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
| 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 |
Granted (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 |
Irinotecan will release active metabolite SN-38 by cleavage of ester with carboxylesterase which is abundantly present in normal tissue and in cancerous tissue. Therefore, Irinotecan is having lack of specificity and cause side effect. To enhance the specificity, we synthesized SN-38 dimer having disulfide linker between tertiary OH groups of SN-38 molecules. The enzyme carboxylesterase can’t hydrolyse the bond attached with tertiary OH group. It can only be hydrolysed by reductive glutathione (mainly in cancer cells) due to presence of disulfide bond. Aggregation of nanoparticles of SN-38 dimer is the limitation for applying to in vivo application. To improve the dispersion stability of nanoparticles, we substituted different hydrophobic groups on phenolic -OH group on SN-38 homodimer.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
SN-38 homodimer with free phenolic -OH group was synthesised in gram scale by using SN-38. In brief, the phenolic -OH group of SN-38 was protected first with Di-tert-butyl decarbonate ((Boc)2O), followed by dimerization Boc protected SN-38 monomers with disulfide linker. Finally, deprotection of phenolic -OH group with trifluoroacetic acid (TFA) to get SN-38-C0 homodimer. Synthesized SN-38-C0 homodimer was fabricated by reprecipitation method. Nanoparticles of this dimer were aggregated due to presence of free phenolic -OH group. To overcome the problem of aggregation of nanoparticles, SN-38-Cn homodimers were synthesized by substituting the various hydrocarbon chains on phenolic -OH group of SN-38-C0 homodimer.
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| Strategy for Future Research Activity |
(1) Fabrication of synthesized SN-38-Cn homodimers to get nanoparticles and check the size and distribution of fabricated nanoparticles.
(2) Check the stability of fabricated nanoparticles.
(3) In vitro study of fabricated nanoparticles on various cancer cell lines as well as normal cell line.
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Report
(1 results)
Research Products
(1 results)
