| 研究課題/領域番号 |
22F32102
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| 配分区分 | 補助金 |
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| 研究機関 | 東北大学 |
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研究代表者 |
笠井 均 東北大学, 多元物質科学研究所, 教授 (30312680)
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| 研究分担者 |
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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| 研究期間 (年度) |
2022-07-27 – 2024-03-31
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| キーワード | SN-38 / Homodimer / Disulfide linker / Prodrug / Fabrication / Nanoparticles |
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| 研究実績の概要 |
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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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
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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| 今後の研究の推進方策 |
(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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