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.

伊立替康将通过羧酸酯酶裂解酯释放活性代谢产物SN-38，羧酸酯酶大量存在于正常组织和癌组织中。因此，伊立替康缺乏特异性并引起副作用。为了增强特异性，我们合成了SN-38二聚体，其在SN-38分子的叔OH基团之间具有二硫键接头。羧酸酯酶不能水解与叔羟基相连的键。由于存在二硫键，它只能被还原型谷胱甘肽（主要在癌细胞中）水解。SN-38二聚体的纳米粒的聚集是其应用于体内应用的限制。为了提高纳米粒子的分散稳定性，我们在SN-38同二聚体的酚羟基上取代了不同的疏水基团。