Small interfering RNA delivery into the liver by cationic cholesterol derivative-based liposomes
Small interfering RNA delivery into the liver by cationic cholesterol derivative-based liposomes
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DOI：
10.1080/08982104.2016.1205599
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发表时间：
2017-01-01
影响因子：
4.4
通讯作者：
Onishi, Hiraku
中科院分区：
文献类型：
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作者：
Hattori, Yoshiyuki;Machida, Yoko;Onishi, Hiraku
目的：我们以前报道过由胆固醇衍生物胆固醇（2-（（2-羟乙基）氨基）乙基）氨基甲酸酯（OH-C-Chol）和1，2-二油酰基-sn-甘油基-3-磷酸乙醇胺（DOPE）组成的阳离子脂质体（LP-C）可以高效率地将小干扰RNA（siRNA）递送到肿瘤细胞中。在这项研究中，为了开发用于体内siRNA递送的脂质体载体，我们制备了聚（乙二醇）（PEG）修饰的阳离子脂质体（LP-C-PEG）的转染，并在体外和体内评估它们的转染效率。我们制备了LP-C-PEG/siRNA复合物（LP-C-PEG脂质复合物）在水或50 mM NaCl溶液中形成，结果：LP-C-PEG脂质体复合物在体外对人乳腺癌MCF-7细胞和LP-C脂质体复合物均表现出较强的基因沉默作用。特别地，在NaCl溶液中形成LP-C和LP-C-PEG脂质复合物增加了细胞缔合。当将在水或NaCl溶液中形成的具有Cy5.5标记的siRNA的LP-C-PEG脂质复合物注射到小鼠中时，观察到siRNA在肝脏中的积累。此外，注射LP-C-PEG lipoplexes与载脂蛋白B siRNA可以抑制载脂蛋白B mRNA在肝脏中的水平和降低血清中的极低密度脂蛋白/低密度脂蛋白水平相比，后Cont siRNA转染，虽然存在的NaCl溶液中形成的lipoplexes在体内基因沉默effects in vivo.Conclusions：LP-C-PEG可能有潜力作为一种基因载体的siRNA传递到肝脏。
Purpose: Previously, we reported that the cationic liposomes composed of a cationic cholesterol derivative, cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (termed LP-C), could deliver small interfering RNAs (siRNAs) with high transfection efficiency into tumor cells. In this study, to develop a liposomal vector for siRNA delivery in vivo, we prepared the poly(ethyleneglycol) (PEG)-modified cationic liposomes (LP-C-PEG) and evaluated their transfection efficiency in vitro and in vivo.Materials and methods: We prepared LP-C-PEG/siRNA complexes (LP-C-PEG lipoplexes) formed in water or 50mM NaCl solution, and evaluated their siRNA biodistribution and gene silencing effect in mice after intravenous injection.Results: LP-C-PEG lipoplexes strongly exhibited in vitro gene silencing effects in human breast tumor MCF-7 cells as well as LP-C lipoplexes. In particular, formation of LP-C and LP-C-PEG lipoplexes in the NaCl solution increased the cellular association. When LP-C-PEG lipoplexes with Cy5.5-labeled siRNA formed in water or NaCl solution were injected into mice, accumulation of the siRNA was observed in the liver. Furthermore, injection of LP-C-PEG lipoplexes with ApoB siRNA could suppress ApoB mRNA levels in the liver and reduce very-low-density lipoprotein/low-density lipoprotein levels in serum compared with that after Cont siRNA transfection, although the presence of NaCl solution in forming the lipoplexes did not affect gene silencing effects in vivo.Conclusions: LP-C-PEG may have potential as a gene vector for siRNA delivery to the liver.