title: SOD1 nanozyme salvages ischemic brain by locally protecting cerebral vasculature.
abstract: Copper/zinc superoxide dismutase (CuZnSOD; SOD1) is widely considered as a potential therapeutic candidate for pathologies involving oxidative stress, but its application has been greatly hindered by delivery issues. In our previous study, nanoformulated SOD1 (cl-nanozyme) was shown to decrease infarct volume and improve sensorimotor functions after a single intravenous (IV) injection in a rat middle cerebral artery occlusion (MCAO) model of ischemia/reperfusion (I/R) injury (stroke). However, it remained unclear how cl-nanozyme was able to deliver SOD1 to the brain and exert therapeutic efficacy. The present study aims to answer this question by exploring micro-distribution pattern of cl-nanozyme in the rat brain after stroke. Immunohistochemistry studies demonstrated cl-nanozyme co-localization with fibrin along damaged arteries and capillaries in the ischemic hemisphere. We further found that cl-nanozyme can be cross-linked into thrombi formed after I/R injury in the brain, and this effect is independent of animal species (rat/mouse) used for modeling I/R injury. This work is also the first report reinforcing therapeutic potential of cl-nanozyme in a well-characterized mouse MCAO model of I/R injury.
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Brynskikh
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: dsmanickam@unc.edu.
authors.forename: Devika
authors.initials: D
authors.lastname: S-Manickam
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Laboratory for Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow 117234, Russia. Electronic address: kabanov@email.unc.edu.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002536:Cerebral Arteries / Q000187:drug effects / Q000473:pathology; D057487:Enzyme Therapy; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072105:Superoxide Dismutase-1 / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D020011:Protective Agents; D000072105:Superoxide Dismutase-1
keywords: Blood–brain barrier; Neurovascular unit; Passive targeting; Stroke; Superoxide dismutase; Thrombus