Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

Abstract

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3 + , CD4 + , CD8 + , and CD19 + ) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

Main trends of immune effects triggered by nanomedicines in preclinical studies

“…[50][51][52] A particularly interesting observation is related to PEG coating frequently used in nanomedicine to provide better stabilization and a lower recognition by the immune system in order to increase the drug circulation time. [53][54][55] Interestingly, PEGylated liposomes, iron oxide NPs and gold NPs were reported to lose their long circulating properties when they were administered repeatedly to the same animal. This unexpected phenomenon called "accelerated blood clearance" (ABC) occurred due to the production of specific anti-PEG IgM antibodies labeling the NPs, followed by the increased uptake of NPs by the macrophages and their accumulation in the liver and spleen ( Figure 5).…”

“…• Immunophenotyping 47,[115][116][117] • Cytokine release 47,118 • Antibodies production 50,52,56,61 • Immune organ weight 21,52,55,109 Mice, rats, chicken, dogs Partially covered by ICH S8 as a part of STS and by additional immunotoxicity studies…”

“…• Activation of inflammatory pathways 17,24,27 • Histopathology 20,23,55 • Production of ROS and RNS 22,119,120 Rodents Partially covered by ICH S8 as a part of STS…”

Cytotoxicity-Related Bioeffects Induced by Nanoparticles: The Role of Surface Chemistry

“…The secretion level of IL-8 induced by PEG decoration was low compared to that induced by pristine iron oxide NPs (Griffete et al, 2012). In a 28 days repeated dose toxicity study, pristine-MWCNTs caused higher levels of inflammation in lung and liver of mice than PEG-MWCNTs (Zhang et al, 2017). Few-layer graphene (FLG, 2-4 layers, lateral dimension of ∼100-200 nm) and FLG-COOH elicited acute and chronic lung inflammation in mice.…”

Different toxicity of cadmium telluride, silicon, and carbon nanomaterials against hemocytes in silkworm, Bombyx mori

“…[11][12][13] Recent studies have focused on the in vivo transport kinetics of nanomaterials, 14 the phagocytosis of nanomaterials by hemocytes, 15 and the changes in the immune response they induce in the blood. 16 However, the mechanisms underlying the differences in toxicity of nanomaterials against circulating hemocytes and the activation of the innate immune responses have not yet been reported.…”