数字中医药（英文）2020，Vol.3Issue(4)：260-274,15.DOI:10.1016/j.dcmed.2020.12.005
叶酸修饰的三氧化二砷前药脂质体的构建及抗肝癌研究
Fabrication of A Folic Acid-Modified Arsenic Trioxide Prodrug Liposome and Assessment of its Anti-Hepatocellular Carcinoma Activity
摘要
Abstract
Objective To reduce the toxicity and side effects of arsenic trioxide (ATO) and provide a new approach for the treatment of primary liver cancer, a folic acid-modified calcium arsenite liposomal "target-controlled" drug delivery system (FA-LP-CaAs) was fabricated using the reverse microemulsion method. Methods A Malvern particle size analyzer and a transmission electron microscope were employed to determine the particle size, distribution, zeta potential and morphology of FA-LP-CaAs. Further, inductively coupled plasma emission spectrometry was employed to determine the drug loading capacity, entrapment efficiency, and in vitro release behavior of FA-LP-CaAs. To determine its toxicity in human hepatoma cells (HepG2) and human normal hepatocytes (LO2) and its effect on HepG2 cell cycle and apoptosis, the MTT method was used. Laser confocal and flow cytometry were also employed to determine the uptake of FA-LP-CaAs by cells. After establishing a mouse liver cancer model, the in vivo distribution of the drug included in the formulation was investigated using in vivo fluorescence. To evaluate the liver cancer targeting and anti-tumor effects of FA-LP-CaAs in vivo, the distribution of ATO in tissues and changes in tumor volume and body weight after liposomal administration were investigated using hematoxylin-eosin (HE)-stained tumor sections. Results The particle size, zeta potential and PDI of FA-LP-CaAs were (122.67 ± 2.18) nm, (12.81 ± 0.75) mV and 0.22 ± 0.01, respectively, while its drug loading capacity was 18.49％ ± 1.14％. In vitro experimental results revealed that FA-LP-CaAs had a strong killing effect on HepG2 cells. Further, the cell uptake capacity of this formulation was found to improve. Based on in vivo assessments, FA-LP-CaAs could significantly increase the distribution of ATO in tumor sites and inhibit tumor growth.Conclusions Herein, an FA-LP-CaAs formulation was successfully fabricated. This liposomal drug delivery system had a round appearance, uniform particle size, good polydispersity coeffi-cient, evident "core-shell" structure, high drug loading capacity and pH response, tumor targeted drug delivery and sustained drug release. These findings support further research and the application of ATO as an anti-liver cancer prodrug and provide a new method for the treatment of liver cancer.关键词
肝癌/三氧化二砷/亚砷酸钙/脂质体/pH-敏感/"靶-控"递药系统Key words
Target-controlled drug delivery system/Liver cancer/Arsenic trioxide/Calcium arsenite/Liposomes/pH-sensitive引用本文复制引用
朱晶晶,陈晓劼,姚文栋,魏颖慧,郑杭生,郑红月,朱志红,王彬辉,李范珠..叶酸修饰的三氧化二砷前药脂质体的构建及抗肝癌研究[J].数字中医药（英文）,2020,3(4):260-274,15.基金项目
We thank for the funding support from the National Natural Science Foundation of China(No.81873014). （No.81873014）
