SOD1 nanozyme with reduced toxicity and MPS accumulation

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• 作者：Yuhang Jiang^a ; Phonepasong Arounleut^b ; Steven Rheiner^c ; Younsoo Bae^c ; Alexander V. Kabanov^a ; ^d ; Carol Milligan^b ; Devika S. Manickam^a ; ¹ ; ^{dsmanickam@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; ^{soundaramanickd@duq.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Antioxidant ; Superoxide dismutase ; Protein delivery ; Stroke ; ALS ; MPS ; PEG-PLL ; PEG-PAsp(DET) ; Toxicity ; Mouse
• 刊名：Journal of Controlled Release
• 出版年：2016
• 出版时间：10 June 2016
• 年：2016
• 卷：231
• 期：Complete
• 页码：38-49
• 全文大小：1784 K

文摘

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 (R_g/R_h = 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.