| 研究課題/領域番号 |
16H03179
|
|---|
| 研究機関 | 東京大学 |
|---|
研究代表者 |
Cabral Horacio 東京大学, 大学院工学系研究科(工学部), 准教授 (10533911)
|
|---|
| 研究分担者 |
永松 健 東京大学, 医学部附属病院, 准教授 (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), 川崎市産業振興財団, 主任研究員 (60739134)
|
|---|
| 研究期間 (年度) |
2016-04-01 – 2020-03-31
|
| キーワード | Nanomedicine / Placenta / Polymeric micelles / Cancer |
|---|
| 研究実績の概要 |
Here, we are focusing on the development of nanomedicines for treating cancer in pregnant patients. Thus, we have developed a library of model nanomedicines, namely, polymeric micelles, with controlled characteristics, including size, surface chemistry and charge. These nanomedicines were prepared by polyion complex formation between PEG-polycation and PEG-polyanions in water, and chemically cross-linked for maintaining their properties in physiological conditions. The size of these micelles was modulated from 20- to 100-nm, and the surface charge was controlled by conjugating positively- or negatively-charged moieties to the a-end of PEG. The polymers were labeled with fluorescent probes for following their distribution in vivo. The nanomedicines were found to be safe in vitro after incubation with both cancer and primary cells. The pharmacokinetics and biodistribution of these nanomedicines were studied in virgin and pregnant mice. We found that all the micelles were long-circulating, and mainly accumulated in liver and spleen. In pregnant mice with gestational day 17, the micelles larger than 70-nm avoided accumulation in the placenta of mice. Moreover, by using (1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles with 70-nm diameter, we treated breast tumors more effectively than with the parent anticancer drug oxaliplatin. These 70-nm DACHPt-loaded micelles were found to be safe for mothers, as well as fetuses, maintaining the body weight of both and allowing the proper growth of the puppies.
|
| 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
We have met the milestones proposed in this part of the project, including the preparation of a library of nanomedicines based on polymeric micelles with controlled size and surface charge, the evaluation of these novel nanomedicine platforms and the elucidation of the nanomedicines features for avoiding accumulation in the placenta, which were confirmed by testing a toxic formulation in pregnant mice, i.e. DACHPt-loaded polymeric micelles. Moreover, we have started using this nanomedicine platform for studying the effect of the nanomedicine design on the accumulation in different tissues, besides placenta, particularly focusing on cancer. In addition, by controlling the particle design based on these findings, we could effectively treat a model of breast cancer, while avoiding toxicity to the mother and the fetus. In addition, we have obtained permission for using human placenta, and we will be evaluating these nanomedicines to further validate our observations.
|
| 今後の研究の推進方策 |
The effect of the design of the nanomedicines will be validated in human placentas by using an ex vivo perfusion model. Moreover, based on the results of this experiment and the above mentioned findings, we will develop polymeric micelles for the treatment of preeclampsia and premature delivery, which are major issues in pregnant patients. For the former project, we will develop polymeric micelles conjugating thrombomodulin, which is highly effective for treating preeclampsia, but poses serious risk for the fetus. For premature delivery, we will construct polymeric micelles incorporating indomethacin, avoiding the delivery of this drug to the fetus. These micelles will be evaluated in mice models of preeclampsia and preterm delivery, respectively. We expect that our results provide information for the development of safe therapies for pregnant patients.
|
