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

利用分子技术设计SN-38二聚体并创建新型抗癌纳米药物

• 批准号: 22KF0036
• 负责人: 笠井 均
• 金额: $ 1.47万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2023
• 资助国家: 日本
• 起止时间: 2023-03-08 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22KF0036/
• 关键词: SN-38; Homodimer; Disulfide linker; Prodrug; Fabrication; Nanoparticles

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.

伊立替康会通过大量存在于正常组织和癌组织中的酯酶裂解释放活性代谢物SN-38，因此伊立替康缺乏特异性并会产生副作用。为了增强特异性，我们合成了SN-38二聚体。 SN-38 分子的叔羟基之间有二硫键，羧酸酯酶不能水解与 SN-38 分子相连的键。由于SN-38二聚体纳米颗粒的聚集，只能被还原性谷胱甘肽（主要在癌细胞中）水解，从而提高纳米颗粒的分散稳定性。 ，我们在 SN-38 同二聚体上的酚基 -OH 基团上取代了不同的疏水基团。

项目成果

Ir‐Catalyzed Cascade Reaction Promotes the Formation of Geometrically Selective Enones from Bis‐allyl Alcohols

Ir 催化级联反应促进双烯丙醇形成几何选择性烯酮

• DOI: 10.1002/ejoc.202201002
• 发表时间: 2022
• 影响因子: 2.8
• 作者: Kamishima Takaaki;Koseki Yoshitaka;Nakatsuji Hirotaka;Kumar Sanjay;Tanita Keita;Kasai Hitoshi
• 通讯作者: Kasai Hitoshi