Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
ALS Center Translational Science Unit, Department of Neurobiology and Anatomy, School of Medicine, Wake Forest University, Winston-Salem, NC 27106, United States.
J Control Release. 2016 Jun 10;231:38-49. doi: 10.1016/j.jconrel.2016.02.038. Epub 2016 Feb 27.
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.
我们之前通过聚离子缩合，使用传统的嵌段共聚物聚乙二醇-b-聚（L-赖氨酸）（PEG-PLL），随后进行化学交联，开发了一种用于铜/锌超氧化物歧化酶（SOD1）的“笼状”纳米制剂（纳米酶）。在此，我们报告了一种新的基于聚乙二醇-b-聚（天冬氨酸二乙酯三胺）（PEG-PAsp（DET），简称 PEG-DET）的 SOD1 纳米酶，它是为慢性给药而设计的。这种新的纳米酶为球形（Rg/Rh=0.785），并且为具有胶体性质的空心（60%水组成）纳米颗粒，与基于 PLL 的纳米酶相似。它对脑微血管内皮/神经元细胞的耐受性更好，在肝脏和脾脏中的积累也更少。这种制剂使缺血性中风小鼠模型的梗塞体积减少了 50%以上。然而，在肌萎缩侧索硬化症（ALS）的突变 SOD1（G93A）小鼠模型中，它不能有效预防运动神经元神经肌肉接头去神经。据我们所知，这是首次使用 PEG-DET 进行蛋白质递送的报道，也是首次直接比较两种阳离子嵌段共聚物，证明聚合物结构在调节单核吞噬细胞系统（MPS）聚离子复合物积累方面的作用。
