The Effect of Carbon Nanomaterials on the Toxicity Indices of Cyclophosphamide under Combined Administration

Abstract

Carbon nanomaterials (CNMs) and single- and multiwalled carbon nanotubes and fullerene derivatives are considered as promising agents for the delivery of pharmacological agents to target organs in anticancer therapy and theranostics. Cytostatic cyclophosphamide (CP) is one of the chemotherapeutic drugs the targeted delivery of which is possible by CNMs. However, due to the presence of its own toxic effect in various CNMs, the question about their possible effect on the general toxic and immunotoxic effect of CP when administered together arises. The combined effect of CP and CNMs, i.e., multiwalled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and polyhydroxylated fullerenol (PHF60), administered orally daily at a dose of 0.1 mg/kg of body weight, was studied in Wistar rats. In two experiments lasting 16 and 35 days with different scenarios of CP-induced immunosuppression, the lethality and integral parameters were assessed; the contents of erythrocytes and leukocytes; the biochemical parameters; the levels of cytokines, chemokines, and growth factors; and the activity of glutathione peroxidase-I of erythrocytes were studied in the blood. The concentration of selenium and the excretion of creatinine and 8-oxo-2-deoxyguanosine were studied in the urine. The level of reduced glutathione was studied in the liver homogenate. In the first experiment, the consumption of both MWCNTs and SWCNTs led to an almost twofold decrease in lethality caused by the introduction of CP. In the second experiment, a twofold decrease in the lethality was noted only for SWCNTs; nevertheless, MWCNTs and PHF60 also had a positive effect on the survival of animals. Consumption of CNMs did not have a significant effect on the biochemical parameters, the state of the erythropoiesis system, the weight of the thymus and spleen, or the levels of key regulatory molecules impaired due to CP treatment. At the same time, MWCNTs, SWCNTs, and PHF60 are able to reduce a number of manifestations of the CP immunotoxic effect, including the lethality, lymphopenia, and impaired balance of cytokines and chemokines/growth factors: IL-4, IL-13, IL-17A, IFN-γ, IL-18, GM-CSF, GRO-KC, IL-12p70, IL-1β, IL-7, TNF-α, and VEGF. Thus, MWCNTs and SWCNTs, when administered together with CP, have a paradoxical effect consisting in the partial cancellation of the disturbances caused by it, which can be explained by the known ability of CNTs to enhance the mobilization, migration, and adhesion of blood cells and to trigger immune responses.