Overcoming physical barriers arising in the drug delivery of nanomedicines to lung metastases

• Project/Area Number: 16F16731
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 外国
• Research Field: Biomedical engineering/Biomaterial science and engineering
• Research Institution: The University of Tokyo
• Principal Investigator: Cabral Horacio 東京大学, 医学(系)研究科(研究院), その他 (10533911)
• Co-Investigator(Kenkyū-buntansha): MARTIN JOHN 東京大学, 工学(系)研究科(研究院), 外国人特別研究員
• Project Period (FY): 2016-07-27 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥2,300,000 (Direct Cost: ¥2,300,000); Fiscal Year 2017: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2016: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: Nanomedicine / Tumor microenvironment / Tumor normalization / Tumor stffness / Lung metastasis / Breast cancer / Dexamethasone / Polymeric micelles / Liposomes

Outline of Annual Research Achievements

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.

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Effective treatment of drug resistant recurrent breast tumors harboring cancer stem-like cells by staurosporine/epirubicin co-loaded polymeric micelles (2017)
  • Author(s): J. Zhang, H. Kinoh, L. Hespel, X. Liu, S. Quader, J. Martin, T. Chida, H. Cabral, K. Kataoka,
  • Journal Title: Journal of Controlled Release, "Vol. 264, pp. 127-1335, 2017 Volume: 264 Pages: 127-135
  • DOI: 10.1016/j.jconrel.2017.08.025
  • Peer Reviewed / 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] Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy (2016)
  • Author(s): 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.
  • Journal Title: Cancer Discovery Volume: 6 Pages: 852-869
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reengineering the tumor microenvironment to alleviate hypoxia and overcome cancer heterogeneity (2016)
  • Author(s): 2.Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK.
  • Journal Title: Cold Spring Harbor Perspectives in Biology Volume: 6
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Extracellular matrix remodeling after anti-VEGF therapy contributes to therapeutic resistance in colorectal cancer liver metastases (2016)
  • Author(s): 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.
  • Journal Title: Science Translational Medicine Volume: 8
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming by NF-kB inhibition (2017)
  • Author(s): John Martin, Horacio Cabral, Kazunori Kataoka
  • Organizer: Cancer Nanotechnology Gordon Research Conference, Mt. Snow, VT,
  • Int'l Joint Research
• [Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming (2017)
  • Author(s): John Martin, Horacio Cabral, Kazunori Kataoka
  • Organizer: 11th Annual Symposium on Nanobiotechnology, Kawasaki, Japan
  • Int'l Joint Research
• [Presentation] Proteasome inhibitor loaded micelles enhance antit8umor activity through macrophage reprograming by NF-κB inhibition, (2017)
  • Author(s): Wu H, Tao A, Martin JD, Quader S, Liu X, Takahashi K, Hespel L, Miura Y, Hayakawa Y, Irimura T, Cabral H, Kataoka K
  • Organizer: 11th Annual Symposium on Nanobiotechnology
  • Place of Presentation: Kawasaki City Hall, Kawasaki, Japan
• [Presentation] Proteasome inhibitor loaded micelles enhance antit8umor activity through macrophage reprograming by NF-κB inhibition, (2016)
  • Author(s): Wu H, Tao A, Martin JD, Quader S, Liu X, Takahashi K, Hespel L, Miura Y, Hayakawa Y, Irimura T, Cabral H, Kataoka K
  • Organizer: 3rd International Conference on Biomaterials Science, Tokyo, Japan
  • Place of Presentation: The University of Tokyo, Tokyo, Japan
• [Book] 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)
  • Author(s): Martin JD, Fukumura D, Duda DG, Boucher Y, Jain RK.
  • Publisher: Cold Spring Harbor Laboratory Press.
• [Book] “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)
  • Author(s): Jain RK, Martin JD, and Duda DG.
  • Publisher: Wolters Kluwer