Nanotechnology in Medicine. Группа авторов

deficiency is associated with numerous human diseases (Vinceti et al. 2017). At the same time, an excess of Se can be toxic and lead to selenosis. Over the past decades, many researchers have identified the significant biomedical potential of SeNPs. However, along with favorable results, it is very important to study the negative and possible side effects associated with the use of Se in nanoforms. NPs are able to enter into the human body by inhalation, oral, parenteral routes and interact with intracellular structures and macromolecules for a long time. Entered NPs can be distributed to various organs, where they are able to retain their structure or to be modified, metabolized.

      Unfortunately, today there is no unambiguous information on whether NРs are absolutely safe for humans or have a certain toxicity. Thus, the study of the absorption, distribution, metabolism, and excretion of NPs also as the mechanisms of interaction with living systems studies are necessary to understand their activity, behavior in biological systems, and potential in vivo hazards.

3.2 Selenium Forms

      In nature, Se exists mainly in the form of selenate (Se⁶⁺), selenite (Se⁴⁺), selenide (Se²⁻), and elemental Se (Se⁰). The latter is insoluble in aqueous media and less toxic and biologically inert. However, it was found that elemental Se in the form of nano‐sized particles is not only biocompatible but also has a number of biological activities (antitumor, antimicrobial, protective). This is the reason for obtaining elemental Se in the NP form by all modern synthesis methods (physical, chemical, and biological) (Wadhwani et al. 2016; Skalickova et al. 2017). Moreover, since the biological properties of SeNPs (such as toxicity, selectivity for various cell types, biocompatibility, and biodegradability) as well as the presence of specific activities directly depend on their physical and chemical properties, special attention is paid to the ability to control the size, shape, composition, and uniformity for forming NPs (Zhang et al. 2004). NPs of the following shapes and configurations are currently known: zero‐dimensional nanocrystals and quantum dots; one‐dimensional nanospheres, nanorods, nanowires, nanotubes, and nanobelts; two‐dimensional arrays of NPs; thin films and three‐dimensional structures such as superlattices (Piacenza et al. 2018).

Conventionally, all physical, chemical, and physicochemical methods for the synthesis of SeNPs can be divided into three groups (Piacenza et al. 2018) (Figure 3.1):

      1 Methods based on “upstream” approaches in which SeNPs are formed from precursors (Se salt) as a result of chemical reactions (reduction, hydrolysis, or oxidation) (Dwivedi et al. 2011; Malhotra et al. 2014; Kumar et al. 2015; Wadhwani et al. 2016; Yu et al. 2016; Skalickova et al. 2017).

      2 “Downstream” processes where smaller nanostructures are formed from a larger precursor by melting or dissociation in a solvent (Triantis et al. 2009; Gusbiers et al. 2015; Sarkar et al. 2015; Badgar 2019).

      3 Matrix processes involving the use of various physical or chemical matrices for the conversion of Se‐containing precursors into NPs.

The third group of methods for the synthesis of SeNPs includes approaches that differ in the use of so‐called matrices or substances adsorbed on the surface of NPs. These matrices play the role of stabilizing agents during the synthesis, as well as determinants for the size and shape of nanostructures. To obtain stable monodisperse NPs, block copolymers (hydroxyethylcellulose, polyvinylpyrrolidone, cetyltrimethylammonium bromide, polyvinyl alcohols, gelatin, chitosan, saccharides, proteins and alkanethiols) are preferred. These polymers can be irreversibly adsorbed on the surface of NPs, determining their size and structure (Shah et al. 2007; Malhotra et al. 2014; Wadhwani et al. 2016; Piacenza et al. 2018). It was shown that the molecular weight of saccharides (poly‐, oligo‐, or mono‐) involved in the reaction affects the growth, morphology, and agglomeration rate of NPs, as well as that saccharides with a larger mass have better stabilizing properties (Bai et al. 2008). The surfactants used as a matrix (e.g. sodium‐bis‐[2‐ethylhexyl] sulfosuccinate, hexadecyltrimethylammonium bromide), on the contrary, are able to desorb from the surface of NPs during the synthesis, which leads to the formation of larger aggregates. The morphology of the forming particles (usually one‐dimensional nanostructures) is controlled using this approach, or by changing the concentration of matrix agents (Mehta et al. 2008), either by adding an acid (e.g. HCl) to the solution. This accelerates the reduction of the precursor to elemental Se and leads to the instantaneous deposition of NPs (Shah et al. 2007).

Figure 3.1 Methods for the synthesis of selenium nanoparticles.

      Source: Based on Piacenza et al. (2018).

      Despite the wide selection of chemical and physical methods for the synthesis of NPs, as well as the use of new reducing agents, catalysts, matrices, the choice of the most effective and least expensive synthesis method remains difficult for the researcher. In addition, chemical and physicochemical methods of synthesis often require the use of toxic and aggressive substances, as well as metal catalysts. During the synthesis process, these materials can be incorporated into the NPs as impurities.

Another group of methods associated with the “upstream” approaches is the biological synthesis of SeNPs. The basis of these methods is the use of living organisms (bacteria, fungi, plants) for the production of NPs. Over the past 20 years, the ability to reduce oxyanions as selenates (SeO₄^2–) and selenites (SeO₃^2–), to elemental Se, was found in bacteria isolated from substrates contaminated with various pollutants, including Se (Stenotrophomonas maltophilia, Cupriavidus metallidurans, Dechloromonas sp., Thauera sp.). The same possibilities were found in anaerobic microorganisms that are capable of using selenites and selenates as electron acceptors of the respiratory chain (Desulfomicrobium sp., Desulfurispirillum indicum, and hyperthermophilic archaea), in some rhizospheric bacteria (Rhizobium, Pseudomonas sp. аnd Azospirillum brasilense), as well as in some species of Enterobacteria (Escherichia coli ATCC 35218, Enterobacter cloacae Z0206, Pantoea agglomerans), Lactobacilli (Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus helveticus), Enterococci and Streptococci (Enterococcus faecalis, Streptococcus thermophilus, Staphylococcus carnosus), bacteria of the genus Bacillus (Bacillus sp., Bacillus subtilis, Bacillus mycoides, Bacillus licheniformis), Actinobacteria (Streptomyces sp., Bifidobacterium BB‐1272), and Cyanobacteria (Arthrospira platensis) (Tugarova and Kamnev 2017; Badgar 2019). It was shown that the synthesis of NPs can occur both under anaerobic and aerobic conditions, and the accumulation of produced particles can be either intracellular or extracellular (Jain et al. 2014; Tugarova and Kamnev 2017).

      In the case of anaerobic synthesis, recovery of selenite/selenate is the main metabolic process. This process is associated with respiration and is mediated either by specialized enzymes (periplasmic selenate reductase in Thauera selenatis) or nonspecific reductases, which also use sulfites and sulfates as electron acceptors (Tugarova and Kamnev 2017). Under aerobic conditions, the synthesis of SeNPs is associated with the regulation of redox homeostasis, detoxification and denitrification processes. The recovery of Se to Se⁰ is carried out by systems such as glutathione/glutathione reductase, thioredoxin/thioredoxin reductase, as well as peroxiredoxins, nitrareductases (in rhizobacteria), and low‐molecular weight thiols (Jain et al. 2014; Tugarova and Kamnev 2017). For extracellular synthesis, a mechanism has been proposed for the recovery of Se oxyanions with the participation of the outer membranes cytochromes (Jain et al. 2014).

      SeNPs synthesized by microorganisms have a number of features. These are quite large sizes (from 50 to 500 nm, the average size usually exceeds 100 nm) and the presence of proteins, polysaccharides, or lipids associated with NPs. These biopolymers presumably perform a stabilizing function during the assembly of nanostructures. Such biogenic NPs have unique spectral properties that distinguish