • Author(s): 寺村侑, 松本有, 星雄二郎, 樫尾明憲, 狩野章太郎, 岩崎真一, 山岨達也
  • Organizer: 第118回日本耳鼻咽喉科学会・学術講演会
• [Presentation] Forster resonance energy transferを用いたsiRNA安定性の定量的評価 (2017)
  • Author(s): 藤加珠子, 松本有, 渡邊秀美代, 福島重人, 宮田完二郎, 片岡一則
  • Organizer: 第66回高分子学会年次大会
• [Presentation] プロテインコロナ制御によりステルス性を獲得する分子インプリントナノゲル (2017)
  • Author(s): 北山雄己哉, 木口健太朗, 山田託也, 藤加珠子, 松本有, 片岡一則, 竹内俊文
  • Organizer: 第66回高分子学会年次大会
• [Presentation] 動的な腫瘍血管透過性（nano eruption）の制御 (2017)
  • Author(s): 井上雄太, 松本有, 藤加珠子, 宮野一樹, Cabral H, 山岨達也, 片岡一則
  • Organizer: 第33回DDS学会学術大会
• [Presentation] In vivoタンパク質認識によってステルス性を獲得する腫瘍蓄積性分子インプリントナノゲル (2017)
  • Author(s): 北山雄己哉, 山田託也, 木口健太郎, 藤加珠子, 松本有, 片岡一則, 竹内俊文
  • Organizer: 第33回DDS学会学術大会
• [Presentation] 表面に形成されるプロテインコロナ組成を制御してステルス性を獲得する分子インプリントナノゲル (2017)
  • Author(s): 竹内俊文, 木口健太郎, 山田託也, 藤加珠子, 松本有, 片岡一則, 北山雄己哉
  • Organizer: 第66回高分子討論会
• [Presentation] 高速共焦点顕微鏡を用いた生体イメージング (2017)
  • Author(s): 松本有
  • Organizer: 第2回岡山大学最先端イメージングセミナー
  • Invited
• [Presentation] Manipulation of Tumor Vascular Bursts (2017)
  • Author(s): Matsumoto Y, Inoue Y, Toh K, Miyano K, Cabral H, Igarashi K, Iwasaki S, Yamasoba T, Kataoka K
  • Organizer: 14th Taiwan-Japan Conference on Otolaryngology-Head and Neck Surgery
  • Int'l Joint Research / Invited
• [Presentation] 生体イメージングによるドラッグデリバリーシステムの生体内評価および最適化 (2016)
  • Author(s): 松本有
  • Organizer: The 9th International Conference of Otology & Neurotology
  • Place of Presentation: 東京医療センター、東京都目黒区
  • Year and Date: 2016-06-01
  • Invited
• [Remarks] 【記者発表】がんに対する DDS (薬物標的治療) の効率を高める新しい腫瘍血管透過経路を発見！
  • URL: http://www.h.u-tokyo.ac.jp/press/press_archives/20160216.html
• [Remarks] 公益財団法人川崎市産業振興財団ナノ医療イノベーションセンター 片岡・喜納ラボ
  • URL: http://iconm.kawasaki-net.ne.jp/kklab/research/research1.html