Well-defined cross-linked antioxidant nanozymes for treatment of ischemic brain injury.
Development of well-defined nanomedicines is critical for their successful clinical translation. A simple synthesis and purification procedure is established for chemically cross-linked polyion complexes of Cu/Zn superoxide dismutase (SOD1) or catalase with a cationic block copolymer, methoxy-poly(ethylene glycol)-block-poly(L-lysine hydrochloride) (PEG-pLL₅₀). Such complexes, termed cross-linked nanozymes (cl-nanozymes) retain catalytic activity and have narrow size distribution. Moreover, their cytotoxicity is decreased compared to non-cross-linked complexes due to suppression of release of the free block copolymer. SOD1 cl-nanozymes exhibit prolonged ability to scavenge experimentally induced reactive oxygen species (ROS) in cultured brain microvessel endothelial cells and central neurons. In vivo they decrease ischemia/reperfusion-induced tissue injury and improve sensorimotor functions in a rat middle cerebral artery occlusion (MCAO) model after a single intravenous (i.v.) injection. Altogether, well-defined cl-nanozymes are promising modalities for attenuation of oxidative stress after brain injury.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center-UNMC, Omaha, NE 68198, USA. dsmanickam@gmail.com
Devika S
DS
Manickam
Anna M
AM
Brynskikh
Jennifer L
JL
Kopanic
Paul L
PL
Sorgen
Natalia L
NL
Klyachko
Elena V
EV
Batrakova
Tatiana K
TK
Bronich
Alexander V
AV
Kabanov
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry; D002374:Catalase / Q000008:administration & dosage* / Q000737:chemistry; D002417:Cattle; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000737:chemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000031:analogs & derivatives / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D013388:Succinimides / Q000737:chemistry; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000737:chemistry
D000975:Antioxidants; D003432:Cross-Linking Reagents; D013388:Succinimides; C117924:mPEG-block-PLL; D011107:Polylysine; D011092:Polyethylene Glycols; C035759:3,3'-dithiobis(sulfosuccinimidyl propionate); D002374:Catalase; D013482:Superoxide Dismutase