研究実績の概要 |
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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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
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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今後の研究の推進方策 |
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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