title: The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain.
abstract: Nanocarrier-based drug delivery systems have attracted wide interest for the treatment of brain disease. However, neurotoxicity of nanoparticle has limited their therapeutic application. Here we demonstrated that lipid nanoparticles (LNs) accumulated in the brain parenchyma within 3 h of intravenous injection to mice and persisted for more than 24 weeks, coinciding with a dramatic activation of brain microglia. Morphological characteristic of microglial activation also observed in LNs-treated Cx3cr1GFP/+ mice. In vivo study with two-photon confocal microscopy revealed abnormal Ca²⁺ waves in microglia following LNs injection. The correlated activation of caspase-1, IL-1β and neurovascular damage following LNs injection was attenuated in P2X₇-/- mice. PEGylation of LNs reduced correlated nanoparticles aggregation. Moreover, PEGylation of LNs ameliorated the P2X₇/caspase-1/IL-1β signalling-dependent microglia activation and neurovascular damage. In conclusion, PEGylation of LNs is a promising biomaterial for brain-targeted therapy that inhibits P2X7₇-dependent neuroinflammatory response.
authors.affiliation: Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, Zhejiang University, Hangzhou, China.
authors.forename: Ji-yun
authors.initials: JY
authors.lastname: Huang
authors.forename: Ying-mei
authors.initials: YM
authors.lastname: Lu
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Mei-hua
authors.initials: MH
authors.lastname: Liao
authors.forename: Ling-juan
authors.initials: LJ
authors.lastname: Hong
authors.forename: Rong-rong
authors.initials: RR
authors.lastname: Tao
authors.forename: Muhammad Masood
authors.initials: MM
authors.lastname: Ahmed
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Shuang-shuang
authors.initials: SS
authors.lastname: Liu
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Yong-zhong
authors.initials: YZ
authors.lastname: Du
authors.forename: Feng
authors.initials: F
authors.lastname: Han
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001927:Brain Diseases / Q000188:drug therapy; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D007249:Inflammation / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000737:chemistry* / Q000493:pharmacokinetics; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D001672:Biocompatible Materials; D053583:Interleukin-1beta; D008055:Lipids; D020170:Caspase 1
keywords: BBB; BSA; Brain; CaMKII; GFAP; HtrA2; IL-1β; Lipid nanoparticles; MMP; Microglia; Neuroinflammatory response; P2X(7) receptor; PEG; PEGylation; SDS-PAGE; blood–brain barrier; bovine serum albumin; calcium/calmodulin-dependent kinase II; glial fibrillary acidic protein; high temperature requirement protein A2; interleulin-1β; matrix metalloproteinase; polyethylene glycol; sodium dodecyl sulphate polyacrylamide gel electrophoresis