title: SOD1 nanozyme with reduced toxicity and MPS accumulation.
abstract: We previously developed a "cage"-like nano-formulation (nanozyme) for copper/Zinc superoxide dismutase (SOD1) by polyion condensation with a conventional block copolymer poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) followed by chemical cross-linking. Herein we report a new SOD1 nanozyme based on PEG-b-poly(aspartate diethyltriamine) (PEG-PAsp(DET), or PEG-DET for short) engineered for chronic dosing. This new nanozyme was spherical (Rg/Rh=0.785), and hollow (60% water composition) nanoparticles with colloidal properties similar to PLL-based nanozyme. It was better tolerated by brain microvessel endothelial/neuronal cells, and accumulated less in the liver and spleen. This formulation reduced the infarct volumes by more than 50% in a mouse model of ischemic stroke. However, it was not effective at preventing neuromuscular junction denervation in a mutant SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). To our knowledge, this work is the first report of using PEG-DET for protein delivery and a direct comparison between two cationic block copolymers demonstrating the effect of polymer structure in modulating the mononuclear phagocyte system (MPS) accumulation of polyion complexes.
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
authors.forename: Yuhang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: ALS Center Translational Science Unit, Department of Neurobiology and Anatomy, School of Medicine, Wake Forest University, Winston-Salem, NC 27106, United States.
authors.forename: Phonepasong
authors.initials: P
authors.lastname: Arounleut
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, KY 40536, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Rheiner
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, KY 40536, United States.
authors.forename: Younsoo
authors.initials: Y
authors.lastname: Bae
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Laboratory for Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, 117234, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.affiliation: ALS Center Translational Science Unit, Department of Neurobiology and Anatomy, School of Medicine, Wake Forest University, Winston-Salem, NC 27106, United States.
authors.forename: Carol
authors.initials: C
authors.lastname: Milligan
authors.affiliation: Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: dsmanickam@gmail.com.
authors.forename: Devika S
authors.initials: DS
authors.lastname: Manickam
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D012157:Mononuclear Phagocyte System / Q000187:drug effects* / Q000473:pathology; D009154:Mutation; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D000975:Antioxidants; D011506:Proteins; C571441:poly(ethylene glycol)-poly(N'-(N-(2-aminoethyl)-2-aminoethyl)aspartamide) block copolymer; D011092:Polyethylene Glycols; D000072105:Superoxide Dismutase-1
keywords: ALS; Antioxidant; MPS; Mouse; PEG-PAsp(DET); PEG-PLL; Protein delivery; Stroke; Superoxide dismutase; Toxicity