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

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Padilha Mendonca, Monique Culturato ; Soares, Edilene Siqueira ; de Jesus, Marcelo Bispo ; Ceragioli, Helder Jose ; Batista, Angela Giovana ; Nyul-Toth, Adam ; Molnar, Judit ; Wilhelm, Imola ; Marostica, Jr., Mario Roberto ; Krizbai, Istvan ; da Cruz-Hofling, Maria Alice

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR PHARMACEUTICS; v. 13, n. 11, p. 3913-3924, NOV 2016.
• Citações Web of Science: 19

Resumo

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. (AU)

• Processo FAPESP: 15/03254-9 - Avaliação da permeabilidade do óxido de grafeno usando um modelo in vitro de barreira hemato-encefálica
• Beneficiário: Monique Culturato Padilha Mendonça
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 12/24782-5 - Óxido de grafeno e sistema nervoso central: avaliação dos efeitos na barreira hematoencefálica e perfil nanotoxicológico
• Beneficiário: Monique Culturato Padilha Mendonça
• Modalidade de apoio: Bolsas no Brasil - Doutorado