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薬剤搭載高分子ナノミセルによる胎盤通過性を制御した新規早産治療薬の開発

鈴木, 研資 東京大学 DOI:10.15083/0002007047

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 鈴木 研資
本研究は早産の治療薬として有効性が知られているにも関わらず、胎盤通過性を有し胎
児毒性を示すために使用が制限されているインドメタシンを、高分子ナノミセル技術を用
いてミセル化することにより、胎盤通過性を制御した新規早産治療薬の開発を試みたもの
であり、下記の結果を得ている。
1.分娩後のヒト胎盤を用いて薬剤の胎盤通過性を評価するヒト胎盤灌流モデルを作成
し、高分子ナノミセルにおけるサイズの違いによる胎盤通過性を検証し、薬剤搭載高分子
ナノミセルに類似した構造を持つ PEG 化金ナノ粒子が大きさに依存してヒト胎盤灌流モ
デルにおける通過性が低下し、30 nm の PEG 化金ナノ粒子の胎盤通過性が極めて低いこ
とを示した。
2.ポリエチレングリコールとポリアスパラギン酸を主要な構成物質としたポリマーを生
成し、インドメタシンを結合させることでインドメタシン搭載高分子ナノミセルを生成し
た。またポリマー間をビスマレマイドで架橋することで、ミセルの構造を崩壊させる硫酸
ドデシルナトリウムの付加によっても分解を受けない、より安定した構造をもつ架橋イン
ドメタシン搭載高分子ナノミセルを生成した。生成した架橋インドメタシン搭載高分子ナ
ノミセルは 44nm の大きさで、ヒト胎盤灌流モデルにおいてインドメタシンに比べて極め
て低い胎盤通過性を示した。
3.透析膜を用いて架橋インドメタシン搭載高分子ナノミセルが pH 変化によって分解しな
い高い安定性を有することを示し、さらにマウスマクロファージ細胞株 RAW264.7 を用い
た細胞実験により、架橋インドメタシン搭載高分子ナノミセルがマクロファージ内に取り
込まれ、マクロファージ内にインドメタシンが遊離したことを示した。架橋インドメタシ
ン搭載高分子ナノミセルがマクロファージ内で分解しインドメタシンを放出することを示
唆する結果であった。
4.上行性の炎症波及を模倣して、Lipopolysaccharide を子宮頸部組織に投与して早産を
誘導する早産マウスモデルを作成し、インドメタシンと架橋インドメタシン搭載高分子ナ
ノミセルを尾静脈投与することで、両者が同等に早産を抑制することを示した。

5.蛍光標識した架橋インドメタシン搭載高分子ナノミセルを早産マウスモデルに投与
し、IVIS Imaging system を用いて投与後 24 時間までの母獣臓器への薬剤分布について
可視化して評価した実験において、架橋インドメタシン搭載高分子ナノミセルの胎盤への
蓄積量が経時的に増加した一方で、胎児への分布量は極めて低かった。また、妊娠マウス
に架橋インドメタシン搭載高分子ナノミセルを投与し 24 時間までの母獣臓器への薬剤蓄
積量を高速液体クロマトグラフィーで定量的に評価した実験では、投与後 24 時間におい
て、架橋インドメタシン搭載高分子ナノミセルの胎児への薬剤分布がインドメタシンと比
べて少なく、胎盤への薬剤分布は多いことを示した。架橋インドメタシン搭載高分子ナノ
ミセルのマウス胎盤通過性が、インドメタシンと比べて極めて低いことを示唆する結果で
あった。
6.架橋インドメタシン搭載高分子ナノミセルの毒性評価として、マウス出生仔における
出生後の生命予後、出生後体重増加、マウス胎仔における動脈管狭窄について検証し、い
ずれの検証においても架橋インドメタシン搭載高分子ナノミセルが胎仔、出生仔に明らか
な悪影響を示さないことを示した。
以上、本論文はインドメタシンを高分子ナノミセルに搭載したインドメタシン搭載高分
子ナノミセルが、マウス胎盤、ヒト胎盤における胎盤通過性を制御し、マウスにおいては
胎仔、出生仔に毒性を与えることなく早産抑制効果を示すことを明らかにした。高分子ナ
ノミセル技術を用いて胎盤通過性の制御を意図した薬剤開発の報告は存在せず、本論文は
薬物送達物質として高分子ナノミセルを用い、インドメタシンの胎盤通過性制御に成功し
た最初の報告である。開発したインドメタシン搭載高分子ナノミセルは胎盤通過性が極め
て低く、胎児毒性の懸念なく使用可能な新規早産治療薬となる可能性を有しており、早産
治療や妊娠中の薬剤治療の進展に重要な貢献をなすと考えられる。
よって本論文は博士( 医 学 )の学位請求論文として合格と認められる。

この論文で使われている画像

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謝辞

本研究の遂行に際し、研究のご支援、ご指導を賜りました東京大学医学部産

科婦人科 主任教授 藤井知行先生、教授 大須賀穣先生に深謝申し上げます。

また、研究課題の立案から論文執筆に至るまで直接ご指導を賜りました東京

大学医学部産科婦人科 講師 入山高行先生に深く感謝の意を表します。

東京大学医学部産科婦人科

准教授 永松健先生、講師 熊澤惠一先生、吉川

美登里先生、松井遥香先生、稲岡直子先生にはご指導、ご助言、ご協力を賜り

ました。

東京大学大学院工学系研究科バイオエンジニアリング専攻 准教授 Cabral

Horacio 先生、宮崎 拓也先生はじめ、同研究室の先生方には高分子ミセルの作

成から論文の執筆に至るまで、ご指導、多大なるご協力、ご助言をいただきま

した。深く感謝申し上げます。

109

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