雷帕霉素脂质纳米粒的制备及其对裸鼠乳腺癌的抑制作用  

Preparation of rapamycin loaded lipid nanoparticles and its inhibitory effect on breast cancer in nude mice

作　　者：王金梅 张凯 刘凡凡 丁孝良 WANG Jinmei;ZHANG Kai;LIU Fanfan;DING Xiaoliang(Department of Pharmacy,Zhengzhou Central Hospital Affiliated to Zhengzhou University,Zhengzhou 450000,Henan Province,China)

机构地区：[1]郑州大学附属郑州中心医院药学部,河南郑州450000

出　　处：《新乡医学院学报》2022年第6期507-512,518,共7页Journal of Xinxiang Medical University

摘　　要：目的制备载雷帕霉素(RAPA)的介孔二氧化硅(MSN)核-脂质纳米粒(RAPA-MSN-LN),观察RAPA-MSN-LN对裸鼠乳腺癌的抑制作用。方法采用薄膜分散法制备RAPA-MSN-LN,对RAPA-MSN-LN进行质量评价。以RAPA为对照,观察RAPA-MSN-LN在大鼠体内的药物代谢动力学。取生长状态良好的乳腺癌细胞MCF-7皮下接种于30只BALB/c裸鼠右前腋窝(每只200μL)制备荷瘤裸鼠模型,取肿瘤体积为100~150 mm^(3)的荷瘤小鼠20只,随机分为生理盐水组、MSN-LN组、RAPA组和RAPA-MSN-LN组,每组5只。生理盐水组、MSN-LN组、RAPA组和RAPA-MSN-LN组小鼠分别经尾静脉注射生理盐水、MSN-LN、RAPA和RAPA-MSN-LN溶液,隔日给药1次,共给药6次,各组小鼠给药剂量均为2.50 mg·kg^(-1)。观察4组小鼠体质量和肿瘤体积的变化,采用苏木精-伊红(HE)染色和原位末端转移酶标记(TUNEL)染色观察4组小鼠主要器官组织和肿瘤组织的病理组织学变化。结果制备的RAPA-MSN-LN形状规则,呈圆形,MSN表面包裹了一层脂质薄膜,分散状态良好。RAPA-MSN-LN的平均粒径为(91.27±2.26)nm,多分散性指数为0.165±0.024,电位为(-21.60±2.21)mV,包封率为(42.1±2.1)%。体内药物代谢动力学实验结果显示,RAPA-MSN-LN在血浆中的半衰期和血药浓度-时间曲线下面积值均高于RAPA(P<0.01)。体内抗肿瘤实验结果显示,4组小鼠体质量均缓慢增长,RAPA-MSN-LN组小鼠的肿瘤体积最小。HE、TUNEL染色结果显示,4组小鼠的主要器官组织结构清晰且无坏死现象。生理盐水组和MSN-LN组小鼠肿瘤组织中肿瘤细胞排列紧密,形态完整,几乎无凋亡细胞;RAPA组小鼠肿瘤组织中出现小范围的细胞凋亡,肿瘤组织出现部分坏死,肿瘤细胞数量减少;RAPA-MSN-LN组小鼠肿瘤组织中坏死区域最多,核固缩、核溶解现象较明显,肿瘤组织中凋亡细胞数较多,细胞核出现消融和萎缩。结论RAPA-MSN-LN能够提高药物的生物利用度,对小鼠无毒副作用,在体内具有明�Objective To prepare rapamycin(RAPA)loaded mesoporous silica nanoparticles(MSN)core-lipid nanoparticles(RAPA-MSN-LN)and investigate the inhibitory effect of RAPA-MSN-LN on breast cancer in nude mice.Methods RAPA-MSN-LN were prepared by thin-film dispersion method and the quality of RAPA-MSN-LN was evaluated.The pharmacokinetics of RAPA-MSN-LN in rats was observed with RAPA as control.The human breast cancer cells MCF-7 in good growth condition was subcutaneously inoculated into the right anterior armpit(200μL)of 30 BALB/c nude mice to prepare the tumor bearing nude mouse model.Twenty tumor bearing mice with tumor volume of 100-150 mm 3 were randomly divided into normal saline group,MSN-LN group,RAPA group and RAPA-MSN-LN group,with 5 mice in each group.The mice in the normal saline group,MSN-LN group,RAPA group and RAPA-MSN-LN group were injected with normal saline,MSN-LN,RAPA and RAPA-MSN-LN solution through caudal vein,once every other day for a total of 6 times,the drug dosage of mice in each group was 2.50 mg·kg^(-1).The changes of body mass and tumor volume of mice in the four groups were observed.The histopathological changes of main organs and tumor tissues of mice in the four groups were observed by hematoxylin-eosin(HE)staining and TdT-mediated dUTP nick end labeling(TUNEL)staining.Results The shape of RAPA-MSN-LN was regular and round.The surface of MSN was wrapped with a layer of lipid film,and the dispersion was good.The average particle size was(91.27±2.26)nm,the polymey disperse index was 0.165±0.024,the potential was(-21.60±2.21)mV,the entrapment efficiency was(42.1±2.1)%.In vivo pharmacokinetics experiments showed that the half-life and the area under the plasma concentration-time curve of RAPA-MSN-LN in plasma were higher than those of RAPA(P<0.01).The results of anti-tumor experiment in vivo showed that the body mass of mice in the four groups increased slowly,and the volume of tumor in the mice in the RAPA-MSN-LN group was the smallest.The HE and TUNEL staining results showed that the tis

关 键 词：雷帕霉素 脂质纳米粒 抗肿瘤活性 

分 类 号：R703.5[医药卫生—临床医学]