Mechanistic Differences in Cell Death Responses to Metal‐Based Engineered Nanomaterials in Kupffer Cells and Hepatocytes

Abstract

The mononuclear phagocyte system in the liver is a frequent target for nanoparticles (NPs). A toxicological profiling of metal‐based NPs is performed in Kupffer cell (KC) and hepatocyte cell lines. Sixteen NPs are provided by the Nanomaterial Health Implications Research Consortium of the National Institute of Environmental Health Sciences to study the toxicological effects in KUP5 (KC) and Hepa 1–6 cells. Five NPs (Ag, CuO, ZnO, SiO2, and V2O5) exhibit cytotoxicity in both cell types, while SiO2 and V2O5 induce IL‐1β production in KC. Ag, CuO, and ZnO induced caspase 3 generated apoptosis in both cell types is accompanied by ion shedding and generation of mitochondrial reactive oxygen species (ROS) in both cell types. However, the cell death response to SiO2 in KC differs by inducing pyroptosis as a result of potassium efflux, caspase 1 activation, NLRP3 inflammasome assembly, IL‐1β release, and cleavage of gasdermin‐D. This releases pore‐performing peptide fragments responsible for pyroptotic cell swelling. Interestingly, although V2O5 induces IL‐1β release and delays caspase 1 activation by vanadium ion interference in membrane Na+/K+ adenosine triphosphate (ATP)ase activity, the major cell death mechanism in KC (and Hepa 1–6) is caspase 3 mediated apoptosis. These findings improve the understanding of the mechanisms of metal‐based engineered nanomaterial (ENM) toxicity in liver cells toward comprehensive safety evaluation.

A pH‐Responsive Polymer‐CeO2 Hybrid to Catalytically Generate Oxidative Stress for Tumor Therapy

“…Initially, the in vitro activities of PN CeO 2 and PN CeO 2 PSS on LX‐2 cells were evaluated by incubating various amounts of the catalysts with the cells for 24 h. As shown in Figure S5, Supporting Information, even with high concentrations of PN CeO 2 and PN CeO 2 PSS (250 µg mL −1 ), the viability of the LX‐2 cells in both cases remained over 90%, indicating the high biocompatibility and nontoxicity of PN CeO 2 and PN CeO 2 PSS in normal human cells. [ 49,52,59 ]…”

“…Initially, the in vitro activities of PNCeO 2 and PNCeO 2 PSS on LX-2 cells were evaluated by incubating various amounts of the catalysts with the cells for 24 h. As shown in Figure S5, Supporting Information, even with high concentrations of PNCeO 2 and PNCeO 2 PSS (250 µg mL −1 ), the viability of the LX-2 cells in both cases remained over 90%, indicating the high biocompatibility and nontoxicity of PNCeO 2 and PNCeO 2 PSS in normal human cells. [49,52,59] Tumor cell cytotoxicity assays are a key indicator for further anti-tumor catalytic chemodynamic therapy capability of catalysts. Before the evaluations of the catalytic performance of PNCeO 2 PSS in HepG2 cells, the evolution of the pH of the cell culture medium was monitored and recorded ( Figure S6, Supporting Information).…”

Nanoparticle‐Based Activatable Probes for Bioimaging

“…MOx with cationic surface coating could induce proton sponge effects in lysosomes after cellular uptake, which can trigger cell death. [ 127–130 ]…”

“…MOx with cationic surface coating could induce proton sponge effects in lysosomes after cellular uptake, which can trigger cell death. [127][128][129][130] For toxicity evaluations of nanoprobes, it is recommended to use the mechanism-based high-throughput screening (HTS) and a predictive toxicological approach, which will make predictions on the physicochemical properties of nanomaterials that may result in pathology or disease in vivo. [131] To establish this approach, four elements are essential: 1) a well combinational nanoparticle library, 2) rigorous physicochemical characterizations of nanomaterials, 3) development of in vitro HTS approaches to assess biological effects of nanomaterials quantitatively, 4) establishment of quantitative structure-activity relationships (SAR) with in vivo results.…”

“…[132] In this predictive toxicological paradigm, HTS will be used to achieve rapid hazard ranking among a batch of nanoprobes. [129,130,133,134] The cells will include epithelial cells, endothelial cells, liver cells including Kupffer cells and hepatocytes, etc. The parameters will include oxidative stress, inflammatory cytokine production, DNA damage, and cell death.…”