Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA
Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA
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DOI：
10.1038/mt.2008.51
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发表时间：
2008-05-01
影响因子：
12.4
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
小干扰RNA（siRNA）选择性递送至转移性肿瘤仍然是一项具有挑战性的任务。我们已经开发了由siRNA、载体DNA、聚阳离子肽和阳离子脂质体组成的纳米颗粒（NP）制剂。通过自组装过程，然后用聚乙二醇（PEG）缀合的配体茴香酰胺进行表面改性，得到NP。将NP PEG化，并将配体呈递至靶向表达σ受体的鼠黑素瘤细胞B16 F10。通过将B16 F10细胞静脉内（IV）注射到C57 BL/6小鼠中建立肺转移模型。在靶向NP中共同配制的针对MDM 2、c-myc和血管内皮生长因子（VEGF）的siRNA混合物导致转移性结节中的每种癌基因同时沉默。在靶向NP中连续两次IV注射siRNA以相对低的剂量（0.45 mg/kg）显著降低肺转移（类似于70-80%），而游离siRNA和非靶向NP显示出很小的效果。与未处理的对照相比，这种靶向NP制剂显著延长了动物的平均存活时间30%。在治疗剂量下，靶向NP显示出很小的局部和全身免疫毒性，并且不降低体重或损害主要器官。
The selective delivery of small interfering RNA ( siRNA) to metastatic tumors remains a challenging task. We have developed a nanoparticle (NP) formulation composed of siRNA, a carrier DNA, a polycationic peptide, and cationic liposomes. The NP was obtained by a self-assembling process, followed by surface modification with a polyethylene glycol ( PEG)-conjugated ligand, anisamide. The NP was PEGylated and a ligand was presented to target sigma receptor-expressing murine melanoma cells, B16F10. The lung metastasis model was established by intravenous (IV) injection of the B16F10 cells into C57BL/6 mice. A mixture of siRNA against MDM2, c-myc, and vascular endothelial growth factor ( VEGF) co-formulated in the targeted NP caused simultaneous silencing of each of the oncogenes in the metastatic nodules. Two consecutive IV injections of siRNA in the targeted NP significantly reduced the lung metastasis (similar to 70-80%) at a relatively low dose ( 0.45 mg/kg), whereas free siRNA and the nontargeted NP showed little effect. This targeted NP formulation significantly prolonged the mean survival time of the animals by 30% as compared to the untreated controls. At the therapeutic dose, the targeted NP showed little local and systemic immunotoxicity and did not decrease the body weight or damage the major organs.