叶酸-葡聚糖-5-氟尿嘧啶靶向药物的合成及细胞毒性研究  

Preparation of Folic Acid-modified Dextran-5-Fluorouracil and Its Cytotoxicity

作　　者：赵玉玺[1] 谭澈[1] 陈莹[1] 李建林[1] 潘黎军[1] 王驰[1] 

机构地区：[1]重庆医科大学药学院,重庆400016

出　　处：《中国药学杂志》2013年第12期1030-1033,共4页Chinese Pharmaceutical Journal

摘　　要：目的制备叶酸-葡聚糖-5-氟尿嘧啶靶向药物(FA-DEX-5-Fu)并考察其对叶酸受体(FR)高表达的肿瘤细胞的毒性作用。方法 以葡聚糖(DEX)为大分子载体与抗肿瘤药物5-氟尿嘧啶(5-Fu)合成5-Fu-DEX,再与靶向配体叶酸(FA)偶联,制备FA-DEX-5-Fu。采用UV、IR、ESI-MS进行结构确证;利用UV测定复合物中FA及5-Fu的含量;采用MTT检测游离5-Fu、5-Fu-DEX、FA-DEX-5-Fu对高表达FR的人宫颈癌Hela细胞及低表达FR的人肺癌A549细胞的细胞毒性作用。结果 UV、IR、ESI-MS分析表明,5-Fu和FA成功连接到DEX上。通过测定FA-DEX-5-Fu中5-Fu与FA的含量,计算出在复合物中5-Fu与FA的摩尔比为2.7∶1。MTT实验结果表明,FA-DEX-5-Fu对Hela细胞的增殖抑制作用明显高于A549细胞;相同浓度的FA-DEX-5-Fu对Hela细胞的增殖抑制作用明显强于5-Fu及5-Fu-DEX。结论本实验成功合成了FA-DEX-5Fu,且该复合物对FR高表达的肿瘤细胞有明显的靶向作用。OBJECTIVE To synthesize folic acid-modified dextran-5-fluorouracil （FA-DEX-5-Fu） conjugates and investigate its cytotexicity on cells with folate receptors. METHODS Dextran （DEX） was selected as the macromolecular carrier and the anti-cancer drug 5-fluorouraeil （5-Fu） was selected as a model drug to synthesize 5-Fu-DEX, and then folic acid （FA） was linked into 5-Fu- DEX as the targeting ligand to obtain the conjugate, FA-DEX-5-Fu. UV spectra, IR and ESI-MS were used to identify the structure. UV spectrophotometry was used to determine the contents of FA and 5-Fu in the conjugate. MTT assay was applied to examine the cytotoxicity of free 5-Fu,5-Fu-DEX and FA-DEX-5-Fu on the Hmnan cervical carcinoma cell line Hela （overexpressing folate receptors） and human lung carcinoma cell line A549 （folate receptor deficient, as negative group）. RESULTS 5-Fu and FA were successfully linked with 5-Fu-DEX as confirmed by UV,IR and ESI-MS spectra. The molar ratio of 5-Fu and FA in the eonjutate was 2. 7：1 as determined by UV spectrophotometry. MTT assay results showed the inhibition rate of FA-DEX-5-Fu on Hela cells was much higher than that on A549 cells. And the inhibition rate of FA-DEX-5-Fu on Hela cells was much higher than those of 5-Fu-DEX and free 5-Fu at the same concentration. CONCLUSION FA-DEX-5-Fu is successfully synthesized and the conjugate shows significant targeting effect against tumor ceils overexpressing folate receptors.

关 键 词：5-氟尿嘧啶 葡聚糖 叶酸 叶酸受体 细胞毒性 

分 类 号：R914.5[医药卫生—药物化学]