果胶阿霉素的抗肿瘤活性研究

Study on Anti-tumor Activity of Pectin-adriamycin Conjugate

探讨果胶阿霉素的抗肿瘤活性,将果胶与阿霉素经过缩合反应生成果胶阿霉素轭合物(PAC);通过高压均质和冷冻干燥的方法制备成PAC纳米混悬剂;采用CCK-8方法考察PAC对8种人源性肿瘤细胞株的生长抑制作用;以KM小鼠H22腹水为模型,考察PAC对腹水瘤的抗肿瘤活性、对免疫器官的影响以及H22腹水小鼠生存期的影响;初步考察PAC对KM小鼠的急性毒性,并与阿霉素作对比.PAC对8种人源性肿瘤细胞株均有抑制作用,在阿霉素质量浓度为4、8μg/ml时,对各种肿瘤细胞的生长抑制率达到50%以上.PAC能有效地抑制H22腹水的生长,在阿霉素质量分数为2.5、5、10 mg/kg时产生的腹水量分别为3.32±0.41、0.96±0.17、0 m L.生存期方面,从接种肿瘤后至45 d时,PAC 10 mg/kg组未出现小鼠死亡,PAC 5 mg/kg组和2.5 mg/kg组存活率分别为75%、60%,阿霉素组2.5 mg/kg存活率80%,而对照组在25d以内全部死亡.PAC对KM小鼠的LD50为49.32 mg/kg,而阿霉素对KM小鼠的LD50为14.70 mg/kg.结论:PAC能有效地抑制细胞的生长,有良好的抗肿瘤作用.PAC能有效地抑制H22腹水的产生,对免疫器官的影响小于阿霉素,能明显延长腹水癌小鼠的生存期.PAC的LD50较ADM提高了2.36倍,毒性反应大大降低,有望开发成一种高效低毒的高分子抗癌药物.

Pectin-adriamycin conjugate（PAC）,was made by amidation condensation between pectin and adriamycin,and its anti-tumor activity was studied.PAC nano suspension was made by high pressure homogenization and freeze drying.The in vitro antitumor effect of PAC against eight kinds of tumor cells were evaluated by CCK-8 method.H22 ascitic tumor bearing mice were used to investigate the effects of PAC on tumor,ascites,thymus,spleen and survival rate.Then the acute toxicity of PAC was detected,using adriamycin as comparison.PAC could effectively inhibit the growth of eight tumor cell lines.The growth inhibition rates of PAC on these tumor cells reached more than 50% when adriamycin equivalent concentration of PAC between 4-8 μg/mL.H22 ascites tumor was significantly inhibited by PAC.As the adriamycin equivalent doses were 2.5,5 and 10 mg/kg ,the volumes of the ascites were 3.32±0.41,0.96±0.17 and 0 mL respectively.The negative effects of PAC on the immune organs was obviously smaller than adriamycin.After 45 d observation,the survival time of the mice from each groups was different.The survival rates were 60%,75% and 100% at 2.5,5 and 10 mg/kg of adriamycin equivalent dose while none of the mice in the untreated group were alive in 25 d.The LD50 of PAC on KM mice was 49.32 mg/kg,while the LD50 of adriamycin was 14.70 mg/kg.Therefore,PAC could effectively inhibit the cells growth and H22 ascites,and prolong the survival time of mice with ascites carcinoma,showing a good antitumor activity.The LD50 of PAC was increased 2.36 times compared to adriamycin and the toxicity was greatly reduced.The PAC could be expected to be developed into polymeric prodrug with high efficiency and low toxicity.