| 研究実績の概要 |
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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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
1: 当初の計画以上に進展している
理由
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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| 今後の研究の推進方策 |
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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