Surface Oxidation of Graphene Oxide Determines Membrane Damage, Lipid Peroxidation, and Cytotoxicity in Macrophages in a Pulmonary Toxicity Model

Ruibin Li, Linda M. Guiney, Chong Hyun Chang, Nikhita D. Mansukhani, Zhaoxia Ji, Xiang Wang, Yu Pei Liao, Wen Jiang, Bingbing Sun, Mark C. Hersam, Andre E. Nel, Tian Xia

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65 Citations (Scopus)

Abstract

While two-dimensional graphene oxide (GO) is used increasingly in biomedical applications, there is uncertainty on how specific physicochemical properties relate to biocompatibility in mammalian systems. Although properties such as lateral size and the colloidal properties of the nanosheets are important, the specific material properties that we address here is the oxidation state and reactive surface groups on the planar surface. In this study, we used a GO library, comprising pristine, reduced (rGO), and hydrated GO (hGO), in which quantitative assessment of the hydroxyl, carboxyl, epoxy, and carbon radical contents was used to study the impact on epithelial cells and macrophages, as well as in the murine lung. Strikingly, we observed that hGO, which exhibits the highest carbon radical density, was responsible for the generation of cell death in THP-1 and BEAS-2B cells as a consequence of lipid peroxidation of the surface membrane, membrane lysis, and cell death. In contrast, pristine GO had lesser effects, while rGO showed extensive cellular uptake with minimal effects on viability. In order to see how these in vitro effects relate to adverse outcomes in the lung, mice were exposed to GOs by oropharyngeal aspiration. Animal sacrifice after 40 h demonstrated that hGO was more prone than other materials to generate acute lung inflammation, accompanied by the highest lipid peroxidation in alveolar macrophages, cytokine production (LIX, MCP-1), and LDH release in bronchoalveolar lavage fluid. Pristine GO showed less toxicity, whereas rGO had minimal effects. We demonstrate that the surface oxidation state and carbon radical content play major roles in the induction of toxicity by GO in mammalian cells and the lung.

Original languageEnglish
Pages (from-to)1390-1402
Number of pages13
JournalACS nano
Volume12
Issue number2
DOIs
Publication statusPublished - Feb 27 2018

Keywords

  • carbon radicals
  • graphene oxide
  • lipid peroxidation
  • lung inflammation
  • structure-activity relationships
  • surface functional groups

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

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    Li, R., Guiney, L. M., Chang, C. H., Mansukhani, N. D., Ji, Z., Wang, X., Liao, Y. P., Jiang, W., Sun, B., Hersam, M. C., Nel, A. E., & Xia, T. (2018). Surface Oxidation of Graphene Oxide Determines Membrane Damage, Lipid Peroxidation, and Cytotoxicity in Macrophages in a Pulmonary Toxicity Model. ACS nano, 12(2), 1390-1402. https://doi.org/10.1021/acsnano.7b07737