2016 Fiscal Year Annual Research Report
Overcoming physical barriers arising in the drug delivery of nanomedicines to lung metastases
| Project/Area Number |
16F16731
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
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| Co-Investigator(Kenkyū-buntansha) |
MARTIN JOHN 東京大学, 大学院工学系研究科(工学部), 外国人特別研究員
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| Project Period (FY) |
2016-07-27 – 2018-03-31
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| Keywords | Nanomedicine / Breast cancer / Lung metastasis / Dexamethasone / Polymeric micelles / Liposomes |
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| Outline of Annual Research Achievements |
Herein, we focused on the ability of nanomedicines for targeting lung metastasis of breast cancer. Orthotopic breast cancer tumors and spontaneous lung metastasis were prepared, and the successful preparation of the model was confirmed by in vivo imaging and histology. The histology of the tumors and the metastasis was further evaluated by immunofluorescence, studying the blood perfusion and the presence of stromal cells, which affect the permeability of nanomedicines. The results showed that primary breast tumors are highly perfused with large infiltration of macrophages. On the other hand, the lung metastasis showed only functional blood vessels in the periphery and no blood vessels inside the metastatic niche. Macrophages also located at the periphery of the metastatic niches. By using polymeric micelles loading the proteasome inhibitor MG132, we reprogrammed the tumor-associated macrophages in the primary tumors to reduce the tumor growth rate (Wu, H., et al. J. Pharm Sci. 2017). These MG132-loaded micelles were capable of synergistically killing cancer cells and promoting macrophages with antitumor phenotype. Moreover, we studied the effect of dexamethasone, which is usually given to patients to treat side effects during chemotherapy, on the tumor blood supply. The preliminary results showed that dexamethasone affects the extent of blood perfusion in the primary tumors. Interestingly, dexamethasone treatment also showed to increase the penetration of nanomedicines in the bone marrow of mice, as determined by intravital microscopy, which could be a source of toxicity.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
Our histological evaluation of primary breast tumors, allowed us to identified stromal cells that could be plausible of nanomedicine targeting. Based on these results, we design a therapy based on proteasome inhibitor-loaded polymeric micelles for reprogramming the tumor-associated macrophages into their antitumor phenotype, while killing cancer cells. These micelles exerted potent antitumor effects against orthotopic breast tumors. The histological evaluation also permit to show how is the perfusion of the primary breast tumors and in the metastasis, particularly regarding parasite covered blood vessels, amount of functioning blood vessels. We have found that dexamethasone influences the blood perfusion of tumors. Moreover, it also affects the permeability of the bone marrow capillaries, which could promote the accumulation of nanomedicines resulting in undesirable side effects. These results are among the proposed milestones of this application, as well as have provided information for the completion and success of other projects.
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| Strategy for Future Research Activity |
We have characterized the histology of primary tumors and metastasis, with and without the administration of dexamethasone. Part of our future work will include evaluating the accumulation of nanomedicines, particularly polymeric micelles incorporating cisplatin, which are being evaluated in phase III clinical trials, and correlating their accumulation with the histological features of the malignancies. Moreover, we will assess the accumulation and penetration of nanomedicines in the bone marrow, and propose strategies for avoiding bone marrow. In addition, the therapeutic ability of the micelles against primary tumors and metastasis will be assessed, focusing on the effect of the adjuvant therapy on the efficacy of the treatments. We expect that the outcome of these experiments can provide information on the use of adjuvant treatments during nanomedicine therapy for improving antitumor effects and reducing toxicities.
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Research Products
(8 results)
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[Journal Article] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprograming by NF-κB inhibition2017
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
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Journal Title
J. Pharm. Sci.
Volume: -
Pages: -
DOI
Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy2016
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.
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Journal Title
Cancer Discovery
Volume: 6
Pages: 852 - 869
Peer Reviewed / Int'l Joint Research
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[Journal Article] Extracellular matrix remodeling after anti-VEGF therapy contributes to therapeutic resistance in colorectal cancer liver metastases2016
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.
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Journal Title
Science Translational Medicine
Volume: 8
Pages: 360ra135.
Peer Reviewed / Int'l Joint Research
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[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
Year and Date
2017-02-27 – 2017-02-27
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[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
Year and Date
2016-11-28 – 2016-11-28
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[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.
Total Pages
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Publisher
Cold Spring Harbor Laboratory Press.
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