title: The systemic toxicity of positively charged lipid nanoparticles and the role of Toll-like receptor 4 in immune activation.
abstract: 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.
authors.affiliation: Laboratory of Nanomedicine, Department of Cell Research and Immunology, George S. Wise Faculty of life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Ranit
authors.initials: R
authors.lastname: Kedmi
authors.forename: Noa
authors.initials: N
authors.lastname: Ben-Arie
authors.forename: Dan
authors.initials: D
authors.lastname: Peer
mesh_terms: D000818:Animals; D007109:Immunity / Q000187:drug effects*; D007249:Inflammation / Q000276:immunology; D008055:Lipids / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity*; D010316:Particle Size; D034741:RNA, Small Interfering / Q000378:metabolism; D013499:Surface Properties / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4