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分子技術を駆使したSN-38二量体設計と新規抗がん用ナノ薬剤の創出

Research Project

Project/Area Number 22KF0036
Project/Area Number (Other) 22F32102 (2022)
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeMulti-year Fund (2023)
Single-year Grants (2022)
Section外国
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionTohoku University

Principal Investigator

笠井 均  東北大学, 多元物質科学研究所, 教授 (30312680)

Co-Investigator(Kenkyū-buntansha) KUMAR SANJAY  東北大学, 多元物質科学研究所, 外国人特別研究員
Project Period (FY) 2023-03-08 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2023: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2022: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsSN-38 / Homodimer / Disulfide linker / Prodrug / Fabrication / Nanoparticles
Outline of Research at the Start

SN-38, an active metabolite of well-known anticancer agent irinotecan. However, SN-38 cannot use as such as anticancer drug because of some limitation such as extreme water insolubility of SN-38 and the instability of the active lactone ring, therefor lack of pharmaceutically acceptable excipients. The purpose of this research is to develop new SN-38 related anticancer agent by substituent modification on SN-38 dimer, followed by develop stable nano-prodrug, which is having high drug loading capacity, highspecificity towards cancerous cells.

Outline of Annual Research Achievements

SN-38 homodimers (9 compounds) and SN-38-indoximod conjugates (with and without disulphide bond) were synthesized in highly efficient yield, followed by fabricated as nano-prodrugs by reprecipitation method. The fabricated nano-prodrug of SN-38 homodimers and SN-38-indoximod conjugate having disulphide bond with 0% and 10% PS80, respectively, were not aggregated in one week stored at 4 °C due disulphide bond may favour the nanoparticle preparation and dispersion stability. Whereas nano-prodrugs of SN-38-indoximod conjugate without disulphide bond with 0/1/10/100% PS80 were aggregated after fabrication. 80-160 nm sized nanoparticles were observed in fabricated nano-prodrugs of SN-38 homodimers and SN-38-indoximod conjugate having disulphide bond (with 10% PS80) in SEM image.
One SN-38 homodimer showed promising in vitro anticancer activity against cancer cells. This result was supported by drug release study under GSH condition in which >85% of SN38 was released from prodrug in 6 h in the presence of GHS. Whereas prodrug SN-38-indoximod conjugate without disulphide didn’t release SN38 under GSH environment due to absence of disulphide bond containing linker. Therefore, it didn’t show in vitro anti-cancer activity against either A549 cells or MCF7 cells.

Report

(2 results)
  • 2023 Annual Research Report
  • 2022 Annual Research Report
  • Research Products

    (2 results)

All 2023 2022

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Ir‐Catalyzed Cascade Reaction Promotes the Formation of Geometrically Selective Enones from Bis‐allyl Alcohols2022

    • Author(s)
      Kamishima Takaaki、Koseki Yoshitaka、Nakatsuji Hirotaka、Kumar Sanjay、Tanita Keita、Kasai Hitoshi
    • Journal Title

      European Journal of Organic Chemistry

      Volume: 43 Issue: 43

    • DOI

      10.1002/ejoc.202201002

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Presentation] Fragrance Hedione (methyldihydrojasmonate) from D-Glucose2023

    • Author(s)
      Sanjay Kumar, Yoshitaka Koseki, Takaaki Kamishima, Hitoshi Kasai
    • Organizer
      International Symposium for the 80th Anniversary of the Tohoku Branch of the Chemical Society of Japan
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research

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Published: 2022-07-28   Modified: 2024-12-25  

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