Toxicity of graphene-family nanoparticles: a general review of the origins and mechanisms

Abstract

Due to their unique physicochemical properties, graphene-family nanomaterials (GFNs) are widely used in many fields, especially in biomedical applications. Currently, many studies have investigated the biocompatibility and toxicity of GFNs in vivo and in intro. Generally, GFNs may exert different degrees of toxicity in animals or cell models by following with different administration routes and penetrating through physiological barriers, subsequently being distributed in tissues or located in cells, eventually being excreted out of the bodies. This review collects studies on the toxic effects of GFNs in several organs and cell models. We also point out that various factors determine the toxicity of GFNs including the lateral size, surface structure, functionalization, charge, impurities, aggregations, and corona effect ect. In addition, several typical mechanisms underlying GFN toxicity have been revealed, for instance, physical destruction, oxidative stress, DNA damage, inflammatory response, apoptosis, autophagy, and necrosis. In these mechanisms, (toll-like receptors-) TLR-, transforming growth factor β- (TGF-β-) and tumor necrosis factor-alpha (TNF-α) dependent-pathways are involved in the signalling pathway network, and oxidative stress plays a crucial role in these pathways. In this review, we summarize the available information on regulating factors and the mechanisms of GFNs toxicity, and propose some challenges and suggestions for further investigations of GFNs, with the aim of completing the toxicology mechanisms, and providing suggestions to improve the biological safety of GFNs and facilitate their wide application.

Keywords: Future prospects; Graphene-family nanomaterials; Mechanisms; Physicochemical properties; Toxicity; Toxicokinetics.

Fig. 1

Graphene materials and their biological interactions. (A) A parameter space for the most widely used graphene materials can be described by the dimensions and surface functionalization of the material, the latter defined as the percentage of the carbon atoms in sp3 hybridization. Green squares represent epitaxially grown graphene; yellow, mechanically exfoliated graphene; red, chemically exfoliated graphene; blue, graphene oxide. Note that a number of other graphene-related materials (such as graphene quantum dots and graphene nanoribbons) are also being used in experiments. (B) Possible interactions between graphene-related materials with cells (the graphene flakes are not to scale). (a) Adhesion onto the outer surface of the cell membrane. (b) Incorporation in between the monolayers of the plasma membrane lipid bilayer. (c) Translocation of membrane. (d) Cytoplasmic internalization. (e) Clathrin-mediated endocytosis. (f) Endosomal or phagosomal internalization. (g) Lysosomal or other perinuclear compartment localization. (h) Exosomal localization. The biological outcomes from such interactions can be considered to be either adverse or beneficial, depending on the context of the particular biomedical application. Different graphene-related materials will have different preferential mechanisms of interaction with cells and tissues that largely await discovery. [90] Copyright (2014), with permission from American Association for Advancement of Science

Fig. 2

A representative trajectory of HP35 adsorbing onto the graphene. (a) Representative snapshots at various time points. The proteins are shown in cartoons with red helix and green loop, and the graphene is shown in wheat. The aromatic residues that form the π-π stacking interactions are shown in blue, others are shown in green. (b) The contacting surface area of HP35 with the graphene. (c) The RMSD of HP35 from its native structure and the number of residues in the α-helix structure. Here, the secondary structures are determined by the DSSP program. (d) The distance between the graphene and the aromatic residues, including F35, W23, F10, F17, and F06. To show the adsorbing process clearer, the χ-axis had been truncated and rescaled. [41] Copyright (2011), with permission from Journal of Physical of Chemistry

Fig. 3

Schematic diagram showed the possible mechanisms of GFNs cytotoxicity. GFNs get into cells through different ways, which induce in ROS generation, LDH and MDA increase, and Ca²⁺ release. Subsequently, GFNs cause kinds of cell injury, for instance, cell membrane damage, inflammation, DNA damage, mitochondrial disorders, apoptosis or necrosis

Fig. 4

Schematic diagram of MAPKs, TGF-beta and TNF-α dependent pathways involved in GFNs toxicity. ROS was the main factors activating the MAPKs and TGF-beta signaling pathways to lead to the activation of Bim and Bax, triggering the cascade of caspases and JNK pathway. The activation of caspase 3 and RIP1 resulted in apoptosis and necrosis finally

Fig. 5

A schematic diagram elucidating signalling pathway of TLR4 and TLR9 responsible for GFNs-induced cytotoxicity. GFNs can be recognized by TLRs, thus activate IKK and IκB by a MyD88-dependent mechanism, resulting in the release of NF-κB subunits and initiating the translocation into the nucleus. Thus, pro-inflammatory factors were transcribed and secreted out of nucleus, modulating the immune responses initiating programmed autophagy, apoptosis and necrosis