SOD1 nanozyme with reduced toxicity and MPS accumulation
SOD1 nanozyme with reduced toxicity and MPS accumulation
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DOI：
10.1016/j.jconrel.2016.02.038
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发表时间：
2016-06-10
影响因子：
10.8
通讯作者：
Manickama, Devika S.
中科院分区：
文献类型：
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作者：
Jiang, Yuhang;Arounleut, Phonepasong;Manickama, Devika S.
我们以前开发了一种“笼”状纳米制剂（nanozyme）的铜/锌超氧化物歧化酶（SOD 1）的聚离子缩合与传统的嵌段共聚物聚（乙二醇）-b-聚（L-赖氨酸）（PEG-PLL），然后通过化学交联。在此，我们报告了一种新的SOD1纳米酶的基础上聚乙二醇-b-聚（天冬氨酸二乙基三胺）（PEG-PAsp（DET），或简称PEG-DET）工程慢性给药。这种新的纳米酶是球形（R-g/R-h = 0.785）和中空（60%水组成）纳米颗粒，具有类似于基于PLL的纳米酶的胶体性质。脑微血管内皮细胞/神经元细胞耐受性更好，在肝脏和脾脏中蓄积较少。该制剂在缺血性中风的小鼠模型中将梗塞体积减少了50%以上。然而，在肌萎缩侧索硬化症（ALS）的突变型SOD1（G93A）小鼠模型中，它不能有效预防神经肌肉接头去神经支配。据我们所知，这项工作是第一次报告使用PEG-DET蛋白质的交付和两个阳离子嵌段共聚物之间的直接比较，表明聚合物结构的影响，在调节单核吞噬细胞系统（MPS）的聚离子复合物的积累。(C)2016爱思唯尔B.V.保留所有权利。
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. (C) 2016 Elsevier B.V. All rights reserved.