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Copper Transport Mediated by Nanocarrier Systems in a Blood–Brain Barrier In Vitro Model
Link to Journal Abstract
Copper (Cu) is a cofactor of various metalloenzymes and has a role in neurodegenerative diseases with disturbed Cu homeostasis, for example, in Alzheimer’s disease (AD) and Menkes disease. To address Cu imbalances, we synthesized two different dendritic nanoparticles (NP) for the transport of Cu(II) ions across the blood–brain barrier (BBB). The synthesized NPs show low toxicity and high water solubility and can stabilize high amounts of Cu(II). The Cu(II)-laden NPs crossed cellular membranes and increased the cellular Cu level. A human brain microvascular endothelial cell (HBMEC) model was established to investigate the permeability of the NPs through the BBB. By comparing the permeability × surface area product (PSe) of reference substances with those of NPs, we observed that NPs crossed the BBB model two times more effectively than 14C-sucrose and sodium fluorescein (NaFl) and up to 60× better than Evans Blue labeled albumin (EBA). Our results clearly indicate that NPs cross the BBB model effectively. Furthermore, Cu was shielded by the NPs, which decreased the Cu toxicity. The novel design of the core–shell NP enabled the complexation of Cu(II) in the outer shell and therefore facilitated the pH-dependent release of Cu in contrast to core–multishell NPs, where the Cu(II) ions are encapsulated in the core. This allows a release of Cu into the cytoplasm. In addition, by using a cellular detection system based on a metal response element with green fluorescent protein (MRE-GFP), we demonstrated that Cu could also be released intracellularly from NPs and is accessible for biological processes. Our results indicate that NPs are potential candidates to rebalance metal-ion homeostasis in disease conditions affecting brain and neuronal systems.
In this paper, the authors report on dendritic core−single shell (CS-NP) and core−multishell nanoparticles (CMS-NP) based on hyperbranched polymers and compare them head-to-head for their chemical, biochemical, and Cu-stabilizing properties relating to the nanoparticle architectures. The transport of Cu into cells, the pH-triggered release of Cu ions from the nanoparticle, and the cytotoxicity and penetration of the nanoparticles in a blood−
brain barrier (BBB) model are reported.
Peer Reviewed Journal Article
Exposure Or Hazard Target
Method Of Study
Risk Exposure Group
Biomacromolecules, 2014, 15(5): 1910-1919
Fehse S, Nowag S, Quadir M, Kim KS, Haag R, Multhaup G
Last updated on June 24, 2014
This work is supported in part by the Nanoscale Science and Engineering Initiative of the National Science Foundation
under NSF Award Number EEC-0118007.
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