Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.
Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.
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DOI：
10.1016/j.jconrel.2010.12.013
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发表时间：
2011-04
期刊：
影响因子：
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通讯作者：
T. Tagami;Y. Uehara;Naoto Moriyoshi;T. Ishida;H. Kiwada
中科院分区：
文献类型：
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作者：
T. Tagami;Y. Uehara;Naoto Moriyoshi;T. Ishida;H. Kiwada
我们最近报道，含有核酸的聚乙二醇化阳离子脂质体，如果在几天后第二次注射，由于产生了抗聚乙二醇IgM，其长循环特性消失。这种加速的血液清除是治疗需要用含有核酸的聚乙二醇化制剂反复治疗的疾病的一个令人担忧的问题。在这项研究中，我们研究了在最近引入的聚乙二醇化脂质纳米载体中包裹siRNA的影响，以及包裹的siRNA的序列对抗PEGIgM产生的影响。与传统的聚乙二醇化脂合物中的siRNA相比，包裹在聚乙二醇WS中的siRNA产生的抗PEGIgM抗体很少。PGWL中的siRNA序列显著影响抗-PEGIgM的产生；一种有效的免疫刺激siRNA诱导更高的抗-PEGIgM的产生。这种增强作用被2‘-O-甲基(2’-OMe)尿苷掺入siRNA序列所消除，可能是通过抑制IL-6和肿瘤坏死因子-α等细胞因子的诱导而实现的。我们的结果有力地表明，使用具有低免疫刺激性siRNA的包封型脂质纳米载体，可以重复给药含有聚乙二醇化制剂的siRNA，而不会诱导对聚乙二醇的强烈免疫反应，从而可能推动合成的siRNA进入广泛的治疗应用。
We recently reported that the prolonged circulation property of PEGylated cationic liposomes containing nucleic acids disappears, if the second dose is injected within a few days later, due to the production of anti-PEG IgM. This accelerated blood clearance is a concern for treating diseases which require repeated treatment with a PEGylated formulation containing nucleic acids. In this study, we investigated the effect of encapsulation of siRNA in a recently introduced PEGylated lipid nanocarrier for which the term “wrapsome” (PEGylated wrapsome, PEG-WS) was proposed as well as the sequence of the encapsulated siRNA on anti-PEG IgM production. siRNA encapsulated in PEG-WS produced little anti-PEG IgM relative to siRNA in conventional PEGylated lipoplexes. The sequence of siRNA in the PEG-WL dramatically affected the anti-PEG IgM production; a potent immune stimulatory siRNA induced a higher anti-PEG IgM production. Such enhanced effect was abrogated by incorporation of 2′-O-methyl (2′-OMe) uridine into the sequence of siRNA, probably via inhibiting cytokine induction such as IL-6 and TNF-α. Our results strongly indicate that the use of an encapsulation-type lipid nanocarrier with a low immuno-stimulatory siRNA may allow repeated dosing of siRNA containing PEGylated formulations without the induction of a strong immune reaction against PEG and thus may advance synthetic siRNA into a broad range of therapeutic applications.