Kurosaki Tomoaki, Kawanabe Saki, Kodama Yukinobu, Fumoto Shintaro, Nishida Koyo, Nakagawa Hiroo, Higuchi Norihide, Nakamura Tadahiro, Kitahara Takashi, Sasaki Hitoshi
Department of Hospital Pharmacy, Nagasaki University Hospital , 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Mol Pharm. 2014 May 5;11(5):1369-77. doi: 10.1021/mp400398f. Epub 2014 Apr 21.
In this study, a novel liver-targeted gene delivery vector was developed by electrostatically coating the cationic complex of pDNA and polyethylenimine (PEI) with glycyrrhizin (GL). The ternary complex, pDNA/PEI/GL, had approximately 100 nm stable particles with a negative charge surface. pDNA/PEI/GL showed high gene expression comparable to that of the complex of pDNA and PEI (pDNA/PEI) in human hepatoma cell line HepG2 without cytotoxicity and agglutination. After intravenous injection of pDNA/PEI/GL into mice, the highest gene expression was observed in the liver. pDNA/PEI/GL showed significantly higher gene expression in parenchymal cells than in nonparenchymal cells. On the basis of these results, we evaluated the pharmacological activity of the ternary complex including the pDNA encoding insulin (pCMV-Ins). The pCMV-Ins/PEI/GL decreased blood glucose concentrations 24 h after its intravenous administration to mice. The ternary complex of pDNA, PEI, and GL may be a promising liver-targeted gene vector.
在本研究中，通过用甘草酸（GL）静电包覆质粒DNA（pDNA）与聚乙烯亚胺（PEI）的阳离子复合物，开发了一种新型的肝靶向基因递送载体。三元复合物pDNA/PEI/GL具有约100nm的稳定颗粒，表面带负电荷。pDNA/PEI/GL在人肝癌细胞系HepG2中表现出与pDNA和PEI复合物（pDNA/PEI）相当的高基因表达，且无细胞毒性和凝集现象。将pDNA/PEI/GL静脉注射到小鼠体内后，在肝脏中观察到最高的基因表达。pDNA/PEI/GL在实质细胞中的基因表达明显高于非实质细胞。基于这些结果，我们评估了包含编码胰岛素的pDNA（pCMV-Ins）的三元复合物的药理活性。pCMV-Ins/PEI/GL静脉注射给小鼠24小时后血糖浓度降低。pDNA、PEI和GL的三元复合物可能是一种有前景的肝靶向基因载体。
