Synthesis of novel tetravalent galactosylated DTPA-DSPE and study on hepatocyte-targeting efficiency in vitro and in vivo.
Synthesis of novel tetravalent galactosylated DTPA-DSPE and study on hepatocyte-targeting efficiency in vitro and in vivo.
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新型四价半乳糖基化DTPA-DSPE的合成及体内外肝细胞靶向效率研究
DOI：
10.2147/ijn.s47495
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发表时间：
2013
影响因子：
8
通讯作者：
Zhao C
中科院分区：
文献类型：
--
作者：
Xiao Y;Zhang H;Zhang Z;Yan M;Lei M;Zeng K;Zhao C
为获得肝细胞选择性给药系统，合成了一种新型四价半乳糖基化二亚乙基三胺五乙酸-二硬脂酰磷脂酰乙醇胺（4Gal-DTPA-DSPE）。通过核磁共振氢谱和质谱确证了4Gal-DTPA-DSPE的化学结构。采用薄膜水合法制备了4种半乳糖修饰脂质体（4Gal-脂质体），采用硫酸铵梯度法将阿霉素（DOX）包封于脂质体中。激光共聚焦显微镜和流式细胞仪分析结果表明，4-Gal-DTPA-DSPE脂质体可通过脱唾液酸糖蛋白受体介导的内吞作用促进HepG 2细胞对阿霉素的摄取。细胞毒性实验表明，4Gal-脂质体对细胞增殖的抑制作用高于不含半乳糖的常规脂质体。此外，在大鼠中的药代动力学实验显示，与常规脂质体相比，4Gal-脂质体显示出从体循环中更慢的清除。小鼠体内器官分布和肝脏冰冻切片研究表明，4Gal脂质体能增强DOX在肝细胞内的摄取，延长循环时间。综上所述，这些结果表明，含有4Gal-DTPA-DSPE的脂质体作为肝细胞选择性靶向的药物递送载体具有很大的潜力。
For the purposes of obtaining a hepatocyte-selective drug delivery system, a novel tetravalent galactosylated diethylenetriaminepentaacetic acid-distearoyl phosphatidylethanolamine (4Gal-DTPA-DSPE) was synthesized. The chemical structure of 4Gal-DTPA-DSPE was confirmed by proton nuclear magnetic resonance and mass spectrometry. The four galactose-modified liposomes (4Gal-liposomes) were prepared by thin-film hydration method, then doxorubicin (DOX) was encapsulated into liposomes using an ammonium sulfate gradient loading method. The liposomal formulations with 4Gal-DTPA-DSPE were characterized by laser confocal scanning microscopy and flow cytometry analysis, and the results demonstrated that the 4Gal-liposomes facilitated the intracellular uptake of DOX into HepG2 cells via asialoglycoprotein receptor-mediated endocytosis. Cytotoxicity assay showed that the cell proliferation inhibition effect of 4Gal-liposomes was higher than that of the conventional liposomes without the galactose. Additionally, pharmacokinetic experiments in rats revealed that the 4Gal-liposomes displayed slower clearance from the systemic circulation compared with conventional liposomes. The organ distributions in mice and the study on frozen sections of liver implied that the 4Gal-liposomes enhanced the intracellular uptake of DOX into hepatocytes and prolonged the circulation. Taken together, these results indicate that liposomes containing 4Gal-DTPA-DSPE have great potential as drug delivery carriers for hepatocyte-selective targeting.