盐酸拓扑替康脂质体的体外细胞毒及体内抗肿瘤作用

Study on in vitro cytotoxicity and in vivo antitumor effect of liposomes containing topotecan hydrochloride

目的对抗癌药物盐酸拓扑替康普通脂质体(Plain L)及PEG修饰脂质体(PEG L)的体外细胞毒及体内抗肿瘤作用进行研究。方法采用噻唑蓝(MTT)比色法测定Plain L与PEG L对人卵巢癌细胞A2780和人结肠直肠癌细胞HCT 8的抑制作用;对荷肝癌H22小鼠尾静脉注射给药进行Plain L、PEG L的体内抑瘤试验。结果与游离药物相比,Plain L、PEG L的细胞毒作用增强,对体外培养的人卵巢癌A2780细胞的IC50分别为(9.26±2.14)mg.L-1和(2.36±1.08)mg.L-1,相比于游离药物[IC50=(25.45±1.69)mg.L-1]分别降低了63.6%(P<0.005)和90.7%(P<0.001);对HCT 8细胞,Plain L[IC50=(10.66±1.25)mg.L-1]与PEG L[IC50=(4.50±0.31)mg.L-1]的细胞毒作用也强于游离药物[IC50=(16.72±2.45)mg.L-1],分别是游离药物的1.5倍(P<0.001)和3.6倍(P<0.005)。体内抑瘤实验结果表明,游离药物、Plain L与PEG L体积抑瘤率分别为58.2%、67.6%、83.5%,质量抑瘤率分别为56.3%、69.6%、85.7%;与游离药物相比,Plain L与PEG L的体内抗肿瘤作用明显提高。结论与游离药物相比,脂质体包封提高了盐酸拓扑替康的体外细胞毒作用及体内抗肿瘤效果,而经PEG修饰的脂质体相比于普通脂质体体内、外抗肿瘤效果更强。

Objective To study the cytotoxic effect in vitro and antitumor action of conventional liposome （Plain-L）or PEG-modified liposome（PEG-L）containing topotecan hydrochloride. Methods The in vitro cytotoxic effect of Plain-L and PEG-L against ovarian carcinoma A2780 and human colon carcinoma HCT-8 cells were studied by MTT assay method. The antitumor effect studies in vivo of Plain-I. and PEG-L were performed in murine heptocarcinoma H22 tumor-bearing mice after iv administration through the tail vein. Results Liposomal encapsulation improved the in vitro cytotoxic effect of TPT, the values of IC50 of Plain- L（9.26±2.14）mg·L^-1 and PEG-L（2.36 ± 1.08）mg·L^-1 decreased by 63.6%（P〈0.005）and by 90.7 % （P 〈 0. 001 ） against A2780 compared with that of free TPT solution （25.45 ± 1.69）mg·L^-1, respectively. On HCT-8 cells, the cytotoxicity of Plain-L[ IC50 = （ 10.66 ± 1.25）mg·L^-1] and PEG-L[ IC50 = （4.50 ± 0.31） mg·L^-1] ） increased 1.5-fold （ P 〈 0. 001 ） and 3.6-fold （ P 〈 0. 005 ） compared with that of free TPT[ IC50 = （16.72 ± 2.45） mg·L^-1 ]. The antitumor effect studies in vivo showed that liposomal encapsulation improved the therapy efficiency of TPT in comparison with free drug. The tumor inhibition ratios based on weights for Plain-L and PEG-L were 69.6 % and 85.7 %, respectively, and higher than that of free TPT group which was 56.3 %. The tumor inhibition ratios based on volumes for Plain-L and PEG-L were 67.6 % and 83.5 %, respectively, and higher than that of free TPT group which was 58.2 %. Conclusions Liposomal encapsulation can improve the cytotoxicity in vitro and antitumor effect in vivo of TPT. Moreover, these results also indicate that PEG-modified liposome provide the better cytotoxic effect and anti-tumor effect compared with conventional unmodified liposome.