Effect of Cationic Lipid Type in Folate-PEG-Modified Cationic Liposomes on Folate Receptor-Mediated siRNA Transfection in Tumor Cells
Effect of Cationic Lipid Type in Folate-PEG-Modified Cationic Liposomes on Folate Receptor-Mediated siRNA Transfection in Tumor Cells
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DOI：
10.3390/pharmaceutics11040181
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发表时间：
2019-04-01
期刊：
影响因子：
5.4
通讯作者：
Onishi, Hiraku
中科院分区：
文献类型：
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作者：
Hattori, Yoshiyuki;Shimizu, Satono;Onishi, Hiraku
在这项研究中，我们研究了叶酸（FA）-聚乙二醇（PEG）修饰的阳离子脂质体中的阳离子脂质类型对使用阳离子脂质体/siRNA复合物（siRNA lipoplexes）在肿瘤细胞中的基因沉默效应的影响。我们使用三种类型的阳离子胆固醇衍生物，胆固醇（3-（（2-羟乙基）氨基）丙基）氨基甲酸酯氢碘酸盐（HAPC-Chol）、N-（2-（2-羟乙基氨基）乙基）胆固醇-3-甲酰胺（OH-Chol）和胆固醇（2-（（2-羟乙基）氨基）乙基）氨基甲酸酯（OH-C-Chol），并且我们制备了三种类型的FA-PEG修饰的siRNA脂质复合物。用1- 2mol%PEG-脂质修饰阳离子脂质体可消除人鼻咽癌KB细胞中的基因沉默效应，该细胞过表达FA受体（FR）。相比之下，FA-PEG修饰的阳离子脂质体恢复基因沉默活性，无论阳离子脂质体中的阳离子脂质类型如何。然而，阳离子脂质体中PEG-脂质和FA-PEG-脂质的选择性基因沉默和细胞摄取的最佳量在三种类型的阳离子脂质体中是不同的。此外，在体外转染Polo样激酶1（PLK 1）siRNA的FA-PEG-修饰的脂质体在KB细胞中表现出较强的细胞毒性，与PEG-修饰的脂质体相比，然而，在体内治疗中，肿瘤内注射PEG-修饰的PLK 1 siRNA脂质体抑制KB异种移植瘤的生长，以及FA-PEG-修饰的PLK 1 siRNA脂质体。从这些结果来看，用于FR选择性基因沉默的PEG和FA-PEG修饰的脂质体的最佳制剂在体外和体内转染之间可能是不同的。
In this study, we examined the effect of cationic lipid type in folate (FA)-polyethylene glycol (PEG)-modified cationic liposomes on gene-silencing effects in tumor cells using cationic liposomes/siRNA complexes (siRNA lipoplexes). We used three types of cationic cholesterol derivatives, cholesteryl (3-((2-hydroxyethyl)amino)propyl)carbamate hydroiodide (HAPC-Chol), N-(2-(2-hydroxyethylamino)ethyl)cholesteryl-3-carboxamide (OH-Chol), and cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol), and we prepared three types of FA-PEG-modified siRNA lipoplexes. The modification of cationic liposomes with 1-2 mol % PEG-lipid abolished the gene-silencing effect in human nasopharyngeal tumor KB cells, which overexpress the FA receptor (FR). In contrast, FA-PEG-modification of cationic liposomes restored gene-silencing activity regardless of the cationic lipid type in cationic liposomes. However, the optimal amount of PEG-lipid and FA-PEG-lipid in cationic liposomes for selective gene silencing and cellular uptake were different among the three types of cationic liposomes. Furthermore, in vitro transfection of polo-like kinase 1 (PLK1) siRNA by FA-PEG-modified liposomes exhibited strong cytotoxicity in KB cells, compared with PEG-modified liposomes; however, in in vivo therapy, intratumoral injection of PEG-modified PLK1 siRNA lipoplexes inhibited tumor growth of KB xenografts, as well as that of FA-PEG-modified PLK1 siRNA lipoplexes. From these results, the optimal formulation of PEG- and FA-PEG-modified liposomes for FR-selective gene silencing might be different between in vitro and in vivo transfection.