Dissolution of 2D Molybdenum Disulfide Generates Differential Toxicity among Liver Cell Types Compared to Non‐Toxic 2D Boron Nitride Effects

Abstract

2D boron nitride (BN) and molybdenum disulfide (MoS2) materials are increasingly being used for applications due to novel chemical, electronic, and optical properties. Although generally considered biocompatible, recent data have shown that BN and MoS2 could potentially be hazardous under some biological conditions, for example, during, biodistribution of drug carriers or imaging agents to the liver. However, the effects of these 2D materials on liver cells such as Kupffer cells (KCs), liver sinusoidal endothelial cells, and hepatocytes, are unknown. Here, the toxicity of BN and MoS2, dispersed in Pluronic F87 (designated BN‐PF and MoS2‐PF) is compared with aggregated forms of these materials (BN‐Agg and MoS2‐Agg) in liver cells. MoS2 induces dose‐dependent cytotoxicity in KCs, but not other cell types, while the BN derivatives are non‐toxic. The effect of MoS2 could be ascribed to nanosheet dissolution and the release of hexavalent Mo, capable of inducing mitochondrial reactive oxygen species generation and caspases 3/7‐mediated apoptosis in KUP5 cells. In addition, the phagocytosis of MoS2‐Agg triggers an independent response pathway involving lysosomal damage, NLRP3 inflammasome activation, caspase‐1 activation, IL‐1β, and IL‐18 production. These findings demonstrate the importance of Mo release and the state of dispersion of MoS2 in impacting KC viability.

Understanding Nanomaterial–Liver Interactions to Facilitate the Development of Safer Nanoapplications

“…[97] The different uptake mechanisms in the liver cells are further confirmed using MoS 2 and nanocellulose. [109,111] Also, Ouyang et al showed that KCs were taking up NPs via receptor-mediated phagocytosis rather than clathrin-and caveolin-mediated endocytosis or micropinocytosis through localization of NPs by TEM and fluorescent imaging. [115] The difference in uptake mechanisms of cells for NMs would determine their intracellular contents in the liver cells.…”

“…Instead, similar to V 2 O 5 NPs, [ 105 ] MoS 2 ‐Agg induced apoptosis, this is because of the earlier onset of caspase 3/7 activation, while the caspase‐1 activation happened later. [ 111 ] Cao et al also showed the sequestration of protein‐coated 24.5 nm MoS 2 @HSA nanocomplexes by the KCs and the long‐term accumulation of MoS 2 nanodots in the mouse liver. In addition, MoS 2 was oxidized and degraded in the KCs, and the dissolved molybdenum ions were chemically transformed from Mo(IV) to Mo(VI) and used for biosynthesis of molybdenum cofactors (Moco) in hepatocytes as we discussed above.…”

“…[98] Li et al and Cao et al also showed a much more uptake of MoS 2 by KCs than other liver cell types, such as hepatocytes or LSECs, respectively. [93,111]…”

TFEB-lysosome pathway activation is associated with different cell death responses to carbon quantum dots in Kupffer cells and hepatocytes

“…Both liver cell types also showed high expression of the pro-apoptotic protein, Bax, and Cleaved caspase3, and low expression of the anti-apoptotic protein, Bcl-2. ROS induced by nanomaterials is the main mechanism of oxidative stress [ 53 , 54 ], and this process correlates with apoptosis to a certain extent [ 14 , 55 ]. Therefore, ROS levels in the two cells were measured as a proxy for apoptosis.…”

“…It follows that liver is the main member involved in the removal of xenobiotics. The liver is an important metabolic detoxification organ composed of 15% macrophages and 60–80% parenchyma cells [ 13 , 14 ]. Thus, the regulatory role of these cell types in the liver is important for metabolic clearance of exogenous toxins.…”