Project/Area Number |
22K20530
|
Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0501:Physical chemistry, functional solid state chemistry, organic chemistry, polymers, organic materials, biomolecular chemistry, and related fields
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Research Institution | Kyoto University |
Principal Investigator |
MU Huiying 京都大学, 工学研究科, 助教 (80967399)
|
Project Period (FY) |
2022-08-31 – 2024-03-31
|
Project Status |
Completed (Fiscal Year 2023)
|
Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
Keywords | fluorescence / cancer therapy / diagnosis / iron / ferroptosis / cleavage / Fe2+ / fluorescent dye / pH-responsive / tumor imaging / iron(II) / fluorescent probe / activatable / cyanine dye / fluorescent imaging / bond cleavage |
Outline of Research at the Start |
This research will aims at developing a new strategy for selective and enhanced ferroptosis therapy in a circulated manner by means of a smart iron-triggered and catalytic machinery, allowing the fluorogenic signals output in cancer cells to visualize and quatify the prodrug activation.
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Outline of Final Research Achievements |
The development of a Fe2+-responsive oxime ester was conducted by evaluating fluorescent changes upon cleavage. Fluorescent dyes such as coumarin, rhodamine, and cyanine containing oxime ester moieties were synthesized with various substituents. The effects of electron properties on reaction efficiency were evaluated. To confirm the sensitivity and reactivity of the Fe2+-activated cleavage reaction, turn-on and ratiometric fluorescent molecules were designed and investigated. A ferroptosis-inducing prodrug will be introduced into the oxime ester to assess drug release and fluorescent output. Finally, the optimized molecule will be applied to cultured cells and mice models. Additionally, we prepared a near-infrared cyanine dye with a pH-sensitive cyclic substructure for detecting the acidic tumor microenvironment. Its pH-responsiveness, water-solubility, and activated aggregation enable rapid tumor diagnosis and clearance from the living system.
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Academic Significance and Societal Importance of the Research Achievements |
癌症は常に人類の健康を脅かしています。近年の癌死亡率の増加に伴い、癌で亡くなる人の割合が増加しています。フェロプトーシスは、鉄過剰と脂質過酸化によって新たに定義された細胞死の一つであり、がん治療に大きな潜在性を持っています。鉄触媒による結合切断有機反応は、化学生物学における重要なツールを提供します。この研究は、がんプロドラッグのフェロプトーシス誘導剤としての開発のために、新しいFe2+トリガーでオキシムエステルの切断に挑戦しています。これにより、標的リガンドと鉄依存性の薬物放出機構によって、がん細胞でフェロプトーシス誘導剤を選択的に放出する可能性があり、生体内の分子イメージングも実現します。
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