PEGylation of reduced graphene oxide induces toxicity in cells of the blood-brain barrier: An in vitro and in vivo study

Monique Culturato Padilha Mendonça, Edilene Siqueira Soares, Marcelo Bispo De Jesus, Helder José Ceragioli, Ângela Giovana Batista, Ádám Nyúl-Tóth, Judit Molnár, I. Wilhelm, Mário Roberto Maróstica, I. Krizbai, Maria Alice Da Cruz-Höfling

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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 μg/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 (β-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.

Original languageEnglish
Pages (from-to)3913-3924
Number of pages12
JournalMolecular Pharmaceutics
Volume13
Issue number11
DOIs
Publication statusPublished - Nov 7 2016

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Graphite
Blood-Brain Barrier
Oxides
Astrocytes
Adherens Junctions
Nanoparticles
Endothelial Cells
Occludin
Tight Junction Proteins
Catenins
Connexin 43
In Vitro Techniques
Poisons
Laminin
Basement Membrane
Reactive Oxygen Species
Cell Survival
Oxidative Stress
Cell Death
Research Design

Keywords

  • central nervous system
  • graphene-based nanomaterials
  • nanotoxicity
  • PEGylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Cite this

Mendonça, M. C. P., Soares, E. S., De Jesus, M. B., Ceragioli, H. J., Batista, Â. G., Nyúl-Tóth, Á., ... Da Cruz-Höfling, M. A. (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), 3913-3924. https://doi.org/10.1021/acs.molpharmaceut.6b00696

PEGylation of reduced graphene oxide induces toxicity in cells of the blood-brain barrier : An in vitro and in vivo study. / Mendonça, Monique Culturato Padilha; Soares, Edilene Siqueira; De Jesus, Marcelo Bispo; Ceragioli, Helder José; Batista, Ângela Giovana; Nyúl-Tóth, Ádám; Molnár, Judit; Wilhelm, I.; Maróstica, Mário Roberto; Krizbai, I.; Da Cruz-Höfling, Maria Alice.

In: Molecular Pharmaceutics, Vol. 13, No. 11, 07.11.2016, p. 3913-3924.

Research output: Contribution to journalArticle

Mendonça, MCP, Soares, ES, De Jesus, MB, Ceragioli, HJ, Batista, ÂG, Nyúl-Tóth, Á, Molnár, J, Wilhelm, I, Maróstica, MR, Krizbai, I & Da Cruz-Höfling, MA 2016, 'PEGylation of reduced graphene oxide induces toxicity in cells of the blood-brain barrier: An in vitro and in vivo study', Molecular Pharmaceutics, vol. 13, no. 11, pp. 3913-3924. https://doi.org/10.1021/acs.molpharmaceut.6b00696
Mendonça, Monique Culturato Padilha ; Soares, Edilene Siqueira ; De Jesus, Marcelo Bispo ; Ceragioli, Helder José ; Batista, Ângela Giovana ; Nyúl-Tóth, Ádám ; Molnár, Judit ; Wilhelm, I. ; Maróstica, Mário Roberto ; Krizbai, I. ; Da Cruz-Höfling, Maria Alice. / PEGylation of reduced graphene oxide induces toxicity in cells of the blood-brain barrier : An in vitro and in vivo study. In: Molecular Pharmaceutics. 2016 ; Vol. 13, No. 11. pp. 3913-3924.
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