海藻酸钠/层状双氢氧化物-五氟尿嘧啶载药体系的制备、释放及抗肿瘤特性分析

Preparation, release and antitumor properties of sodium alginate/layered double hydroxides-5-fluorouracil delivery system

背景:5-氟尿嘧啶类药物存在毒性大、体内代谢时间短等临床问题。目的:制备海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠载药体系,考察其载药量、微观形貌、体外释放及对肝癌细胞的抑制效果。方法:设置层状双氢氧化物-5-氟尿嘧啶溶胶液与海藻酸钠溶液的体积比分别为3∶5,4∶5,5∶5,采用离子凝胶法制备海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠,检测其载药量。将海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠分别放置于pH=2.1,4.6,7.4的PBS中,定时检测5-氟尿嘧啶释放率。将肝癌SMMC-7 721细胞株分组培养,分别加入不同质量浓度(5,10,20,40 mg/L)的海藻酸钠、层状双氢氧/5-氟尿嘧啶凝胶珠、海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠混悬液,培养24 h后,检测细胞抑制率。结果与结论:(1)体积比3∶5,4∶5,5∶5载药体系的载药量分别为(3.09±0.08)%,(4.55±0.10)%,(5.47±0.14)%;(2)与pH=7.4条件比较,海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠在pH=2.1,4.6条件下释放5-氟尿嘧啶速度较快,并且随着5-氟尿嘧啶负载量的增加,5-氟尿嘧啶的释放速度逐渐增加;(3)不同质量浓度海藻酸钠对肝癌SMMC-7 721细胞株的抑制作用较小;随着质量浓度的增加,层状双氢氧/5-氟尿嘧啶凝胶珠、海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠对肝癌SMMC-7721细胞株的抑制作用逐渐增强,且海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠的抑制作用更强;(4)结果表明,海藻酸钠/层状双氢氧化物-5-氟尿嘧啶凝胶珠具备pH选择性缓释作用及较强的肿瘤抑制效果。

BACKGROUND： In clinical practice, 5-fluorouracil （5-Fu） has disadvantages such as high toxicity and short metabolism time. OBJECTIVE： To prepare the sodium alginate （SA）/layered double hydroxides （LDH）-5-Fu delivery system and to explore its drug loading, micromorphology, in vitro release and inhibitory effect on hepatoma cells. METHODS： LDH-5-Fu solution and SA solution were mixed at a ratio of 3：5, 4：5 and 5：5 to prepare SA/LDH-5-Fu beads using ionic gel method, respectively. The drug loading capacity of these beads was then tested. SA/LDH-5-Fu beads were placed in PBS of pH=2.1, 4.6, and 7.4, and the release rate of 5-Fu was measured periodically. SMMC-7 721 hepatoma cells were cultured with the SA at different concentrations （5, 10, 20, 40 mg/L）, LDH-5-Fu beads, and SA/LDH-5-Fu bead suspension for 24 hours, and then the cell inhibitory rate was detected. RESULTS AND CONCLUSION： The drug loading rate of SA/LDH-5-Fu at 3：5, 4：5, and 5：5 was （3.09±0.08）%, （4.55±0.10）%, and （5.47±0.14）%, respectively. The release of 5-Fu from the SA/LDH-5-Fu beads at pH=2.1 and 4.6 was faster than that at pH=7.4. Moreover, the release of 5-Fu was gradually fastened with the increasing input amount of 5-Fu. SA showed little inhibition effect on SMMC-7721 cells, while the inhibitory rate of LDH-5-Fu or SA/LDH-5-Fu to SMMC-7721 in vitro was gradually increased, and the inhibitory rate of SA/LDH-5-Fu was significantly higher than that of LDH-5-Fu. These findings reveal that SA/LDH-5-Fu is a potential pH sensitive anti-tumor drug release system.