Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles
Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles
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DOI：
10.1016/j.jconrel.2007.11.002
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发表时间：
2008-02-18
影响因子：
10.8
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
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作者：
Li, Shyh-Dar;Chono, Sumio;Huang, Leaf
我们已经开发了用于将siRNA全身递送到转移性肿瘤中的纳米颗粒（NP）制剂。采用自组装方法制备了由核酸、聚阳离子肽和阳离子脂质体组成的纳米粒。然后通过含有靶向配体茴香酰胺的PEG-脂质修饰NP，并因此修饰用于靶向表达σ受体的B16 F10肿瘤。将靶向NP的活性与裸NP（无PEG化）和非靶向NP（无配体）进行比较。靶向NP的递送效率比非靶向NP高4倍，并且可以被过量的游离配体竞争。使用荧光素酶siRNA来评估B16 F10细胞中的基因沉默活性，所述B16 F10细胞用荧光素酶基因稳定转导。靶向NP的基因沉默活性显著高于其他制剂，并持续4天。虽然共聚焦显微镜显示裸NP不提供组织选择性并且非靶向NP对于肿瘤摄取无效，但靶向NP有效地穿透肺转移，但不穿透肝。在单次静脉注射（150 μ g siRNA/kg）后，它导致转移模型中70-80%的基因沉默。这种有效的制剂也显示出非常小的免疫毒性。(C)2007 Elsevier B. V.保留所有权利。
We have developed a nanoparticle (NP) formulation for systemically delivering siRNA into metastatic tumors. The NP, composed of nucleic acids, a polycationic peptide and cationic liposome, was prepared in a self-assembling process. The NP was then modified by PEG-lipid containing a targeting ligand, anisamide, and thus was decorated for targeting sigma receptor expressing B16F10 tumor. The activity of the targeted NP was compared with the naked NP (no PEGylation) and non-targeted NP (no ligand). The delivery efficiency of the targeted NP was 4-fold higher than the non-targeted NP and could be competed by excess free ligand. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene. The gene silencing activity of the targeted NP was significantly higher than the other formulations and lasted for 4 days. While confocal microscopy showed that the naked NP provided no tissue selectivity and non-targeted NP was ineffective for tumor uptake, the targeted NP effectively penetrated the lung metastasis, but not the liver. It resulted in 70-80% gene silencing in the metastasis model after a single i.v. injection (150 mu g siRNA/kg). This effective formulation also showed very little immunotoxicity. (C) 2007 Elsevier B.V. All rights reserved.