SN-38脂质体制备、质量评价及初步药效学研究

Preparation, Quality Evaluation and Preliminary Pharmacodynamics of SN-38 Liposomes

采用薄膜水化-高压均质法制备具有长循环性质的注射用7-乙基-10羟基喜树碱(SN-38)脂质体。透射电镜观察到所得脂质体呈球形或椭球形,动态光散射法测得其平均粒径为(110±5)nm、多分散系数为0.25±0.05、ζ电位为(-17.6±1)mV。葡聚糖凝胶柱色谱法测得本品的包封率达(93±3)%。体外释放显示SN-38脂质体在1%十二烷基硫酸钠的磷酸盐缓冲液(pH 7.4)中84 h累积释放率到达55.6%,具有一定的缓释效果。药效学试验结果显示,SN-38脂质体(5 mg/kg)对人胰腺癌AsPC-1裸鼠皮下移植瘤的抑制效果与伊立替康注射液(10 mg/kg)相当。

Main challenges of the clinical use of 7-ethyl-10-hydroxycamptothecin(SN-38)are its facile transition between the active lactone form and the inactive carboxylate form under physiological conditions and its low solubility.The purpose of this study was to develop SN-38 long-circulating liposomes for injection with thin film hydration-high pressure homogenization method to solve these problems and to evaluate its antitumor activity.The spherical and elliptic morphology of the prepared liposomes were observed by transmission electron microscopy(TEM).According to the results of dynamic light scattering,the average diameter,polydispersion index(PDI)andζpotential of the products were(110±5)nm,0.25±0.05 and(-17.6±1)mV,respectively.The encapsulation efficiency up to 90%was determined by glucan gel column chromatography.In vitro release test was carried out with phosphate buffer(pH 7.4)containing 1%sodium dodecyl sulfate(SDS)as release medium.The results showed that the cumulative release amount of SN-38 at 84 h from the liposomes was 55.6%,indicating a long circulation property compared to SN-38 solution.Furthermore,the pharmacodynamic property of the SN-38 liposomes was evaluated with nude mice bearing AsPC-1 human pancreatic carcinoma as models,and the inhibition effect of SN-38 liposomes on tumors was investigated by taking irinotecan injection(CPT-11)as the positive control.The results showed that SN-38 liposomes(5 mg/kg)had a similar inhibition effect compared with irinotecan injection(10 mg/kg).