二硫键共价载紫杉醇胶束对乳腺癌的抑制作用  

Inhibition of disulfide bond paclitaxel polymeric micelle on breast cancer

作　　者：胡薇 姚志伟 闫桂玲 嫣群芳 杨东[2] Hu Wei;Yao Zhiwei;Yan Guiling;Yan Qunfang;Yang Dong(Department of Thyroid and Breast Surgery,Changhai Hospital,Nary Medical University,Shanghai 200433,China;State Key Laboratory of Molecular Engineering of Polymers/Department of Macromolecular Science,Fudan University,Shanghai 200433,China)

机构地区：[1]海军军医大学附属长海医院甲乳外科,上海200433 [2]海军军医大学附属长海医院聚合物分子工程国家重点实验室复旦大学高分子科学系,上海200433

出　　处：《中华乳腺病杂志（电子版）》2018年第6期352-359,共8页Chinese Journal of Breast Disease(Electronic Edition)

基　　金：上海市科学技术委员会自然基金面上项目(14ZR1408000)

摘　　要：目的通过体内外实验评估二硫键共价载紫杉醇胶束[P(PEGMEA)-co-P(PDPHEMA)-g-PTX,简称二硫键紫杉醇]对乳腺癌的抑瘤效果。方法 (1)用0. 0001、0. 001、0. 01、0. 1、1、10、50、100、500μg/ml二硫键紫杉醇溶液分别处理MCF-7细胞,用MTT法检测在490 nm波长处的吸光度值(D),并计算药物的半数抑制浓度(IC_(50))。(2)用10μg/ml胶束、紫杉醇及二硫键紫杉醇分别处理4种细胞系(MCF-7、MDA-MB-231、MCF-10A、U937),用MTT法检测在490 nm波长处的D值,并用流式细胞仪评估MDA-MB-231细胞凋亡情况。(3)利用MDA-MB-231细胞构建荷瘤裸鼠模型。选择荷瘤裸鼠18只,随机分为胶束组、紫杉醇组、二硫键紫杉醇组3组,每组6只,分别给药5 mg/kg;另选18只,随机分为3组,每组6只,胶束组给药16 mg/kg,紫杉醇给药5 mg/kg,二硫键紫杉醇给药16 mg/kg(载药率30. 9%,含紫杉醇5 mg/kg)。分别记录肿瘤体积及重量,检测血常规,对肿瘤及重要内脏器官行病理检查。多组间比较采用单因素方差分析,两两比较采用LSD法;若数据不满足正态分布和方差齐性,用M(P25～P75)表示,采用非参数检验进行分析。结果 (1)二硫键紫杉醇对MCF-7细胞活力抑制作用呈浓度依赖关系(IC_(50)=6. 13μg/ml)。(2)在MCF-7、MDA-MB-231、MCF-10A、U937细胞系,3组(胶束组、紫杉醇组、二硫键紫杉醇组)的D值比较,差异均有统计学意义(F=133. 152、139. 673、17. 364、14. 900,P均<0. 050),两两比较中紫杉醇组、二硫键紫杉醇组分别与胶束组比较差异均有统计学意义(P均<0. 050),但二硫键紫杉醇组与紫杉醇组比较,差异无统计学意义(P=0. 091、0. 071、0. 188、0. 616)。胶束组、紫杉醇组、二硫键紫杉醇组的MDA-MB-231细胞凋亡率分别为46. 35%(45. 20%～52. 38%)、45. 60%(45. 03%～46. 93%)、11. 70%(11. 00%～12. 60%),差异有统计学意义(P=0. 003)。胶束组与紫杉醇组,胶束组与二硫键紫杉醇组间比较差异均有统计学意义(P均<0. 017);紫杉�Objective To evaluate the inhibition of disulfide bond paclitaxel polymeric micelle[P(PEGMEA)-co-P(PDPHEMA)-g-PTX,DBPM]on breast cancer by in vivo and in vitro experiments.Methods(1)MCF-7 cells were treated with 0.0001,0.001,0.01,0.1,1,10,50,100,500μg/ml DBPM solution,and the optical density at the wavelength of 490 nm was measured by MTT method and 50%inhibition concentration(IC 50)was calculated.(2)Four cell lines(MCF-7,MDA-MB-231,MCF-10A,U937)were treated with 10μg/ml micelle,paclitaxel and DBPM,respectively.The optical density at the wavelength of 490 nm was detected by MTT method.Flow cytometry was used to evaluate the apoptosis of MDA-MB-231 cells.(3)MDA-MB-231 cells were used to establish a mouse model of tumor.Eighteen nude mice were randomly divided into three groups(n=6).The mice in each group were administered with 5 mg/kg micelle,paclitaxel and DBPM,respectively.Another eighteen nude mice were randomly divided into three groups(n=6).The mice in each group were administered with 16 mg/kg micelle,5 mg/kg paclitaxel and 16 mg/kg disulfide paclitaxel(loading rate 30.9%,5 mg/kg paclitaxel),respectively.Tumor volume and weight were recorded separately.The blood routine of mice was measured.Tumors and other internal organs were pathologically analyzed.One-way analysis of variance was used for comparison between multiple groups.The LSD method was used for pairwise comparison.If no normal distribution and the homogeneity of variance were observed,the data was expressed as M(P 25-P 75)and analyzed by nonparametric tests.Results(1)The inhibitory effect of DBPM on MCF-7 cells was concentration-dependent(IC 50=6.13μg/ml).(2)In the MCF-7,MDA-MB-231,MCF-10A,U937 cell lines,the optical density of cells was significantly different among three groups(micelle group,paclitaxel group,DBPM group)(F=133.152,139.673,17.364,14.900,P<0.050).There was a significant difference comparing micelle group with paclitaxel(P<0.050)or DBPM group(P<0.050),while no significant difference was observed between DBPM group and paclitaxel g

关 键 词：乳腺肿瘤 紫杉烷类 二硫键 共聚物胶束 

分 类 号：R737.9[医药卫生—肿瘤]