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Figure 3.2 Toxic effects of selenium nanoparticles.

      A serious problem is the genotoxicity of NPs, since it plays an important role in the initiation and progression of abnormalities, such as destructive genetic changes, including gene mutations, structural chromosome aberrations, and recombination (Barabadi et al. 2019). Genotoxicity is divided into primary and secondary. Primary genotoxicity implies direct or indirect interaction of NPs with genetic material (Cooke et al. 2003). The mechanism of secondary genotoxicity of NPs is associated with excessive ROS production by activated phagocytes (neutrophils and macrophages) (Singh et al. 2009). It was shown that Se nanocomposites on polysaccharide matrices from 54.35 to 123.04 nm in size with a Se content of 0.172, 0.274, and 0.305% inhibited nitric oxide (NO) production in lipopolysaccharide‐induced (LPS) inflammatory macrophages RAW 264.7, and suppressed expression of mRNA TNF‐α, IL‐1β. Smaller SeNPs had higher anti‐inflammatory effects (Hu et al. 2020). Also, oxidative stress activates specific signaling pathways, including mitogen‐activated protein kinase (MAPK) (Shurygina et al. 2017) and NF‐kB, which lead to the release of pro‐inflammatory cytokines. The result of this signaling is a triggering of inflammation cascade. This protective reaction leads to the further release of ROS from inflammatory cells (e.g. neutrophils). Moreover, in healthy and tumor cells, the effects of SeNPs are different. SeNPs temporarily suppress the expression of p53‐associated genes in healthy mice (Sun et al. 2019). Multifunctional SeNPs decorated with a polysaccharide–protein complex and loaded with tetramethylpyrazine and monosialotetrahexosylganglioside can reduce ROS overproduction to prevent mitochondrial dysfunction by inhibiting p53 and MAPK pathway activation (Rao et al. 2019).

      Researchers have discovered another effect of SeNPs on tumor cells associated with features of ROS induction in tumors. Folate‐conjugated SeNPs easily penetrated HepG2 hepatoma cells by endocytosis, generated the overproduction of ROS, and induced apoptosis by activating p53 and MAPK pathways (Liu et al. 2015).There were studied changes in the expression of the ATF4, Bcl‐xL, BAD2, HSP70, and SOD2 genes in human dermal fibroblasts under oxidative stress, nutrient deprivation stress, and control with the admission of SeNPs. Incubation with SeNPs led to a decrease in ROS generation for all conditions tested. Under stress, the expression of ATF4 and Bcl‐xL increased for cells treated with SeNPs, leading to attenuation of the cells under stress (Chung et al. 2019).

      The genotoxicity of NPs, as well as general toxicity, is greatly influenced by their size, properties, composition, shape, surface properties, physicochemical characteristics (pH, temperature, etc.), solubility, and other factors, such as dose, time exposure, type of cells used. From a toxicological point of view, the size and surface area of particles are the most important characteristics, since interactions between NPs and biological objects occur, as a rule, on the surface (Hoshyar et al. 2016; Wu and Tang 2018; Keyhani et al. 2020). The smaller NPs have a larger relative surface area. Therefore, the surface of the particles becomes more reactive, and the potential catalytic surface for chemical reactions also increases (Magdolenova et al. 2014; Zijlstra and Vizio 2018). Along with the size, surface area, and charge of NPs, the chemical composition and surface coating of the particles play an important role. Thus, the toxic effects of NPs can be prevented by applying surface coatings that can stabilize particles and avoid agglomeration. Coating also has an effect for preventing the dissolution of NPs and the release of toxic ions (Kirchner et al. 2005).

The use of amino acids in the synthesis of SeNPs allows nanoselenes to be obtained with high stability and increased antitumor activity. Thus, if the production of SeNPs used valine, an initiation of cancer cell apoptosis was observed in an experiment on MCF‐7 adenocarcinoma cells. A similar effect was observed with using of 5‐fluorouracil. Cancer cells actively absorb such NPs by endocytosis. Also, polysaccharide–protein complexes of fungi were used as a coating for NPs. Thus, synthesized SeNPs inhibited the growth of human MCF‐7 breast cancer cells by inducing apoptosis due to the cleavage of poly (ADP‐ribose) polymerase (PARP) and activation of caspase (Wu et al. 2012). Other authors also indicated caspase activation in tumor cells by SeNPs (Zhang et al. 2019). Similar studies were carried out also on other cell lines. Treatment of A375 human melanoma cells with SeNPs resulted in dose‐dependent cell apoptosis. In this case, DNA fragmentation was observed. Further studies of intracellular mechanisms have shown that exposure to SeNPs causes apoptotic death of A375 cells with activation of oxidative stress and the development of mitochondrial dysfunction (Chen et al. 2008; Yu et al. 2012).

      SeNPs are currently considered promising for use in medicine: they are less toxic and more biocompatible agents than selenite (SeO₃⁻²) and selenate (SeO₄⁻²), and also have antitumor properties (Tan et al. 2019). At present, it is generally accepted that Se compounds exhibit their antitumor ability in various ways, where one of the main effects are direct or indirect antioxidant properties, which intracellularly support oxidation‐reduction status and protect healthy cells from ROS (Prasad et al. 2017; Zhao et al. 2018).The cytotoxic effects of SeNPs in tumor cells are achieved by inducing apoptosis. The activation of enzymes involved in the processes of cell death occurs. This mechanism of action is similar to many chemotherapeutic agents that initiate apoptosis by affecting the regulation of intracellular ROS generation. Thus, the production of ROS induced by Se compounds is an important fact for cell cycle arrest and cell apoptosis.

      Apoptosis can be activated externally or internally. The external pathway is initiated by the attachment of a proapoptotic ligand to the Fas/TNF cell death receptor (tumor necrosis factor receptor) on the cell membrane. During the interaction of the ligand, receptor, adapter, and procaspase, apoptosomes are formed. These complexes initiate cell death when autolytic activation of caspases occurs, including caspase 8 (Creagh 2014; Khan et al. 2019). The internal or mitochondrial pathway is activated by DNA damage due to excessive ROS formation or exposure to another cytotoxic factor that activates the p53 protein. This protein, in turn, increases the activity of the Bcl‐2 protein, a mitochondrial membrane permeability regulator. As a result, apoptotic proteins are released, including procaspase 9, which is additionally activated in the apoptosome with the participation of cytochrome C (Wang et al. 2015). Activated caspase 9 interacts and activates effector procaspase 3. During apoptosis, caspase 3 is responsible for chromatin condensation and DNA fragmentation. The sequential activation of caspases, the so‐called caspase cascade, plays a key role in cell apoptosis. In addition to the caspase pathway, PARP activity increases, and its high level is also a marker for apoptotic cells (Zhang et al. 2013).

Most chemotherapeutic drugs have low selectivity and are extremely toxic to body cells. The use of SeNPs in combination with chemotherapeutic and hormonal drugs reduces side effects. So, spherical SeNPs coated with 11‐mercapto‐1‐undecanol have a nephroprotective and antiapoptotic effect, significantly increase mitochondrial activity and cell viability, and prevent DNA fragmentation in the cells of the proximal tubules of the kidneys. Caspase‐3 activation in cells exposed to cisplatin is also blocked by this composite (Li et al. 2011). In addition, the composite penetrates the cells 10 times more actively due to enhanced endocytosis, while uncoated SeNPs easily aggregate in aqueous solutions and hardly penetrate the cell membrane (Menon et al. 2018). A possible mechanism of antitumor action is the effect of SeNPs on the expression of the estrogen receptor α (Erα). In the study (Vekariya et al. 2012), the antitumor activity of SeNPs was correlated with ERα levels