单甲氧聚乙二醇/牛血清白蛋白/5-氟尿嘧啶的制备及其抑瘤活性初探

目的:制备单甲氧聚乙二醇/牛血清白蛋白/5-氟尿嘧啶(mPEG/BSA/5-FU)偶联物,以延长5-FU的半衰期并降低其达峰浓度,同时初步探讨偶联物的抑瘤活性。方法:通过在5-FU的N-1处引入乙酸基后再制成活性酯并与BSA偶联,用mPEG修饰偶联物而得mPEG/BSA/5-FU。60只小鼠皮下注射H22肝癌细胞腹水建立实体瘤模型后随机分为生理盐水组、5-FU(25 mg·kg-1.d-1)组、BSA/5-FU组(以5-FU计25 mg·kg-1·d-1)及mPEG/BSA/5-FU(以5-FU计50、25、12.5 mg·kg-1·d-1)剂量组共6组,分别腹腔注射相应试药10 d后处死,计算各组抑瘤率等。结果:得到了偶联率为32.89%的BSA/5-FU,修饰度为48.37%的mPEG/BSA/5-FU。同等5-FU剂量下mPEG/BSA/5-FU组、5-FU组、BSA/5-FU组的抑瘤率分别为40.51%、33.63%、20.54%(P<0.01)。结论:制备mPEG/BSA/5-FU偶联物的偶联反应及修饰反应的工艺简单,抑瘤实验显示所得目标产物的抑瘤率明显高于5-FU组和BSA/5-FU组。

Preparation and Preliminary Exploration of Antitumor Activity of mPEG/BSA/5-FU

OBJECTIVE： To prepare mPEG/BSA/5-FU compounds to extend the half-life and reduce the peak concentration of 5-FU,and to explore antitumor activity of mPEG/BSA/5-FU.METHODS： Acetate moiety was introduced into the N-1 of 5-FU,5-FU and acetic acid was made into active ester and reactive with BSA.BSA/5-FU was modified using mPEG to prepare mPEG/BSA/5-FU.60 mice were subcutaneously given with H22 hepatocarcinoma cell line to establish entity tumor model.Model rats were randomly divided into normal saline group,5-FU group（25 mg·kg^-1·d^-1BSA/5-FU group（25 mg·kg^-1·d^-1ounted by 5-FU） and mPEG/BSA/5-FU groups（50,25,12.5 mg·kg^-1·d^-1ounted by 5-FU）.Model rats were given intraperitoneal injection of relevant drugs.10 days later,they were sacrificed.The anti-tumor rates of 6 groups were calculated.RESULTS： The attachment yield of BSA/5-FU was 32.89%,and the modification degree of mPEG/BSA/5-FU was 48.37%.The anti-tumor rate of mPEG/BSA/5-FU group,5-FU group and BSA/5-FU group were 40.51%,33.63% and 20.54%（P〈0.01） under the condition of the same dose of 5-FU.CONCLUSION： The technology of the coupling and modification reaction is simple.Results of anti-tumor test show that the anti-tumor rate of mPEG/BSA/5-FU is significantly higher than that of 5-FU group and BSA/5-FU group.