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SeNPs reported to have potential anticancer activity and hence they can be used in chemotherapy for cancer (Yang et al. 2012; Bao et al. 2015; Jia et al. 2015; Liao et al. 2015; Yanhua et al. 2016). Antitumor effects of SeNPs are usually mediated by their ability to inhibit the growth of cancer cells through induction of S phase arrest of cell cycle (Luo et al. 2012). Particularly, SeNPs induced mitochondria‐mediated apoptosis in A375 human melanoma cells. Treatment of this Nano‐Se cancer cell line resulted in a dose‐dependent apoptosis of the cells manifested by DNA fragmentation and phosphatidylserine translocation (Chen et al. 2008). Apart from unique anti‐cancer efficacy, SeNPs provide better selectivity between normal and cancer cells. It was demonstrated that SeNPs were not toxic to human osteoblast‐like cells of the GRL‐11372 line (Tran and Webster 2008); however, these nanoparticles were able to inhibit the growth of mouse osteosarcoma cells (Tran et al. 2010). In addition, it was shown that SeNPs, when given in conjugation to anastrozole, lower the bone toxicity caused by anastrozole and thus reduce the probable damage to the bone (Vekariya et al. 2013). SeNPs at a concentration of only 2 μg Se per ml effectively inhibited proliferation and induced caspase‐independent apoptosis in adenocarcinoma cells of human prostate glands without any significant toxicity to human peripheral blood mononuclear cells (Sonkusre et al. 2014). SeNPs inhibit the growth of HeLa cells and human breast cancer cells MDA‐MB‐231 depending on the dosage. In this case, the dose of Nano‐Se0 (10 μmol l⁻¹) happened to be effective (Luo et al. 2012).

Selenium nanocomposite and arabinogalactan had significant inhibitory effect on the cancerous cells lines such as A549, HepG‐2, and MCF‐7 in a dose‐dependent manner. The nanocomposite induced apoptosis of these cancer cells (Tang et al. 2019). The studies performed showed that elemental selenium nanocomposites and arabinogalactan are nanoparticles of zero‐valent selenium with particle size of 0.5–250 nm (depending on the production conditions) stabilized by nontoxic polysaccharide matrix‐arabinogalactan. The selenium concentration in the obtained samples of nanocomposites is 0.5–60.0% (depending on the initial ratio of arabinogalactan/precursor of selenium and on other synthesis conditions). Nanocomposites have an antitumor effect with accumulation of Se in the nucleus of a tumor cell. Tests were conducted in a culture of Ehrlich's carcinoma cells. These cells were incubated with nanocomposite of elemental selenium and arabinogalactan at a dose of 2.5, 5, and 7.5 mg l⁻¹ (calculated as Se) in RPMI‐1640 nutritional medium at 37 °C for 24 hours, and with no addition of nanocomposite to the control group (Sukhov et al. 2017).

The evaluation of effect on the culture of tumor cells and distribution of nanocomposite of elemental selenium and arabinogalactan was carried out using light microscopy in a mixed mode (differential interference contrast + fluorescence). It was observed that nanostructured selenium‐containing compounds based on arabinogalactan have fluorescent abilities in a wide range of wavelengths from 405 to 514 nm (Shurygina et al. 2015a). Swabs were prepared, and the visualization of luminescence was recorded using a Nikon Eclipse 80i research microscope with a DIH‐M epifluorescence device with a Nikon TRITC filter (excitation 528–553 nm, dichroic mirror 565 LP, emission 590–650 nm). It was found that there was no luminescence of Ehrlich's carcinoma cells in the control group after 24 hours of incubation (Figure 2.3a). On the contrary, during incubation of Ehrlich's carcinoma cells after incubation with nanocomposite of elemental selenium and arabinogalactan at a dose of 7.5 mg l⁻¹ calculated as Se after 24 hours of incubation, a bright luminescence of cell nuclei was observed (Figure 2.3b). Thus, selective accumulation of selenium nanocomposite in the nucleus of tumor cells is shown (Sukhov et al. 2017). Moreover, it was also reported that during incubation at concentrations of 20 and 10 mg l⁻¹ Ehrlich's carcinoma cells actively died on the first day of exposure. At the same time, at concentrations of 5 and 2.5 mg l⁻¹, cell death was more pronounced in the first hours and reached 50% faster than when exposed to higher concentrations. When incubating cells at low concentrations (1.25 mg l⁻¹), the effect of the test agent was minimal: death of carcinoma cells was observed only on day 1 and then their number stabilized and did not reach 50% mortality until the end of the experiment (Trukhan et al. 2018). The study was conducted using the equipment of the center of collective use of scientific equipment “Diagnostic images in surgery.”

In in vivo experiments in the Ehrlich's carcinoma model, it was found that when the elemental selenium and arabinogalactan nanocomposite were administered intraperitoneally singly at a dose of 2.5, 5, and 7.5 mg kg⁻¹ of live weight (calculated as Se), a sharp increase in the number of cells with signs of degeneration was noted (Figure 2.4a,b) (Sukhov et al. 2017). Zeng et al. (2019) synthesized SeNPs covered in water‐soluble polysaccharides extracted from various mushrooms having spherical shape and particle size of 91–102 nm. Further, they demonstrated significant in vivo antitumor activity, inducing caspases and mitochondria‐mediated apoptosis, but did not show pronounced toxicity for normal cells. Similarly, Huang et al. (2018) studied SeNPs conjugated with Pleurotus tuber‐regium for the treatment of colorectal cancer. It was found that these nanoparticles were absorbed by cancer cells through clathrin‐mediated endocytosis into lysosomes and caveolae‐mediated endocytosis into the Golgi apparatus. Nanocomposites stopped cell growth in the phase G2/M and started apoptosis depending on dosage and time through nanocomposite‐activated autophagy (Huang et al. 2018). The mechanism of the antitumor effect of biogenic SeNPs obtained from Bacillus licheniformis on PC‐3 cells is associated with the fact that SeNPs at a concentration of Se 2 μg ml⁻¹ induce cell death using reactive oxygen species (ROS)‐mediated necroptosis activation (Sonkusre and Cameotra 2017).

Figure 2.3 The nuclei of Ehrlich's carcinoma cells after exposure to nanocomposite elemental selenium and arabinogalactan, fluorescence microscopy: (a) control group, no light; (b) experimental group, bright glow of nuclei.

Figure 2.4 Ehrlich's carcinoma cells after exposure to nanocomposite elemental selenium and arabinogalactan, DIC (a) control group; (b) experimental group.

In another study, the antitumor activity of SeNPs synthesized biologically using Acinetobacter sp. SW30 and chemically in breast cancer cells (4T1, MCF‐7) was evaluated. The obtained results revealed that chemically synthesized SeNPs demonstrated higher anticancer activity than SeNPs synthesized by Acinetobacter sp. SW30. However, chemically synthesized SeNPs were also found to be toxic to non‐cancerous cells (NIH/3T3, HEK293). On the contrary, biogenic SeNPs were found to be more selective for breast cancer cells (Wadhwani et al. 2017). Krug et al. (2019) synthesized SeNPs coated with sulforaphane. The in vivo studies in rats showed SeNPs administered intraperitoneally were mainly excreted with urine (and, to a lesser degree, with feces), however it was partially accumulated in the animal organism. On the other hand, modified SeNPs are mainly accumulated in liver. Moreover, SeNPs conjugated with sulforaphane showed significant anticancer effect in vitro. At the same time, the cytotoxic effect on normal cells is relatively low. High antitumor activity and selectivity of the conjugate toward sick and healthy cells are extremely promising from the point of view of cancer treatment (Krug et al. 2019). Considering these facts it is clear that modification of SeNPs can increases cellular uptake and anticancer efficacy (Yang et al. 2012; Wu et al. 2013). For example, decorating the surface of SeNPs with spirulina polysaccharides significantly increased the cellular uptake and cytotoxicity of SeNPs against several cancer cell lines (Yang et al. 2012).

SeNPs can be selectively internalized by cancer cells through endocytosis by means of affinity of membrane proteins to the components administered into the composition of nanoparticles, which leads to activation of the transmission pathway of apoptotic signal and induction apoptosis of cells (Pi et al. 2013; Wu et al. 2013; Zhang et al. 2013). Folate‐coated SeNPs showed greater cytotoxicity and potential tumor growth inhibitory effect in mice for both in vitro and in vivo tests against breast cancer compared to naked SeNPs (without surface modification). Moreover, folate‐modified SeNPs showed a significant anti‐proliferative effect against 4T1 cells, significantly increased lifespan, and also prevented tumor growth (Shahverdi et al. 2018). In other study, SeNPs loaded with ferulic acid (FA‐SeNPs) were reported to cause damage of tumor cells as a result of apoptosis induction and direct interaction with DNA. Although the antitumor effect of both ferulic acid and SeNPs singly is relatively weak, the combination of these two biologically active ingredients exhibits high antitumor activity. It was shown that FA‐SeNPs induced intracellular overproduction of ROS and destruction of mitochondrial membrane potential by activating caspase‐3/9 to trigger HepG‐2 cell apoptosis through the mitochondrial pathway. The antitumor activity of FA‐SeNPs has also been associated with their binding to DNA (Cui et al. 2018).

SeNPs functionalized with walnut peptides and having average size diameter of 89.22 nm showed high antitumor activity. These modified SeNPs were also reported to show excellent selectivity between cancer cells and normal cells. Targeted induction of apoptosis in human mammary adenocarcinoma cells (MCF‐7) was confirmed by cell‐cycle arrest in the S‐phase, nuclear condensation, and DNA disruption (Liao et al. 2016). Similarly, in another study chitosan‐stabilized iron oxide nanoparticles decorated with selenium having size diameter of 5–9 nm, zeta potential 29.59 mV, and magnetic properties of 35.932 emu g⁻¹ were prepared. Further, the authors evaluated their anticancerous activity using breast cancer cells MB‐231. After one day of incubation the viability of breast cancer cells was reduced to 40.5% in the presence of 1 μg ml⁻¹ of these composite nanoparticles without using chemotherapeutic pharmaceutical drugs (Hauksdóttir and Webster 2018). Chen et al. (2018) evaluated the possibility of SeNPs as new radio‐sensitizers in MCF‐7 breast cancer cells. Nano‐Se enhanced the toxic effects of radiation which resulted in high tumor cell death compared to any separate treatment causing cell cycle arrest in G2/M phase and activation of autophagy, and increasing the formation of both endogenous and radiation‐induced active oxygen forms (Chen et al. 2018). Similar findings were reported against lung cancer cell lines by Cruz et al. (2019).

Biocompatible crystalline nanoparticles which release antitumor non‐organic elements are promising therapy for bone tumors. Selenium‐doped hydroxyapatite nanoparticles were reported to cause apoptosis of bone cancer cells in vitro with the help of caspase‐dependent apoptosis pathway and inhibit tumor growth in vivo while reducing systemic toxicity (Wang et al. 2016). Thus, all these studies performed in the last decade demonstrate the prospect of SeNPs for cancer therapy, which forms an actively progressing field for anticancer agent development.