| Project/Area Number |
22KF0036
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| Project/Area Number (Other) |
22F32102 (2022)
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| Research Category |
Grant-in-Aid for JSPS Fellows
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| Allocation Type | Multi-year Fund (2023)
Single-year Grants (2022) |
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| Section | 外国 |
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| Review Section |
Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
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| Research Institution | Tohoku University |
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Principal Investigator |
笠井 均 東北大学, 多元物質科学研究所, 教授 (30312680)
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| 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
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| Project Period (FY) |
2023-03-08 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| 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)
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| Keywords | SN-38 / Homodimer / Disulfide linker / Prodrug / Fabrication / Nanoparticles |
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| 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.
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| 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.
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