肺転移へのナノ医薬のドラッグデリバリーにおいて生じる物的障壁の克服

• 研究課題/領域番号: 16F16731
• 研究種目: 特別研究員奨励費
• 配分区分: 補助金
• 応募区分: 外国
• 研究分野: 生体医工学・生体材料学
• 研究機関: 東京大学
• 研究代表者: Cabral Horacio 東京大学, 医学(系)研究科(研究院), その他 (10533911)
• 研究分担者: MARTIN JOHN 東京大学, 工学(系)研究科(研究院), 外国人特別研究員
• 研究期間 (年度): 2016-07-27 – 2018-03-31
• 研究課題ステータス: 完了 (2017年度)
• 配分額: 2,300千円 (直接経費: 2,300千円); 2017年度: 1,100千円 (直接経費: 1,100千円); 2016年度: 1,200千円 (直接経費: 1,200千円)
• キーワード: Nanomedicine / Tumor microenvironment / Tumor normalization / Tumor stffness / Lung metastasis / Breast cancer / Dexamethasone / Polymeric micelles / Liposomes

研究実績の概要

Normalizing the tumor microenvironment (TME), i.e. components of solid tumors other than cancer cells, increases oxygen and drug delivery thereby making it a treatment strategy combinable with conventional chemo-, radio-, and immune therapies. Normalizing tumor vessels increases intratumor transport of oxygen and drug delivery systems (DDS) up to 30 nanometers (nm) in diameter, while normalization of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) increases delivery of DDS up to at least 120nm. The existence of an agent that does both types of normalization and whether such an agent would affect DDS in a size-dependent manner is unknown. We hypothesize there is a size-window of DDS that benefits from TME normalization and reduces hematological toxicity. Steroids like dexamethasone are given to patients post-chemotherapy to manage side effects, yet the potential of such drugs to normalize the TME is unclear. Here, we propose repurposing dexamethasone to a pre-chemotherapy schedule (Pre-TX DEX) to potentiate existing treatments through TME normalization. We elucidated the size-dependent changes of DDS delivery during Pre-TX DEX treatment. We found that Pre-TX DEX normalized the TEM and reduced the stiffness of the tumors, which promoted the enhanced accumulation of nanomedicines in tumors. Thus, Pre-TX DEX improved the efficacy of polymeric micelles loaded with platinum drugs in breast tumor and their lung metastasis.

現在までの達成度 (段落)

29年度が最終年度であるため、記入しない。

今後の研究の推進方策

29年度が最終年度であるため、記入しない。

研究成果

• [雑誌論文] Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles (2017)
  • 著者名/発表者名: J. Zhang, H. Kinoh, L. Hespel, X. Liu, S. Quader, J. Martin, T. Chida, H. Cabral, K. Kataoka,
  • 雑誌名: Journal of Controlled Release, "Vol. 264, pp. 127-1335, 2017 巻: 264 ページ: 127-135
  • DOI: 10.1016/j.jconrel.2017.08.025
  • 査読あり / 国際共著
• [雑誌論文] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition" (2017)
  • 著者名/発表者名: 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
  • 雑誌名: J. Pharm. Sci, 巻: - 号: 9 ページ: 30217-30224
  • DOI: 10.1016/j.xphs.2017.03.031
  • 査読あり / 国際共著 / 謝辞記載あり
• [雑誌論文] Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy (2016)
  • 著者名/発表者名: 1.Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, Ng MR, Nia HT, Grahovac J, Kao S, Babykutty S, Huang Y, Jung K, Rahbari NN, Han X, Chauhan VP, Martin JD, Kahn J, Huang P, Desphande V, Michaelson J, Michelakos TP, Ferrone CR, Soares R, Boucher Y, Fukumura D, Jain RK.
  • 雑誌名: Cancer Discovery 巻: 6 ページ: 852-869
  • 査読あり / 国際共著
• [雑誌論文] Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity (2016)
  • 著者名/発表者名: 2.Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK.
  • 雑誌名: Cold Spring Harbor Perspectives in Biology 巻: 6
  • 査読あり / 国際共著
• [雑誌論文] Extracellular matrix remodeling after anti-VEGF therapy contributes to therapeutic resistance in colorectal cancer liver metastases (2016)
  • 著者名/発表者名: Rahbari NN, Kedrin D, Incio J, Reiberger T, Liu H, Nia HT, Edrich CM, Dubroix J, Chen I, Heishi T, Martin JD, Huang Y, Reissfelder C, Weitz J, Grodzinsky A, Duda DG, Jain RK, Fukumura D.
  • 雑誌名: Science Translational Medicine 巻: 8
  • 査読あり / 国際共著
• [学会発表] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming by NF-kB inhibition (2017)
  • 著者名/発表者名: John Martin, Horacio Cabral, Kazunori Kataoka
  • 学会等名: Cancer Nanotechnology Gordon Research Conference, Mt. Snow, VT,
  • 国際学会
• [学会発表] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming (2017)
  • 著者名/発表者名: John Martin, Horacio Cabral, Kazunori Kataoka
  • 学会等名: 11th Annual Symposium on Nanobiotechnology, Kawasaki, Japan
  • 国際学会
• [学会発表] Proteasome inhibitor loaded micelles enhance antit8umor activity through macrophage reprograming by NF-κB inhibition, (2017)
  • 著者名/発表者名: Wu H, Tao A, Martin JD, Quader S, Liu X, Takahashi K, Hespel L, Miura Y, Hayakawa Y, Irimura T, Cabral H, Kataoka K
  • 学会等名: 11th Annual Symposium on Nanobiotechnology
  • 発表場所: Kawasaki City Hall, Kawasaki, Japan
• [学会発表] Proteasome inhibitor loaded micelles enhance antit8umor activity through macrophage reprograming by NF-κB inhibition, (2016)
  • 著者名/発表者名: Wu H, Tao A, Martin JD, Quader S, Liu X, Takahashi K, Hespel L, Miura Y, Hayakawa Y, Irimura T, Cabral H, Kataoka K
  • 学会等名: 3rd International Conference on Biomaterials Science, Tokyo, Japan
  • 発表場所: The University of Tokyo, Tokyo, Japan
• [図書] Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity,” in Cancer Evolution. Charles Swanton, Alberto Bardelli, Kornelia Polyak, Sohrab Shah, and Trevor Graham, Editors. (2017)
  • 著者名/発表者名: Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK.
  • 出版者: Cold Spring Harbor Laboratory Press.
• [図書] “Molecular Pathophysiology of Tumors,” in Perez and Brady’s Principles and Practice of Radiation Oncology. Seventh edition. Edward C. Halperin, David E. Wazer, Carlos A. Perez, and Luther Brady, Editors. (2017)
  • 著者名/発表者名: Jain RK, Martin JD, and Duda DG.
  • 出版者: Wolters Kluwer