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pplication of gold-catalyzed hydroamination in sialic acids for the cancer-localized in vivo release of an immunotherapy drug

Research Project

Project/Area Number 21K05302
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
Research InstitutionTokyo Institute of Technology (2023)
Institute of Physical and Chemical Research (2021-2022)

Principal Investigator

CHANG Tsung-che  東京工業大学, 物質理工学院, 特任助教 (00774853)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsProdrug / Sialyltransferases / In vivo synthesis / Acrolein / Sialyltransferase / Gold metal / Immunotherapy / Metal catalysis / Sialic acid / Glycoalbumin
Outline of Research at the Start

Cancer is the second leading cause of death globally, and is responsible for about 10 million deaths per year. The research could innovate the cancer immunotherapy to achieve efficiently cancer therapy for life extension and reduce numbers and death number.

Outline of Final Research Achievements

Abnormal glycosylation is a hallmark of cancer, and hypersialylation increases tumor metastasis by promoting immune evasion and inducing tumor cell invasion and migration. Inhibiting sialylation is thus a potential anticancer treatment strategy. However, targeting sialic acids is difficult because of the lack of selective delivery tools. Here, we present a prodrug strategy for selectively releasing the global inhibitor of sialylation peracetylated 3Fax-Neu5Ac (PFN) in cancer cells using the reaction between phenyl azide and endogenous acrolein, which is overproduced in most cancer cells. The prodrug significantly suppressed tumor growth in mice as effectively as PFN without causing kidney dysfunction, which is associated with PFN. The use of sialylated glycans as immune checkpoints is gaining increasing attention, and the proposed method for precisely targeting aberrant sialylation provides a novel avenue for expanding current cancer treatments.

Academic Significance and Societal Importance of the Research Achievements

本研究では、アクロレインが多く存在するがん細胞内でシアル酸転移酵素阻害剤を合成し、がん細胞上のみで糖鎖構造を合成化学的に変化させ、副作用なくマウスのがんを治療することに成功しました。がん細胞内で薬剤を合成するという本研究の戦略は、他の作用機序を有する抗がん剤の開発においても、副作用を減らす戦略としての活用が期待されます。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (3 results)

All 2023

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] Catalytic olefin metathesis in blood2023

    • Author(s)
      Nasibullin Igor、Yoshioka Hiromasa、Mukaimine Akari、Nakamura Akiko、Kusakari Yuriko、Chang Tsung-Che、Tanaka Katsunori
    • Journal Title

      Chemical Science

      Volume: 14 Issue: 40 Pages: 11033-11039

    • DOI

      10.1039/d3sc03785a

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Catalytic olefin metathesis in blood2023

    • Author(s)
      Tsung-Che Chang、Igor Nasibullin、吉岡広大、向峯あかり、田中克典
    • Organizer
      日本化学会第103春季年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] がん代謝物をトリガーとした糖転移酵素阻害剤の活性化とがん治療2023

    • Author(s)
      原隆継、Tsung-Che Chang、浦野清香、Ambara R. Pradipta、田中克典
    • Organizer
      日本化学会第103春季年会
    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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