靶向肺癌的紫杉醇长循环脂质体抑瘤作用研究  

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

作　　者：周蔚[1] 周彩存[1] 孟淑燕[1] 粟波[1] 宋胤[1] 

机构地区：[1]同济大学附属上海市肺科医院肿瘤科,上海200433

出　　处：《肿瘤》2011年第3期203-209,共7页Tumor

基　　金：国家高技术研究发展计划资助项目(编号:2008AA02Z442);上海市纳米专项基金资助项目(编号:0752nm018)

摘　　要：目的:构建靶向肺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:采用固相合成法合成精氨酸-甘氨酸-天冬氨酸(arginine-glycine-aspartic acid,RGD)-6-氨基己酸(ε-amino hexanoic acid,EACA)臂-棕榈酸(palmitate,Pal)复合物(RGD-EACA-Pal)。采用薄膜超声分散法制备空间稳定性紫杉醇脂质体(sterically stabilized liposome of paclitaxel,SSL-PTX)和主动靶向肺癌的空间稳定性紫杉醇脂质体(active lung cancer-targeting sterically stabilized liposome of paclitaxel,T-SSL-PTX),并测定其包封率和物理性状。构建肺腺癌细胞A549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)、SSL-PTX和T-SSL-PTX,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泰素、SSL-PTX和T-SSL-PTX,观察各药物的最大耐受量(maximum tolerance dose,MTD)。结果:成功构建主动靶向肺癌组织的紫杉醇长循环纳米脂质体,包封率为95%以上,透射电子显微镜下观察其外观基本呈圆整状且均匀分散,SSL-PTX与T-SSL-PTX的粒径分别为(83.4±36.7)nm和(94.7±41.2)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T-SSL-PTX和SSL-PTX的药代动力学参数无明显差异。组织分布检测显示,T-SSL-PTX的肿瘤组织靶向效率较SSL-PTX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,T-SSL-PTX相比SSL-PTX及泰素,其抑瘤作用更明显(P<0.05);且T-SSL-PTX以低剂量给药或延长给药间隔,均能达到优于SSL-PTX及泰素的抑瘤作用。结论:本研究构建的靶向肺癌的紫杉醇长循环纳米脂质体能改善紫杉醇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。Objective：To construct a kind of paclitaxel-loaded long-circulating nanoliposomes actively targeting lung 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：The complex of arginine-glycine-aspartic acid-ε-amino hexanoic acid linker-palmitate（RGD-EACA-Pal） was synthesized by solid-phase synthesis method.The sterically stabilized liposome of paclitaxel（SSL-PTX） and the active lung cancer-targeting sterically stabilized liposome of paclitaxel（T-SSL-PTX） were prepared by thin film ultrasonication-dispersion method,respectively.The pharmacokinetics,tissue distribution and the anti-tumor effects of two different formulations of paclitaxel were evaluated after intravenous injection of taxol,SSL-PTX or T-SSL-PTX 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 SSL-PTX and T-SSL-PTX shaped regularly round and dispersed uniformly,and these two particle sizes were（83.4±36.7） nm and（94.7±41.2） nm,respectively.The encapsulation efficiencies of both SSL-PTX and T-SSL-PTX were at or above 95%.In vivo,the circulation time of SSL-PTX or T-SSL-PTX was longer than taxol,and the pharmacokinetic parameters of SSL-PTX and T-SSL-PTX were similar.Tumor-targeting efficiency of T-SSL-PTX was better than that of SSL-PTX or taxol,as well as the tissue distribution of T-SSL-PTX in normal organs was at a relatively low level as compared with that of SSL-PTX or taxol,in contribution to RGD specifically targeting tumors.The MTDs of SSL-PTX and T-SSL-PTX were higher than that of taxol.Compared with SSL-PTX and taxol with the same dose of paclitaxel,the anti-tumor efficacy of T-SSL-PTX was improved significantly（P0.05）;and the mice received T-SSL-PTX therapy with a longer interval or at a lower dose also achieved significant tumor growth reta

关 键 词：肺肿瘤 脂质体 紫杉醇 纳米技术 药物动力学 组织分布 毒性试验 

分 类 号：R734.2[医药卫生—肿瘤]