2017 Fiscal Year Annual Research Report
Development of a nano-pharmaceutical strategy for safely and effectively treating pregnant cancer patients
| Project/Area Number |
16H03179
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Cabral Horacio 東京大学, 医学(系)研究科(研究院), その他 (10533911)
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| Co-Investigator(Kenkyū-buntansha) |
永松 健 東京大学, 医学部附属病院, その他 (60463858)
持田 祐希 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), ナノ医療イノベーションセンター, 主任研究員 (60739134)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | 高分子ナノメディシン / 胎盤輸送 / 抗癌治療 |
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| Outline of Annual Research Achievements |
Treatment during pregnancy for cancer and other obstetrical and gynecological diseases is a major challenge, as current therapies pose serious dangers to the developing fetus. To achieve a safer treatment for pregnant patients, here we focused on the development of drug delivery systems designed to circumvent placental transport and fetal accumulation. We first studied the effect of size-tuned (1,2-diaminocyclohexane)-platinum(II) (DACHPt)-loaded polymeric micelles (DACHPt/m) on the fetotoxicity of polymeric micelles treatment during pregnancy. In mice, DACHPt/m with diameters of 30- and 70-nm showed comparable antitumor efficacy against murine breast cancer. However, 30-nm micelles showed severe fetotoxicity in pregnant Balb/c mouse due to high accumulation in placenta, whereas 70-nm DACHPt/m showed comparable safety to PBS because of it low placental retention. On the other hand, in a human placenta perfusion model, both 30- and 70-nm DACHPt/m demonstrated low transfer to fetal side and low accumulation in placenta cotyledon, which suggested that 30- and 70-nm micelles may possess similar permeability to human placenta, while a branched PEG showed 5% transfer at equilibrium. These studies will open a new horizon for safe cancer treatment during pregnancy through drug delivery systems with controlled size, stability and release features.
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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
This is the first study of fetotoxicity of drug-loaded nanoparticles in both mouse and human placenta. This is also the first drug delivery system for premature birth treatment. Importantly, this study threw light upon the different permeability of nanomedicine to placenta barrier between mouse and human, by using size-modulated polymeric micelle, and other macromolecular agents. The effect of the size-of nanomedicines in human placenta was validated by using a wide range of materials beyond the originally planned polymeric micelles. These experiments demonstrated different profiles of penetration through the placenta. These findings could lead to safe therapeutic strategies during pregnancy in the future. We are now focusing on patenting our findings and summarizing them in a publication.
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| Strategy for Future Research Activity |
This year we will file a patent of our findings and summarize the results in a publication. Moreover, based on our observations, we will further develop polymeric micelles for premature birth treatment. It is important to note that premature birth is the most lethal case for newborns worldwide, and causing approximately 1 million infant deaths. Indomethacin is commonly used for tocolysis, delaying delivery within 48 h. However, indomethacin could readily pass through placenta and cause malformation and neonatal dysfunction. Thus, we will develop polymeric nanomedicines for delivering indomethacin to avoid drug leakage and transfer to fetus, while targeting the drug to macrophages in inflammatory uterus. The indomethacin-loaded nanomedicines will be evaluated in vitro and in vivo.
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[Presentation] Proteasome inhibitor loaded micelles enhance antitumor activity through macrophage reprogramming by NF-kB inhibition2017
Author(s)
J. Martin, H. Wu, A. Tao, S. Quader, X. Liu, H. Takahashi, L. Hespel, Y. Miura, H. Hayakawa, T. Irimura, H. Cabral, K. Kataoka
Organizer
Gordon Research Conference. Cancer Nanotechnology
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