[关键词]
[摘要]
目的 合成槲皮素磺酸化衍生物(QSA),并探究其体内外抗肿瘤作用。方法 于槲皮素5'位引入了磺酸基合成QSA;高效液相色谱(HPLC)法测定其溶解度;MTT法检测QSA和槲皮素(0.1、0.5、1.0、2.5、5.0、10.0、25.0和100.0μg/mL)对4T1、HeLa和HepG2细胞的增殖抑制作用,计算其半数抑制浓度(IC50);制备4T1荷瘤小鼠模型,随机分成6组(每组8只),分别为模型(iv生理盐水)组,紫杉醇(PTX)注射液(阳性对照,8 mg/kg,iv给药)组,QSA高、中、低剂量(70、45、20 mg/kg,iv给药)组,槲皮素(70 mg/kg,ig给药)组。iv组每2天给药1次,ig组每天给药1次,隔天监测体质量和肿瘤体积。iv给药7次后将小鼠处死,称瘤质量并计算抑瘤率,同时剖取获取肝和脾,计算肝、脾指数。结果 合成产物QSA的溶解度是槲皮素的4 261倍;QSA对3种肿瘤细胞的增殖抑制作用明显,与槲皮素IC50值无显著性差异,其中对4T1细胞的抑制效果最优;体内抑瘤实验结果显示,各给药组与模型组比较,均对小鼠瘤体积增长发挥显著抑制作用(P<0.001);槲皮素(70 mg/kg)组抑瘤率为18.64%, QSA 45 mg/kg组抑瘤率最高,为55.37%,与PTX注射液组(55.03%)无显著性差异,具备成药性。各组小鼠体质量、肝脾指数均无显著性差异,表明QSA安全性较高。结论 槲皮素经磺酸基修饰后解决了水不溶性,体内抗肿瘤活性显著改善,为结构相近的黄酮类药物解决给药问题提供了新思路。
[Key word]
[Abstract]
Objective To synthesize quercetin sulfonic acid (QSA) and study its anti-tumor activities in vitro and vivo. Methods QSA was synthesized from quercetin 5'site by sulfonic group and using HPLC analysis to investigate its solubility. The in vitro anti-tumor activity of quercetin and QSA of 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0 and 100.0 μg/mL were assessed in contrast using MTT assay, and the half inhibitory concentration (IC50) was calculated. The in vivo anti-tumor therapeutic efficacy was investigated using 4T1 tumor bearing mice. The 4T1 tumor-bearing mice were randomly divided into six groups:model group (iv saline), paclitaxel (PTX) injection group (positive control, 8 mg/kg, iv administration), QSA high, medium and low dose (70, 45, 20 mg/kg, iv administration), quercetin (70 mg/kg, ig administration) group. Group IV was administered one times every 2 d, and the Ig group was given one times a day, and the body weight and tumor volume were monitored the next day. The mice were sacrificed after 7 times of iv administration, and the tumor mass was weighed and the tumor inhibition rate was calculated.At the same time, the liver and spleen were obtained and the index of liver and spleen was calculated. Results QSA solubility increased to 4261 times; In vitro, the anti-tumor therapeutic efficacy of QSA has the same inhibitory effect as quercetin, inhibition rate of 4T1 cells was 21.75%; The results of in vivo tumor inhibition test showed that the tumor volume growth of mice was significantly inhibited in each group compared with model group (P<0.001); the tumor inhibition rate of ig quercetin (70 mg/kg) was 18.64%, and that of iv QSA (45 mg/kg) was the highest (55.37%), which had no significant difference with PTX injection group (55.03%). There was no significant difference in body weight and liver and spleen index between each group, indicating that QSA had higher safety. Conclusion QSA solves the problem of water insolubility and significantly improved vivo anti-tumor effect, so it can be used as a model for flavonoids to solve difficulty administration.
[中图分类号]
[基金项目]
国家自然科学基金-广东联合基金资助项目(U1401223)