title: Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Institute of Health Biosciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tagami
authors.forename: Yumi
authors.initials: Y
authors.lastname: Uehara
authors.forename: Naoto
authors.initials: N
authors.lastname: Moriyoshi
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D000818:Animals; D001483:Base Sequence; D004337:Drug Carriers / Q000008:administration & dosage; D007075:Immunoglobulin M / Q000096:biosynthesis*; D008081:Liposomes; D008297:Male; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage*; D053758:Nanoparticles / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*
chemical_list: D004337:Drug Carriers; D007075:Immunoglobulin M; D008081:Liposomes; D053769:Nanocapsules; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols