Tumor-targeted delivery of siRNA by self-assembled nanoparticles
Tumor-targeted delivery of siRNA by self-assembled nanoparticles
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DOI：
10.1038/sj.mt.6300323
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发表时间：
2008-01-01
影响因子：
12.4
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Li, Shyh-Dar;Chen, Yun-Ching;Huang, Leaf
我们已经开发了一种自组装纳米颗粒（NP），通过静脉内（IV）给药有效地将小干扰RNA（siRNA）递送到肿瘤。通过混合载体DNA、siRNA、鱼精蛋白和脂质，然后用聚乙二醇和配体茴香酰胺进行后修饰来获得NP。将制剂IV注射到异种移植模型中后4小时，70-80%的注射siRNA/g在肿瘤中积累，在肝脏中检测到类似于10%，在肺中回收类似于20%。共聚焦显微镜显示，荧光标记的siRNA通过靶向的NP有效地递送到表达σ受体的NCI-H460异种移植肿瘤的细胞质中，而游离siRNA和非靶向的NP显示出很少的摄取。每日三次注射（1.2 mg/kg）靶向NP中配制的siRNA使肿瘤中的表皮生长因子受体（EGFR）沉默，并诱导类似于15%的肿瘤细胞凋亡。通过靶向NP治疗实现了40%的肿瘤生长抑制，而当与顺铂组合时，完全抑制持续1周。给药期间肝酶的血清水平和体重监测表明制剂的毒性水平较低。载体本身也表现出很小的免疫毒性（IMT）。
We have developed a self-assembled nanoparticle (NP) that efficiently delivers small interfering RNA ( siRNA) to the tumor by intravenous (IV) administration. The NP was obtained by mixing carrier DNA, siRNA, protamine, and lipids, followed by post-modification with polyethylene glycol and a ligand, anisamide. Four hours after IV injection of the formulation into a xenograft model, 70-80% of injected siRNA/g accumulated in the tumor, similar to 10% was detected in the liver and similar to 20% recovered in the lung. Confocal microscopy showed that fluorescent-labeled siRNA was efficiently delivered into the cytoplasm of the sigma receptor expressing NCI-H460 xenograft tumor by the targeted NPs, whereas free siRNA and non-targeted NPs showed little uptake. Three daily injections (1.2 mg/kg) of siRNA formulated in the targeted NPs silenced the epidermal growth factor receptor ( EGFR) in the tumor and induced similar to 15% tumor cell apoptosis. Forty percent tumor growth inhibition was achieved by treatment with targeted NPs, while complete inhibition lasted for 1 week when combined with cisplatin. The serum level of liver enzymes and body weight monitoring during the treatment indicated a low level of toxicity of the formulation. The carrier itself also showed little immunotoxicity (IMT).