The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation
The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation
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DOI：
10.1016/j.biomaterials.2010.05.027
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发表时间：
2010-09-01
期刊：
影响因子：
14
通讯作者：
Peer, Dan
中科院分区：
文献类型：
--
作者：
Kedmi, Ranit;Ben-Arie, Noa;Peer, Dan
使用带正电荷的脂质纳米粒子 ((+)NP) 递送核酸被广泛用作研究试剂，并且由于其能够将核酸递送到细胞质中而潜在地用于治疗。然而，大多数报告很少关注它们的毒性作用。在本研究中，我们对与 (+)NP 相关的潜在毒性进行了全面分析。与用中性或带负电的 NPs (()NPs) 治疗的小鼠相比，用 (+)NPs 治疗的小鼠表现出肝酶释放增加和体重减轻，表明存在肝毒性。在不同白细胞亚群中，静脉注射 (+) NP 可诱导 I 型干扰素反应，并且干扰素反应基因的 mRNA 水平比中性和 () NP 高 15-25 倍。此外，(+)NPs 治疗可诱导 Th1 细胞因子表达（IL-2、IFN γ 和 TNF α）比对照颗粒治疗高 10-75 倍，从而引发显着的促炎反应。最后，我们表明，当使用 (+)NP 时，TLR4 的激活可能是诱导免疫反应的潜在机制。这些结果表明，当不同类型的 (+)NP 被开发为纳米治疗药物时，必须小心谨慎。 (C) 2010 Elsevier Ltd. 保留所有权利。
Delivery of nucleic acids with positively charged lipid nanoparticles ((+)NPs) is widely used as research reagents and potentially for therapeutics due to their ability to deliver nucleic acids into the cell cytoplasm. However, in most reports little attention has been made to their toxic effects. In the present study, we performed comprehensive analyses of the potential toxicity associated with (+)NPs. Mice treated with (+)NPs showed increased liver enzyme release and body weight loss compared to mice treated with neutral or negatively charged NPs (()NPs), suggesting hepatotoxicity. Intravenous administration of (+) NPs induced interferon type I response and elevated mRNA levels of interferon responsive genes 15-25-fold higher than neutral and ()NPs in different subsets of leukocytes. Moreover, treatment with (+)NPs provoked a dramatic pro-inflammatory response by inducing Th1 cytokines expression (IL-2, IFN gamma and TNF alpha) 10-75-fold higher than treatment with control particles. Finally, we showed that activation of TLR4 might serve as the underlying mechanism for induction of an immune response when (+)NPs are used. These results suggest that a careful attention must be made when different types of (+)NPs are being developed as nanotherapeutics. (C) 2010 Elsevier Ltd. All rights reserved.