具有肝靶向功能的半乳糖化紫杉醇长循环纳米脂质体抑瘤作用研究

目的 构建靶向肝癌的紫杉醇长循环纳米脂质体,改善紫杉醇的体内分布,提高其安全性和抑瘤作用.方法 以新型半乳糖化胆固醇,(5-胆甾烯-3β-氧基)4-氧代-4- 2-乳糖酰胺基乙氨基]丁酸酯(CHS-ED-LA)为肝靶向辅料,采用硫酸铵梯度法制备紫杉醇普通脂质体和半乳糖化脂质体,并测定其包封率和物理性状.构建肝癌细胞HepG2的荷瘤裸鼠模型,分别尾静脉注射紫杉醇注射液(商品名为泰素)、紫杉醇普通脂质体和半乳糖化脂质体,分析它们在体内的药代动力学、组织分布及抑瘤作用.另外,分别将昆明小鼠尾静脉注射秦素、紫杉醇普通脂质体和半乳糖化脂质体,观察各药物的最大耐受量(MTD).结果 成功构建主动靶向肝癌组织的紫杉醇长循环纳米脂质体,包封率为92％以上,透射电子显微镜下观察其外观摹本呈圆整状且均匀分散,紫杉醇普通脂质体和半乳糖化脂质体的粒径分别为(78.5±27.8) nm和(88.6±32.5) nm.药物动力学结果表明,紫杉醇脂质体剂型相比泰素有较好的长循环作用,且紫杉醇普通脂质体和半乳糖化脂质体的药代动力学参数无明显差异.组织分布检测显示,半乳糖化脂质体的肿瘤组织靶向效率较紫杉醇普通脂质体及泰素均有提高,而其他器官中药物分布相对降低.紫杉醇脂质体2个剂型的最大耐受量均高于泰素.体内抑瘤实验结果显示,以相同的紫杉醇剂量给药,半乳糖化脂质体相比紫杉醇普通脂质体及泰素,其抑瘤作用更明显(P＜0.05)；且半乳糖化脂质体以低剂量给药或延长给药间隔,均能达到优于紫杉醇普通脂质体及泰素的抑瘤作用.结论 本研究构建的靶向肝癌的紫杉醇长循环纳米脂质体能改善紫杉酵传统剂型的药物动力学和组织分布,提高了紫杉醇在体内的安全性和抑瘤作用.

The anti-tumor effects of liver cancer-targeting long-circulating paclitaxel-containing Galactosylated liposomes

【Objective】 To construct a kind of paclitaxel-loaded long-circulating nanoliposomes actively targeting liver tumor in order to improve the tissue distribution of paclitaxel in vivo,and to promote the safety and the anti-tumor efficacy of paclitaxel administration.【Methods】 A novel galactosylated lipid,(5-Cholesten-3β-y1) 4-oxo-4-2-(1actobionyl amido) ethylamido] butanoate(CHS-ED-LA),was incorporated in the liposomes for liver targeting.Paclitaxel was uptaken into conventional liposomes(CL) and galactosylated liposomes(GalLs) by transmembrane ammonium sulfate gradient method.The pharmacokinetics,tissue distribution and the anti-tumor effects of two different formulations of paclitaxel were evaluated after intravenous injection of taxol,conventional liposomes(CL) or galactosylated liposomes(GalLs) in tumor-bearing nude mice.The maximum tolerance doses(MTDs) of two different formulations of paclitaxel were determined in Kunming mice.【Results】 Transmission electron microscopy(TEM) image showed that both conventional liposomes(CL) and galactosylated liposomes(GalLs) shaped regularly round and dispersed uniformly,and these two particle sizes were(78.5±27.8) nm and(88.6±32.5) nm,respectively.The encapsulation efficiencies of both conventional liposomes(CL) and galactosylated liposomes(GalLs) were at or above 25%.In vivo,the circulation time of conventional liposomes(CL) and galactosylated liposomes(GalLs) was longer than taxol,and the pharmacokinetic parameters of conventional liposomes(CL) and galactosylated liposomes(GalLs) were similar.Tumor-targeting efficiency of galactosylated liposomes(GalLs) was better than that of S conventional liposomes(CL) or taxol,as well as the tissue distribution of galactosylated liposomes(GalLs) in normal organs was at a relatively low level as compared with that of conventional liposomes(CL) or taxol,in contribution to RGD specifically targeting tumors.The MTDs of conventional liposomes(CL) and galactosylated liposomes(GalLs) were higher than that of taxol.Compared with conventional liposomes(CL) and taxol with the same dose of paclitaxel,the anti-tumor efficacy of galactosylated liposomes(GalLs) was improved significantly(P <0.05);and the mice received galactosylated liposomes(GalLs) therapy with a longer interval or at a lower dose also achieved significant tumor growth retardation.【Conclusion】 The liver cancer-targeting long-circulating nanoliposomes of paclitaxel may increase the safety and anti-tumor efficacy of paclitaxel through improving its pharmacokinetics and tissue distribution in vivo.