摘要
本研究针对P-糖蛋白(P-glycoprotein,P-gp)在肿瘤耐药性中的关键作用,利用P-gp细胞膜转运及其外排效应的三磷酸腺苷(adenosine triphosphate,ATP)依赖性,通过水热合成法、薄膜分散法构建了线粒体靶向亚砷酸钙/多柔比星(doxorubicin,DOX)脂质纳米粒。结果表明,该脂质纳米粒尺寸均一、分散性良好,平均粒径为(261±7)nm,zeta电位为(-9.6±1.3)mV。DOX的载药量和包封率分别为22.6%和84.0%;体外释放具有明显的pH依赖性;显著增加药物在细胞线粒体中的积累,引起钙离子局部超载,抑制P-gp以及ATP的生成,逆转肿瘤耐药性,同时释放亚砷酸根(AsO_(3)^(3-))和DOX,协同杀死肿瘤细胞。综上所述,本研究制备的脂质纳米粒粒径均一,载药量高和包封率、稳定性好,具有pH响应性及良好的逆转肿瘤耐药能力,有应用于临床研究的潜力。
This study aims at the critical role of P-glycoprotein(P-gp)in tumor drug resistance,taking advantage of the adenosine triphosphate(ATP)dependence of P-gp mediated drug transport and efflux across the cell membrane.Mitochondrial targeted calcium arsenite/doxorubicin(DOX)lipid nanoparticles were constructed via hydrothermal method and thin-film dispersion method for reversing tumor drug resistance.The results showed that the lipid nanoparticles were uniform in size and well dispersed with a mean particle size of(261±7)nm,zeta potential of(-9.6±1.3)mV.The DOX loading efficiency and encapsulation efficiency were 22.6%and 84.0%.The in vitro drug release profile was pH-dependent;the drug accumulation at mitochondria was significantly increased,which then caused overload of calcium and inhibition of P-gp and ATP,thereby reversing tumor drug resistance.The simultaneously released arsenite ion and DOX could synergistically kill the tumor cells.In summary,the lipid nanoparticles prepared in this study have uniform particle size,high drug loading efficiency and encapsulation efficiency,excellent colloidal stability,pH responsiveness,and impressive ability to reverse tumor drug resistance,which may hold great potential in further clinical applications.
作者
张钶
岳天祥
程梦莹
梁曾颖
朴寄纲
郑红月
徐恒武
李范珠
ZHANG Ke;YUE Tian-xiang;CHENG Meng-ying;LIANG Zeng-ying;PIAO Ji-gang;ZHENG Hong-yue;XU Heng-wu;LI Fan-zhu(College of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou 310000,China;Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province,Hangzhou 310000,China;Libraries of Zhejiang Chinese Medical University,Zhejiang Chinese Medical University,Hangzhou 310000,China;Department of Pharmacy,Jinhua People's Hospital,Jinhua 321000,China)
出处
《药学学报》
CAS
CSCD
北大核心
2021年第12期3243-3251,共9页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(82074027,81873014)
金华市科技局公益类项目(2019-4-037)。
关键词
肿瘤
线粒体
三氧化二砷
脂质纳米粒
耐药性
neoplasm
mitochondria
arsenic trioxide
lipid nanoparticle
drug resistance
作者简介
通讯作者:李范珠,Tel:86-571-61768130,Fax:86-571-61768181,E-mail:lifanzhu@zcmu.edu.cn;通讯作者:朴寄纲,E-mail:jgpiao@zcmu.edu.cn。
