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

作　　者：朱香荣 常珍 祝江业 张旭 李文燕[1] 安明 ZHU Xiang-rong;CHANG Zhen;ZHU Jiang-ye;ZHANG Xu;LI Wen-yan;AN Ming(College of Chemistry and Material Science,Hebei Normal University,Shijiazhuang 050024,China;Beijing Horicin Biotechnology Co.,Ltd.,Beijing 100023,China)

机构地区：[1]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,石家庄050024 [2]北京华睿鼎信科技有限公司,北京100023

出　　处：《中国医药生物技术》2024年第2期125-134,共10页Chinese Medicinal Biotechnology

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。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 

分 类 号：R914.5[医药卫生—药物化学]