基于金纳米棒的pH敏感控释纳米递药系统联合热疗的体内抗肿瘤作用  

Study on a pH-sensitive controlled release nano-drug delivery system based on gold nanorods combined with hyperthermia in the treatment of cancer in vivo

作　　者：蔡锋[1] 薛飞[2] 朱运海[1] 赵杰[1] 叶赛 马红岩[3] Cai Feng;Xue Fei;Zhu Yunhai;Zhao Jie;Ye Sai;Ma Hongyan(Department of Gastroenterobiliary Surgery,the First People’s Hospital,Shangqiu 476100,China;Department of Hepatobiliary Surgery,Henan Provincial People's Hospital,Zhengzhou 450003,China;Department of Clinical Mediciney Shangqiu Medical College,Shangqiu 476100,China)

机构地区：[1]商丘市第一人民医院胃肠肝胆外科,476100 [2]河南省人民医院肝胆外科,郑州450003 [3]河南商丘医学高等专科学校临床医学系,476100

出　　处：《中华实验外科杂志》2019年第9期1605-1610,共6页Chinese Journal of Experimental Surgery

基　　金：2018年度河南省医学科技攻关计划联合共建项目(2018020941).

摘　　要：目的探讨一种具有pH敏感特性的金纳米棒(AuNR)纳米递药系统联合热疗的小鼠体内抗肿瘤疗效.方法使用金种子生长法制备AuNR,并使用巯基-PEG2000-氨基(SH-PEG2000-NH2)对其进行修饰,通过腙键连接模型药物阿霉素(DOX),构建具有pH敏感控释的AuNR-聚乙二醇(PEG)-DOX纳米递药系统.使用紫外全波长扫描(UV-Vis)考察AuNR的特征吸收峰;使用透射电镜(TEM)考察AuNR的形态及大小;使用傅里叶红外光谱(FT-IR)考察各阶段产物合成;使用高效液相色谱法(HPLC)考察DOX的载药能力及pH敏感控释能力;使用X线CT考察纳米递药系统的体外及体内成像效果;将荷瘤小鼠随机分组,考察纳米递药系统联合热疗后的体内抗肿瘤情况.应用SPSS 17.0统计软件分析,多组差异比较采用单因素方差分析,两组间比较采用t检验.结果制备的AuNR形态稳定,呈分布均一的棒状,长径比为3.6∶1.0,在800 nm左右具有特征吸收峰,可作为近红外(NIR)热疗增敏剂用于后续研究.FT-IR结果表明,DOX可通过pH敏感腙键连接至载体表面.DOX的载药率为(12.3±2.4)%,包封率为(58.3±4.7)%.体外释药结果表明AuNR-PEG-DOX具有良好的pH敏感性,当释放介质的pH由7.4下降至5.5时,DOX累积释放量由(14.5±2.5)%增加至(80.3±2.1)%.体内及体外X线成像结果表明,该给药系统可增强X线CT成像对比度,可用于给药系统的体内实时观测,且能证明该递药系统具有良好的肿瘤蓄积能力.体内抗肿瘤实验结果表明,AuNR-PEG-DOX与热疗联合治疗结束后小鼠相对肿瘤体积为0.9,与其他实验组比较差异均有统计学意义(P<0.05).表明该疗法可有效抑制体内肿瘤的发生与发展.结论AuNR-PEG-DOX纳米递药系统具有pH敏感控释能力、X线成像增强作用、NIR热疗增敏作用,可有效抑制体内肿瘤增殖.Objective To investigate the in vivo anti-tumor effect combined with hyperthermia of a pH sensitive nano-drug delivery system based on the gold nanorods(AuNR).Methods AuNR was prepared by seed mediated growth method firstly,and then it was modified with SH-PEG2000-NH2.Finally,doxorubicin(DOX)was connected through hydrazine bond to construct the AuNR-polyethylene glycol(PEG)-DOX nano-drug delivery system with pH-sensitive controlled release effect.Ultraviolet-Visible spectroscopy(UV-Vis)and transmission electron microscope(TEM)were used to detect the characteristic absorption peaks,shape and size of AuNR,respectively.The products of each step of chemical reaction was determined by fourier transform infrared spectroscopy(FT-IR).High performance liquid chromatography(HPLC)was used for the investigation of drug loading efficiency and pH sensitive controlled release effect.The ex vitro and in vivo imaging effect of this drug delivery system was detected by X-Ray CT.And the tumor-bearing mice were randomly divided into groups to investigate the anti-tumor effect of nano-drug delivery system combined with hyperthermia in vivo.Results The prepared AuNR has stable morphology,uniform rod-like distribution,the aspect ratio was 3.6∶1.0,and the long-diameter characteristic absorption peak at-800 nm,which can be used as a near infrared(NIR)hyperthermia sensitizer for futher research.The FT-IR result showed that DOX can be connected to the carrier surface through hydrazine bond.The drug loading efficiency and encapsulation efficiency of DOX were(12.3±2.4)%and(58.3±4.7)%,respectively.When the pH of the release medium decreased from 7.4 to 5.5,the cumulative release rate of DOX increased from(14.5±2.5)%to(80.3±2.1)%,indicating that AuNR-PEG-DOX has good pH sensitivity effect.In vivo and in vitro X-Ray imaging results showed that the drug delivery system can enhance the contrast of X-Ray CT imaging,which can be used for in vivo real-time observation.And these results also can prove that the drug delivery system has good tumo

关 键 词：金纳米棒 PH敏感 X线成像 热疗 纳米递药系统 

分 类 号：R730.5[医药卫生—肿瘤] TB383.1[医药卫生—临床医学]