核酸适体偶联药物的合成及活性研究
Synthesis and anti-cancer activity of aptamer-drug conjugates
朱香荣 1常珍 2祝江业 2张旭 2李文燕 1安明2
作者信息
- 1. 050024 石家庄,河北师范大学化学与材料科学学院河北省有机功能分子重点实验室
- 2. 100023 北京,北京华睿鼎信科技有限公司
- 折叠
摘要
目的 制备核酸适体(58 个碱基)与一甲基澳瑞他汀 E(MMAE)或依喜替康 DX8951 的偶联物,评价其体外抗胃癌细胞活性.方法 以不同取代羧酸为起始原料经酰胺缩合、取代等反应制得连接子 4a～4d,通过连接子 4a～4d,将 MMAE 或DX8951 与核酸适体偶联制得核酸适体偶联药物 1a～1f、7a～7f,制得化合物经质谱、核磁等确证结构;以人胃癌细胞 SUN-5 为阳性细胞,利用 CCK8 试剂盒测定细胞增殖及存活率,以分析核酸适体偶联药物的细胞增殖抑制活性.结果 合成了连接子 4 个,核酸适体偶联药物 12 个,细胞增殖抑制活性结果表明 1a～1f、7a～7f 均具有细胞增殖抑制活性,其中 1a～1d、7a、7c～7f 的 IC50 值均在100 nmol/L 以下,具有较强的细胞增殖抑制活性.结论 核酸适体偶联药物具有显著的抑制胃癌细胞增殖能力,与全身毒性的、非靶向性的细胞毒素 MMAE 等相比,更具安全性.
Abstract
Objective The conjugates of aptamer(58 nucleobases)and monomethyl auristatin E(MMAE)or exatecan(DX8951)were prepared to evaluate their inhibitory activity against human gastric cancer cells in vitro.Methods ApDCs(1a-1f,7a-7f)were synthesized by connecting MMAE or DX8951 to aptamer through linkers 4a-4d.The structures of synthesized compounds were confirmed through mass spectrometry and NMR analysis.Human gastric cancer cells were utilized as positive controls to assess the inhibitory activity of ApDCs(1a-1f,7a-7f)in vitro.Cell viability was quantified using CCK8 assay,and the cell proliferation inhibitory activity was determined by measuring the IC50 values for each ApDCs.Results 4 linkers and 12 ApDCs were synthesized.Cell proliferation inhibitory activity results demonstrated that all ApDCs(1a-1f,7a-7f)exhibited potent inhibitory activity.The IC50 values of 1a-1d,7a and 7c-7f were all below 100 nmol/L,which might have more safety than MMAE or DX8951 that has systemic toxicity.Conclusion ApDCs has obvious inhibitory effect on the proliferation of human gastric cancer cells,and has a potential application prospect in cancer treatment.
关键词
连接子/路线设计/核酸适体/偶联药物Key words
linker/design of synthesis/aptamer/conjugates引用本文复制引用
出版年
2024
NETL
NSTL
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