期刊
JOURNAL OF CONTROLLED RELEASE
卷 151, 期 2, 页码 149-154出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2010.12.013
关键词
Accelerated blood clearance (ABC) phenomenon; Polyethylene glycol (PEG); Anti-PEG IgM; Small interfering RNA (siRNA), 2 '-O-methyl-uridine modified siRNA (2 '-OMe siRNA)
资金
- Ministry of Health, Labour and Welfare of Japan
- Grants-in-Aid for Scientific Research [23390012] Funding Source: KAKEN
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-alpha. 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. (C) 2011 Published by Elsevier B.V.
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