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PEGylation of Reduced Graphene Oxide Induces Toxicity in Cells of the Blood-Brain Barrier: An in Vitro and in Vivo Study

Mendonca, M. C. P.

Soares, E. S.

de Jesus, M. B.

Ceragioli, H. J.

Batista, A. G.

Nyúl-Tóth, Ádåm

MolnĂĄr, Judit

Wilhelm, Imola MĂĄria

Krizbai, IstvĂĄn AdorjĂĄn

American Chemical Society

2016

QH3015 Molecular biology / molekulĂĄris biolĂłgia

RS Pharmacy and materia medica / gyĂłgyszerĂŠszet, gyĂłgyĂĄszati eszkĂśzĂśk

Polyethylene glycol (PEG) coating has been frequently used to improve the pharmacokinetic behavior of nanoparticles. Studies that contribute to better unravel the effects of PEGylation on the toxicity of nanoparticle formulation are therefore highly relevant. In the present study, reduced graphene oxide (rGO) was functionalized with PEG, and its effects on key components of the blood-brain barrier, such as astrocytes and endothelial cells, were analyzed in culture and in an in vivo rat model. The in vitro studies demonstrated concentration-dependent toxicity. The highest concentration (100 mu g/mL) of non-PEGylated rGO had a lower toxic influence on cell viability in primary cultures of astrocytes and rat brain endothelial cells, while PEGylated rGO induced deleterious effects and cell death. We assessed hippocampal BBB integrity in vivo by evaluating astrocyte activation and the expression of the endothelial tight and adherens junctions proteins. From 1 h to 7 days post-rGO-PEG systemic injection, a notable and progressive down-regulation of protein markers of astrocytes (GFAP, connexin-43), the endothelial tight (occludin), and adherens (beta-catenin) junctions and basal lamina (laminin) were observed. The formation of intracellular reactive oxygen species demonstrated by increases in the enzymatic antioxidant system in the PEGylated rGO samples was indicative of oxidative stress-mediated damage. Under the experimental conditions and design of the present study the PEGylation of rGO did not improve interaction with components of the blood brain barrier. In contrast, the attachment of PEG to rGO induced deleterious effects in comparison with the effects caused by non-PEGylated rGO.

angol

Article

PeerReviewed

info:eu-repo/semantics/article

text

http://real.mtak.hu/46180/1/MendoncaMolPharm2.pdf

Mendonca, M. C. P. and Soares, E. S. and de Jesus, M. B. and Ceragioli, H. J. and Batista, A. G. and Nyúl-Tóth, Ádåm and Molnår, Judit and Wilhelm, Imola Måria and Krizbai, Istvån Adorjån (2016) PEGylation of Reduced Graphene Oxide Induces Toxicity in Cells of the Blood-Brain Barrier: An in Vitro and in Vivo Study. MOLECULAR PHARMACEUTICS, 13 (11). pp. 3913-3924. ISSN 1543-8384

http://real.mtak.hu/46180/

http://dx.doi.org/10.1021/acs.molpharmaceut.6b00696

MTMT:3148300; doi:10.1021/acs.molpharmaceut.6b00696