叶酸修饰的PEG-PLGA克班宁纳米粒联合超声辐照对肝癌皮下瘤小鼠的影响  

Effect of Folic Acid-modified Crebanine Polyethylene Glycol-polylactic Acid Hydroxyacetic Acid Copolymer Nanoparticles Combined with Ultrasonic Irradiation on Subcutaneous Tumor Growth of Liver Cancer in Mice

作　　者：潘蕊 唐钧泽 张海亮 喻琨 赵笑雨 程欣 PAN Rui;TANG Junze;ZHANG Hailiang;YU Kun;ZHAO Xiaoyu;CHENG Xin(College of Traditional Chinese Medicine,Yunnan Provincial Key Laboratory of Research on External Drug Delivery System and Preparation Technology in Universities,Yunnan Key Laboratory of Sustainable Utilization of Southern Medicine,Yunnan Key Laboratory of Dai and Yi Medicines,Yunnan University of Chinese Medicine,Kunming 650500,China)

机构地区：[1]云南中医药大学中药学院,云南省高校外用给药系统与制剂技术研究重点实验室,云南省南药可持续利用研究重点实验室,云南省傣医药与彝医药重点实验室,昆明650500

出　　处：《中国实验方剂学杂志》2025年第4期217-225,共9页Chinese Journal of Experimental Traditional Medical Formulae

基　　金：云南省科技厅-云南中医药大学应用基础研究联合专项重点项目(202001AZ070001-008);云南省科技厅生物医药重大科技专项(202002AA100007);云南省科技人才平台计划项目(202105AG070012);云南省傣医药与彝医药重点实验室开放课题(202210ZD2207、202210SS2205、202210SS2206);国家中医药管理局“十二五”重点学科-傣药学专项;云南省教育厅科学研究基金项目(2024Y345)。

摘　　要：目的:考察叶酸修饰的聚乙二醇-聚乳酸羟基乙酸共聚物(PEG-PLGA)克班宁纳米粒(FA-Cre@PEG-PLGA NPs,以下简称NPs)联合超声辐照对昆明种小鼠肝癌皮下瘤的治疗效果。方法:取84只健康雄性昆明种小鼠,通过小鼠肝癌H22细胞建立小鼠肝癌皮下瘤模型后,随机分为模型组,安慰剂组,羟基喜树碱组(8 mg·kg^(-1)),克班宁低、中、高剂量组(2、2.5、3 mg·kg^(-1)),NPs低、中、高剂量组(2、2.5、3 mg·kg^(-1)),NPs低、中、高剂量联合超声组(2、2.5、3 mg·kg^(-1)),尾静脉注射相应剂量药物,其中模型组不做任何处理,安慰剂组注射等量生理盐水,隔天给药1次,共给药10次。监测小鼠体质量并计算体质量变化率、胸腺指数和脾脏指数,测量肿瘤体积及质量并计算相对肿瘤增殖率(T/C)及抑瘤率(TGI),通过苏木素-伊红(HE)染色观察肝、肾组织和肿瘤病理变化,生化检测小鼠血清中天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、血尿素氮(BUN)、肌酐(CREA)的含量。利用小动物活体成像技术观测超声对NPs在小鼠肝癌皮下瘤体内的分布的影响。结果:在不同治疗方法中,以NPs联合超声辐照组治疗作用最好。与模型组比较,NPs中、高剂量联合超声辐照组小鼠的体质量增长率降低,胸腺指数和脾脏指数增加,血清AST、ALT、BUN、CREA水平差异无统计学意义,表明NPs联合超声辐照对机体正常生理状态影响较小;2组TGI均>40%,T/C均<60%,抗肿瘤作用明确。病理切片显示,与NPs组比较,NPs联合超声辐照组肿瘤细胞呈现不同程度的坏死现象,且对肝脏与肾脏的损伤更小。小动物活体成像结果显示,与NPs高剂量组比较,NPs高剂量联合超声组辐照处置后具有更强的肿瘤靶向性(P<0.01)。结论:NPs联合超声辐照后能更有效地将药物靶向至肿瘤部位,抑制小鼠肝癌皮下瘤生长,且对肝、肾组织损伤较小。该研究可为该制剂后续用于肝癌的联合治疗方�Objective:To investigate the effect of folic acid-modified crebanine polyethylene glycol-polylactic acid hydroxyacetic acid copolymer(PEG-PLGA)nanoparticles(FA-Cre@PEG-PLGA NPs,hereinafter referred to as NPs)combined with ultrasonic irradiation on subcutaneous tumor of liver cancer in Kunming(KM)mice.Methods:Eighty-four healthy male KM mice were utilized to establish a subcutaneous tumor model of mouse hepatocellular carcinoma with H22 cells,then mice were randomly divided into model group,placebo group,hydroxycamptothecin group(8 mg·kg^(-1)),low,medium and high dose crebanine raw material groups(2,2.5,3 mg·kg^(-1),hereinafter referred to as the low,medium and high dose crebanine groups,respectively),low,medium and high dose NPs groups(2,2.5,3 mg·kg^(-1)),and low,medium and high dose NPs combined with ultrasonic irradiation groups(2,2.5,3 mg·kg^(-1),hereinafter referred to as the low,medium and high dose combination groups,respectively).The corresponding doses of drugs were administered via tail vein injection,the model group received no treatment,while the placebo group was injected with an equivalent amount of normal saline.Dosing was conducted for a total of 10 times on alternate days.The body mass of the mice was monitored,and parameters such as body mass change rate,thymus index,spleen index,tumor volume,tumor weight,relative tumor growth rate(T/C),and tumor inhibition rate(TGI)were calculated.Pathological changes in liver and kidney tissues as well as the tumor were observed by hematoxylin-eosin(HE)staining.Additionally,the levels of aspartate aminotransferase(AST),alanine aminotransferase(ALT),blood urea nitrogen(BUN)and creatinine(CREA)in serum of mice were detected by biochemical method.Furthermore,the effect of ultrasound on the distribution of NPs in subcutaneous tumors of mouse hepatocellular carcinoma was observed by in vivo imaging technique.Results:Among different treatment methods,the combination of NPs and ultrasound irradiation had the best therapeutic effect.Compared with the model group,th

关 键 词：叶酸 聚乙二醇-聚乳酸羟基乙酸 纳米粒 克班宁 超声辐照 皮下瘤 小动物活体成像 

分 类 号：R22[医药卫生—中医基础理论] R28[医药卫生—中医学] R735.7R94