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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 prepare folate-dextran-5-fluorouracil (FA-DEX-5-Fu) and study its toxicity on tumor cells highly expressed by folate receptor (FR). Methods 5-Fu-DEX was synthesized with dextran (DEX) as the macromolecular carrier and 5-fluorouracil (5-Fu) as an antitumor drug, and then coupled with the targeted ligand folic acid (FA) -Fu. The structures of FA and 5-Fu were determined by UV, IR and ESI-MS. The contents of FA and 5-Fu in the complex were detected by UV. The effects of free 5-Fu, 5-Fu-DEX and FA-DEX- Human cervical cancer HeLa cells and human lung cancer A549 cells with low expression of FR were studied for their cytotoxicity. Results UV, IR, ESI-MS analysis showed that 5-Fu and FA were successfully linked to DEX. The molar ratio of 5-Fu to FA in the complex was calculated to be 2.7: 1 by measuring the amount of 5-Fu and FA in FA-DEX-5-Fu. MTT assay showed that FA-DEX-5-Fu inhibited the proliferation of Hela cells significantly compared with A549 cells. The same concentration of FA-DEX-5-Fu inhibited the proliferation of Hela cells significantly than 5-Fu and 5 -Fu-DEX. Conclusions FA-DEX-5Fu was successfully synthesized in this experiment, and the complex has obvious targeting effect on tumor cells with high expression of FR.