Copper Transport Mediated by Nanocarrier Systems in
a Blood–Brain Barrier In Vitro Model
Posted on 2014-05-12 - 00:00
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.
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Fehse, Susanne; Nowag, Sabrina; Quadir, Mohiuddin; Kim, Kwang Sik; Haag, Rainer; Multhaup, Gerd (2016). Copper Transport Mediated by Nanocarrier Systems in
a Blood–Brain Barrier In Vitro Model. ACS Publications. Collection. https://doi.org/10.1021/bm500400k
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AUTHORS (6)
SF
Susanne Fehse
SN
Sabrina Nowag
MQ
Mohiuddin Quadir
KK
Kwang Sik Kim
RH
Rainer Haag
GM
Gerd Multhaup