pH敏感阿霉素前药纳米粒的制备及体外抗肿瘤评价  

Preparation and in vitro antitumor evaluation of pH-sensitive doxorubicin prodrug nanoparticles

作　　者：游宠昭 毛静 许嘉敏 邱立朋 陈敬华 YOU Chong-zhao;MAO Jing;XU Jia-min;QIU Li-peng;CHEN Jing-hua(School of Pharmaceutical Sciences,Jiangnan University,Wuxi 214122,China)

机构地区：[1]江南大学药学院,无锡214122

出　　处：《中国新药杂志》2020年第11期1285-1291,共7页Chinese Journal of New Drugs

基　　金：国家自然科学基金资助项目(81503007,21574059)。

摘　　要：目的:合成肝靶向的阿霉素(doxorubicin,DOX)前药,并选择p H敏感的ZIF-8载体构建一种新型的抗肿瘤药物给药系统。方法:利用DOX与半乳糖醛酸[D-(+)-galacturonic acid,D-Gal acid]进行酰胺化反应得到半乳糖-阿霉素(galactose-doxorubicin,Gal-DOX)前药,并通过氢核磁共振(1H nuclear magnetic resonance,1H NMR)、傅里叶红外光谱分析(fourier transform infrared,FTIR)和全紫外可见光全波长扫描(UV-visible full-wave-length scanning,UV-VIS)对Gal-DOX进行结构表征;选择金属有机框架聚合物ZIF-8为载体包载Gal-DOX,构建pH敏感Gal-DOX/ZIF-8纳米给药系统,并考察Gal-DOX/ZIF-8的理化性质及其体外药物释放行为;通过MTT法研究Gal-DOX/ZIF-8对HepG2肝肿瘤细胞的毒性。结果:成功合成Gal-DOX前药,制备的Gal-DOX/ZIF-8为粒径约200 nm的均匀球形颗粒。体外释药实验中酸性环境的释药速率高于正常环境,表明其具有明显的p H敏感性释药特征。MTT结果表明ZIF-8空白载体没有明显毒性,但GalDOX/ZIF-8对HepG2细胞的毒性高于游离DOX。结论:Gal-DOX/ZIF-8具有良好的pH敏感释药特性,能够提高肝靶向性,为肝癌治疗提供新的思路。Objective:To synthesize a liver-targeting doxorubicin(DOX)prodrug and construct a new available ZIF-8 based pH-sensitive antitumor drug delivery system.Methods:Galactose-doxorubicin(Gal-DOX)prodrug was synthesized by bonding DOX with galacturonic acid[D-(+)-galacturonic acid,D-Gal acid]through amidation.The chemical structure of Gal-DOX was characterized by 1H nuclear magnetic resonance(1H NMR),fourier transform infrared(FTIR)and UV-visible full-wavelength scanning(UV-VIS).ZIF-8,a metal organic framework polymer,was used to carry Gal-DOX in order to construct a pH-sensitive Gal-DOX/ZIF-8 drug delivery system.The physicochemical properties,as well as in vitro release behaviors,of Gal-DOX/ZIF-8 were also studied.In vitro antitumor effects of blank nanoparticles and drug-loaded nanoparticles were evaluated using MTT assay.Results:Gal-DOX prodrug was successfully synthesized,and Gal-DOX/ZIF-8 nanoparticles were developed with uniform spherical structure in the diameter of about 200 nm.In vitro release rate of Gal-DOX/ZIF-8 at acid condition was faster than that in normal environment,suggesting that Gal-DOX/ZIF-8 had obvious pH sensibility.The results of MTT antitumor experiments showed that blank ZIF-8 nanoparticles had no obvious cytotoxicity,while Gal-DOX/ZIF-8 presented stronger cytotoxicity against HepG2 cells compared with free DOX.Conclusion:The Gal-DOX/ZIF-8 nanoparticles had good pH sensitive release characteristic and could improve liver-targeting ability.Therefore,Gal-DOX/ZIF-8 nanoparticles would be a potential drug delivery system for liver carcinoma therapy.

关 键 词：阿霉素 前药 pH敏感释药 金属有机框架聚合物 

分 类 号：R967[医药卫生—药理学]