Tumor site-specific silencing of NF-kappaB p65 by targeted hollow gold nanosphere-mediated photothermal transfection.
Tumor site-specific silencing of NF-kappaB p65 by targeted hollow gold nanosphere-mediated photothermal transfection.
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DOI：
10.1158/0008-5472.can-09-3379
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Lu W;Zhang G;Zhang R;Flores LG 2nd;Huang Q;Gelovani JG;Li C
核因子-κB (NF-κB) 转录因子是肿瘤形成和进展相关基因表达的关键调节因子。成功的靶向 NF-κB 的 RNA 干扰 (RNAi) 疗法受到 siRNA 递送系统的挑战，该系统可以实现靶向体内递送、有效的内溶酶体逃逸以及对 RNAi 激活的动态控制。在这里，我们报告了通过携带识别 NF-κB p65 亚基的 siRNA 的叶酸受体靶向空心金纳米球，近红外光诱导的 NF-κB 下调。使用微正电子发射断层扫描/计算机断层扫描成像，静脉注射后，靶向纳米结构在携带 HeLa 宫颈癌异种移植物的裸鼠中表现出比非靶向纳米粒子显着更高的肿瘤摄取。在空心金纳米球的介导下，通过光热效应在近红外光照射下实现了 siRNA 的可控细胞质递送。仅在用近红外光照射的肿瘤中才实现了 NF-κB p65 的有效下调，但在同一小鼠中生长的未照射肿瘤中则没有实现。肝脏、脾脏、肾脏和肺脏并未受到治疗的影响，尽管这些器官中 siRNA 纳米粒子的摄取量显着增加。我们将这种作用模式称为“光热转染”。与其他治疗方案相比，p65 siRNA 光热转染和伊立替康联合治疗可显着增强肿瘤细胞凋亡并显着延迟肿瘤生长。因此，光热转染NF-κB p65 siRNA可以有效提高肿瘤对化疗药物的敏感性。由于近红外光可以穿透皮肤并以高度时空控制的方式传递，因此治疗性 RNAi 可能会受益于这种新颖的转染策略，同时避免不必要的副作用。
Nuclear factor-κB (NF-κB) transcription factor is a critical regulator of the expression of genes involved in tumor formation and progression. Successful RNA interference (RNAi) therapeutics targeting NF-κB is challenged by siRNA delivery systems, which can render targeted in vivo delivery, efficient endo-lysosomal escape and dynamic control over activation of RNAi. Here, we report near-infrared light-inducible NF-κB down-regulation through folate receptor-targeted hollow gold nanospheres carrying siRNA recognizing NF-κB p65 subunit. Using micro-positron emission tomography/computed tomography imaging, the targeted nanoconstructs exhibited significantly higher tumor uptake in nude mice-bearing HeLa cervical cancer xenografts than non-targeted nanoparticles following intravenous administration. Mediated by hollow gold nanospheres, controllable cytoplasmic delivery of siRNA was obtained upon near-infrared light irradiation through photothermal effect. Efficient down-regulation of NF-κB p65 was achieved only in tumors irradiated with near-infrared light, but not in non-irradiated tumors grown in the same mice. Liver, spleen, kidney, and lung were not affected by the treatments, in spite of significant uptake of the siRNA nanoparticles in these organs. We term this mode of action “photothermal transfection”. Combined treatments with p65 siRNA photothermal transfection and irinotecan caused substantially enhanced tumor apoptosis and significant tumor growth delay compared with other treatment regimens. Therefore, photothermal transfection of NF-κB p65 siRNA could effectively sensitize the tumor to chemotherapeutic agents. Because NIR light can penetrate skin and be delivered with high spatiotemporal control, therapeutic RNAi may benefit from this novel transfection strategy while avoiding unwanted side effect.