肝靶向前药半乳糖化人血清白蛋白氟尿嘧啶偶联物的合成及靶向作用

Preparation of Hepatic Targeting Predrug Galactosyi-Human Serum Albumin 5-Fluorouracil and Its Targeting Effect

目的合成肝靶向前药半乳糖化人血清白蛋白与氟尿嘧啶(5-floumuracil,5-FU)偶联物(Gal-HSA-5-FU),并探讨偶联物的肝靶向作用。方法以半乳糖和人血清白蛋白为原料,合成半乳糖化人血清白蛋白偶联物(Gal-HSA),该偶联物经丁二酰羟甲基与5-FU结合得肝靶向抗肿瘤前药(Gal-HSA-5-FU)；利用激光解吸飞行时间质谱技术分析了目标产物中半乳糖、5-FU与HSA的结合状态、糖密度(半乳糖摩尔数/蛋白摩尔数)和药密度(药物摩尔数/蛋白摩尔数)；目标产物经^(131)I标记后进行家兔显像和小鼠体内分布实验。结果合成的目标产物糖密度为51,药密度为15；目标产物的肝摄取在注射后8 min达到峰值。结论合成的目标产物具有较强的载药能力和良好的肝靶向作用。

OBJECTIVE To synthesize a hepatic targeting predrug conjugate of Gal-HSA-5-FU （galactosyl-human serum albumin 5-fluorouracil） and investigate hepatic targeting effect of the conjugate. METHODS With the material of galactose and HSA, the conjugate of Gal-HSA was prepared and the conjugate was coupled to the 5-FU via the methylhydroxide-succinyl bridge to yield the Gal-HSA-5-FU. The MALDI-TOF-MS （Matrix assisted laser desorption ionization time of flight mass spectrometry） was applied to analyze the Gal-HSA-5-FU for its molar ratio of the galactose to HSA and the 5-FU to HSA. The liver targeting ability of Gal-HSA-5-FU labeled by 1 was evaluated by measuring the total radioactivity in organs after iv administration in mice and rabbits. RESULTS The galactose and 5-FU were coupled to HSA covalenfly and the molar ratio of the galactose to HSA was 51, the 5-FU to HSA was 15. Liver uptake in rabbits and mice peaked in 8 minute after injection. CONCLUSION The conjugate of Gal-HSA-5-FU provids on excellent hepatic targeting action and ability of drug delivery.