Silver nanoparticles: An integrated view of green synthesis methods, transformation in the environment, and toxicity

Ecotoxicology and Environmental Safety 171 (2019) 691–700

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Ecotoxicology and Environmental Safety journal homepage: www.elsevier.com/locate/ecoenv

Review

Silver nanoparticles: An integrated view of green synthesis methods, transformation in the environment, and toxicity Tiago Alves Jorge de Souzaa,b,

⁎,1

T

, Lilian Rodrigues Rosa Souzac,1, Leonardo Pereira Franchia,c

a

Department of Genetics, FMRP-USP, University of São Paulo - USP, Bloco G. Av. Bandeirantes, 3900, Monte Alegre Zip Code: 14049-900, Ribeirão Preto, SP, Brazil Department of Agronomic Engineering, Adventist University of São Paulo – UNASP, Engenheiro Coelho, SP, Brazil c Department of Chemistry, FFCLRP-USP, University of São Paulo - USP, Ribeirão Preto, SP, Brazil b

A R T I C LE I N FO

A B S T R A C T

Keywords: AgNPs Green chemistry Environmental transformation Genotoxicity Cytotoxicity Therapeutic approaches

Nowadays, silver nanoparticles (AgNPs) are the most widely used nanoparticles (NPs) in the industry due to their peculiar biocidal features. However, the use of these NPs still runs into limitations mainly because of the low efficiency of environmental friendly synthesis methods and lack of size standardization. When NPs are release in the environment, they can be transformed by oxidation, adsorption or aggregation. These modification shows a dual role in toxic response of AgNPs. The adsorption of natural organic matter from environment on AgNPs, for example, can decrease their toxicity. Otherwise oxidation occurred in the environment is also able to increase the release of toxic Ag+ from NPs. Thus, the current review proposes an integrated approach of AgNP synthetic methods using bacteria, fungi, and plants, AgNP cytotoxic and genotoxic effects as well as their potential therapeutic applications are also presented.

1. Introduction The unique properties of silver nanoparticles (AgNPs) have been explored in a range of products that are present in the different areas of human life such as fabrics, washing machines, food and medicine (Farkas et al., 2011; Gaillet et al., 2015; Zhang et al., 2016b; McGillicuddy et al., 2017; Shimabuku et al., 2017). However, this extensive use of AgNPs results in their large release into the environment, mainly on aquatic ecosystems. In this context, several studies demonstrated the adverse effects of these nanoparticles (NPs) to aquatic organisms, plants and potentially to humans (Begum et al., 2016; Cui et al., 2016; Minghetti and Schirmer, 2016; Osborne et al., 2016). This release could cause interaction between AgNPs and many environmental factors such as inorganic anions, organic compounds, and metal cations, which affect the composition and surface of AgNPs (Zhang et al., 2015). The AgNPs can be oxidized and release silver ions, which are toxic to human health and environment. When natural organic matter (NOM) is present, it can be adsorbed on the AgNPs reducing their agglomeration. In addition, the ionic strength of the environment can also influence the stability of AgNPs enhancing their agglomeration, especially in acid pH. Due to all these transformations of ocurred in the environment and the changes in toxicity and

bioavailability, it is critically important the determination of the risks posed by AgNPs for human health and environment (Zhang et al., 2018). On the other hand, these transformations of AgNPs can also decrease their toxicity (in case of NOM adsorption) or their uptake can be changed, which can be a key for new strategies of therapeutic approaches, such as anticancer therapy (Mukherjee et al., 2014). The Ag+ ions, formed by dissolution of AgNPs can be used to induce the production of reactive oxygen species (ROS) and cause damage to tumor cells (Barbasz et al., 2017b). In this context, the NP properties are intrinsically related to their synthesis methods. A variety of chemical and physical methodologies are employed for AgNP synthesis. However, many of them employ toxic compounds or require large amounts of energy during the synthesis process. Therefore, the precaution regarding the use of AgNPs begins with the elaboration of environmeal friendly synthesis (Faried et al., 2016; Souza et al., 2016). Under such circumstances, different methods based on bacteria, fungi, and plants have proven to be extremely promising for a large-scale AgNP production without negative impact on human health and in the environment. In this scenario, the constant improvement of the green methods for AgNPs synthesis will allow a better modeling of the physicochemical characteristics of these NPs,

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Corresponding author at: Department of Genetics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Bloco G. Av. Bandeirantes, 3900, Monte Alegre Zip Code: 14049-900, Ribeirão Preto, SP, Brazil. E-mail address: [email protected] (T.A. Jorge de Souza). 1 Both these authors contributed equally to this manuscript. https://doi.org/10.1016/j.ecoenv.2018.12.095 Received 3 May 2018; Received in revised form 26 December 2018; Accepted 27 December 2018 0147-6513/ © 2019 Elsevier Inc. All rights reserved.

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which in turn will facilitate the control of their toxicity. 2. Synthesis of silver nanoparticles The synthesis of AgNPs is an important aspect of nanotechnology (Wei et al., 2015; Faried et al., 2016). The size, structure and their corresponding physical, chemical and biological properties are strongly dependent on the synthetic method, thus, there are a large variety of synthesis approaches (Nair and Laurencin, 2007). Generally, the synthesis of AgNPs can be divided into 3 different categories: (1) chemical methods, (2) physical methods and (3) biological methods. The chemical methods, in turn, can be divided into (i) chemical reduction, (ii) electrochemical techniques, (iii) pyrolysis and (iv) irradiation-assisted chemical methods (Wei et al., 2015). The most common and widely reported synthesis method of AgNPs is the chemical reduction of Ag+ species to Ag° using reducing agents such as NaBH4, citrate (classic method proposed by Turckevich), and ascorbate (Panacek et al., 2006; Kim et al., 2007; Dong et al., 2009; Qin et al., 2010; Fabrega et al., 2011; Marin et al., 2015). In the method proposed by Turckevich, the citrate act not only reducing Ag+ species but also as a stabilizing agent (electrostatic stabilization) which is able to double the electric layer formed in NPs surface avoiding their agglomeration (Henglein and Giersig, 1999). The chemical reduction of AgNO3 in which the ethylene glycol serves as both reductant and solvent during the reaction was also reported in this approach (Sun and Xia, 2002). Electron radiation method can also be used to produce AgNPs, for this energetic electrons are pumped in poly-vinyl alcohol (PVA) and AgNO3 solutions. The Ag+ ions formed by AgNO3 ionization produce Ag° by means of the capture of one electron. These Ag° species can encounter the excess of Ag+ ions and progressively form AgNPs in the solution (Bogle et al., 2006). AgNPs can also be synthesized by flame spray pyrolysis which has many advantages as its low-cost, simple processing, and high-yield production. This methodology consists in the utilization of a solvent and a precursor which are sprayed and vaporized in a high-temperature flame. After that, the thermal decomposition and nucleation take place resulting in solid NPs (Koo et al., 2011; Harra et al., 2016). Physical methods usually are fast, do not involve toxic chemicals and form a narrow size distribution of the synthesized AgNPs. However, the disadvantage of these methods is the high consumption of energy demanded during the synthesis process. Examples of such methods include ball milling (Jayaramudu et al., 2016; Kumar et al., 2016), arc discharge (Zhang et al., 2017) physical vapour condensation (Abou ElNour et al., 2010) and laser ablation (Mafune et al., 2000). Biological methods for AgNP production include fungi, plants, and bacteria and do not employ toxic reducing agents (Wei et al., 2015). The fungi Arthroderma Fulvum and Penicillium Decumbens (Singh et al., 2013; Syed et al., 2013; Devi and Joshi, 2015; Majeed et al., 2016; Xue et al., 2016), and plants such as Eucalyptus hybrid, Aloe vera, Allium sativum are examples of organisms used in biological production of AgNPs. They are known as green synthesis or environmental friendly approaches (Ahmed et al., 2016). Fig. 1 summarizes a variety of methods employed for AgNPs synthesis.

Fig. 1. Methods employed for the synthesis of AgNPs.

here 3 categories of the green synthesis of AgNPs: (i) utilization of microorganisms like bacteria, fungi and actinomycetes; (ii) use of plants and their extracts; (iii) use of templates like membranes, viruses, and DNA (Rafique et al., 2016). Besides the use of non-toxic reagents, economy in energy input and other characteristic mentioned before, the green synthesis is also efficient. Biological green synthesis, at room temperature, from extracts of Chlorella vulgaris resulted AgNPs with low polydispersity and a good yield (> 55%) (Sharma et al., 2009). Ali et al. also achieved a high efficiency in the AgNPs synthesis using aqueous extract from Artemisia absinthium reaching a yield of approximately 90% (Ali et al., 2016). Despite the advantages of biological green synthesis, control the polydispersity of the NPs is a important challenge. To overcome this problem, the reaction conditions can be improved by changing the pH, temperature, incubation period, irradiation, salt concentration and redox conditions. In high temperatures, for instance, the enzyme responsible for NP synthesis is more active, thus is recommended growing the microorganism at the highest temperature possible. The pH can also affect the size of NPs, in case of the plants, pH variations lead to changes in the charge of the phytochemicals which affects the reduction and biding of the Ag during the synthesis process (Singh et al., 2016). It is also important to take into account the best methodology for the extraction of NPs from the organisms (plants and microorganism). Physico-chemical methods such as freeze-thawing, heating, and osmotic shock can be used for this purpose, however; these methodologies can change the structure, size, aggregation and shape of NPs. The enzymatic lysis method has also problems because it is expensive and due to this cannot be employed for industrial scale. A possible option for the extraction of NPs is the use of surfactants which can not only extract but

3. Green synthesis of AgNPs The conventional methods for synthesis of AgNPs employ toxic and non-environment friendly reagents (Rafique et al., 2016), as shown in Table 1, and this is the reason why many researchers are now employing the green chemistry as a new route for AgNP-synthesis. The green chemistry is defined as the “design of chemical products and processes to reduce or eliminate the use and generation of hazardous substances”, it rethinks the processes of the traditional chemistry towards a benefit way to the environment and economy (Horton, 1999; Anastas and Kirchhoff, 2002; Anastas and Eghbali, 2010). We discuss 692

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Table 1 Comparison of conventional methods and green synthesis method.

Stabilizing and reducing reagents Solvents Energy input Recoverability and reusability

Conventional methods

Green synthesis method

References

Toxic reducing and stabilizing reagents such as sodium borohydride, hydrazine and dimethyl formamide Synthesis with toxic and/or flammable solvents (organic solvents) High energy inputs (heat sources such as water/oil bath and heating mantle) Difficult recovery

Non-toxic reducing reagents such as citrate, β-D-glucose, carboxymethyl cellulose sodium, plant and microorganism extracts Synthesis in aqueous medium

(Rauwel et al., 2015), (Chen et al., 2008)

Low energy inputs (synthesis at room temperature)

(Duan et al., 2015), (Ashok et al., 2014) (Virkutyte and Varma, 2011)

Easy recovery (e.g. by using magnetic separation for silver/ iron oxide composite)

(Duan et al., 2015)

2007). In this approach, AgNPs are basically synthesized using bacterial biomass and AgNO3 solution under appropriate conditions of temperature and pressure. After the formation of AgNPs, they can be characterized by different types of techniques (e.g. scanning electron microscopy (SEM), transmission electron microscopy (MET)). AgNPs can be synthesized by bacteria by bioreduction in which the reductase enzymes reduce the Ag+ ions to AgNPs. This reaction can occur either in intracellular or extracellular environment depending on the location of reduction of silver ions. In this process, NADH-dependent reductase enzyme gets the electrons from NADH and at the same time Ag+ ions are reduced to AgNPs (Hulkoti and Taranath, 2014b; Javaid et al., 2018). The main disadvantage related to synthetic methods based on bacteria is the limited spectrum of sizes and shapes obtained (Rafique et al., 2016). The AgNP synthesis using Rhodococcus spp. was investigated by Otari and colleagues. They reported that the synthesis was accomplished after 10 h of incubation at room temperature; the AgNPs were spherical with a mean diameter of 10–12 nm. The antimicrobial activity of these AgNPs were tested and showed excellent bacteriostatic and bactericidal activity against Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus vulgaris (Otari et al., 2015). Wang et al. synthesized AgNPs in the culture supernatant of Bacillus methylotrophicus. The synthesis was accomplished in 48 h at 28 °C and the antimicrobial activity of AgNPs were tested against Candida albicans, Salmonella entérica, Escherichia coli, and Vibrio parahaemolyticus and achieved a better inhibition growth than antibiotics (Wang et al., 2016). The Table 2 shows some species of fungi and bacteria used in AgNPs synthesis.

also stabilize these particles (Iravani, 2011). 3.1. Synthesis of AgNPs by microorganisms The potential of fungi to produce AgNPs has been recently explored (Du et al., 2015; Owaid et al., 2015; Amerasan et al., 2016; Al-Bahrani et al., 2017). The use of these organisms as biofactories has some advantages such as the production of NPs in different sizes and chemical compositions in a monodisperse way (Hulkoti and Taranath, 2014a). Furthermore, fungi not exposed to a large concentration of toxic metals have an inherent ability to produce higher concentrations of proteins which act in metal reduction (Dhillon et al., 2012). The AgNP synthesis can occur inside or outside of the cell (intracellular or extracellular). The reduction of Ag+ ions occurs by the cell wall polymers or electron shuttle quinones, which act as redox centers. The NADPH-dependent nitrate reductase reduces Ag+ ions and peptides or nitrogenous biomacromolecules stabilizes the AgNPs (Zhao et al., 2018). Li et al. synthesized AgNPs in the culture supernatants of Aspergillus terreus. They were polydispersed with a mean diameter ranging from 1 to 10 nm and this synthesis was mediated by an extracellular enzyme (Li et al., 2012). Recently, Seetharaman and colleagues used Phomopsis liquidambaris for AgNPs synthesis. They obtained NPs with spherical shape and with an average size of 18.7 nm, which were effective as antimicrobial and mosquitocidal agent (Kumar et al., 2018). The first evidence of AgNP production by bacteria was obtained in the Pseudomonas stutzeri AG259 strain which was isolated from silver mine (Prabhu and Poulose, 2012). Bacteria produce many extra and intracellular inorganic materials and they can be used in AgNP production, making these microorganisms efficient biofactories (Rafique et al., 2016). It is well known that AgNPs are toxic to bacteria, however, these biofactories can become resistant to these NPs through the incorporation of the ‘sil’ gene using plasmids (Vigneshwaran et al., 2007). Many authors (Klaus et al., 1999; Shahverdi et al., 2007; Korbekandi et al., 2012; Kalpana and Lee, 2013; Siva Kumar et al., 2014) studied the production of AgNPs by bacteria and they reported that the time required for this process ranged from 24 to 120 h (Shahverdi et al.,

3.2. Synthesis of AgNPs by plants The AgNP synthetic methods based on plants and their extracts are non-pathogenic, they are simple, involves only a single step and in addition, they have a higher bio-reduction potential compared to microbial culture filtrates (Rajan et al., 2015; Ahmed et al., 2016). Many

Table 2 Some microorganisms used in AgNPs synthesis. Fungi Species

Size of AgNPs (nm)

Morphology

References

Aspergillus tamarii Aspergillus niger Penicllium ochrochloron Fusarium oxysporum Verticillium Bacteria Species Bacillus Methylotrophicus Streptomyces sp. SS2 Bhargavaea indica strain DC1 Rhodococcus sp.

3.5 ± 3 8.7 ± 6 7.7 ± 4.3 5–15 25 ± 12

Spherical Spherical Spherical spherical and triangular Spherical

(Devi and Joshi, 2015) (Devi and Joshi, 2015) (Devi and Joshi, 2015) (Zhao et al., 2018) (Zhao et al., 2018)

Size of AgNPs (nm) 10–30 67.95 ± 18.52 30–100 10–12

Morphology Spherical Spherical Spherical, triangular, hexagonal, pentagonal, icosahedral Spherical

References (Wang et al., 2016) (Javaid et al., 2018) (Javaid et al., 2018) (Javaid et al., 2018)

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positive charges can reduce the stability of AgNPs by eliminating the surface charge, compressing the electric double layer, andthen removing the repulsive energy. Divalent cations such as Ca2+ and Mg2+ can impact more significant the aggregation of NPs due to the increase of ionic strength. In this way, the increase of this strength can significantly raise the aggregation of AgNPs (Zhang et al., 2016a). The pH is another factor that influences AgNP aggregation. When the pH of the environment is equal to the pH corresponding to the point zero charge (pHPZC) of AgNPs, unstable AgNPs and aggregates are formed. The pHPZC of AgNPs is estimated to be 2, and due to this; acid solutions (acid pH) can enhance the aggregation as observed by Badawy and co-workers (Badawy a et al., 2010; Zhang et al., 2016a). However, this process can be more complex due to the different surface coating of AgNPs (Zhang et al., 2016a). Besides agglomeration and dissolution, AgNPs can adsorb different substances in the environment mainly NOM. This adsorption depends on the capping agent of AgNPs and the composition of NOM. If the bonds between the capping agent and the AgNPs is not strong, the AgNPs will be effectively stabilized by NOM, on the other hand if the amount of sulfur and nitrogen is higher in NOM, its adsorption on AgNPs will increase (Gunsolus et al., 2015; Souza et al., 2018). In view of this fact, the NOM adsorption may affect both dissolution and agglomeration. The NOM can stabilize AgNPs by the formation of a coating which provides electric and steric stabilization and due to this, the agglomeration decreases (Grillo et al., 2015). NOM can reduce silver ions and form AgNPs through the Ag+-fulvic acid under relevant environmental conditions and due to this, the dissolution of AgNPs decrease (Dwivedi et al., 2015). All these transformations are illustrated in Fig. 2. It is important to mention that in the environment all these factors act together, which means that one can interfere with the other. An example of this is the behavior of AgNPs in an environment with natural organic matter and high ionic strength. A high ionic strength destabilizes the AgNPs increasing the agglomeration, which can be seen by the increase of the hydrodynamic diameter (HDD) from nm to μm even in the presence of NOM. This behavior indicates that the NOM stabilization of AgNPs may decreases when they move from freshwater to seawater (Sharma and Zboril, 2017).

authors reported the synthesis of AgNPs by plants (Jagtap and Bapat, 2013; Roopan et al., 2013; Dinesh et al., 2015; Mittal et al., 2015; Bhakya et al., 2016; Chaudhuri et al., 2016) and their several applications. AgNPs can be produced using the whole plant or its extract, however, the availability of the reducing agent is more concentrated in the extract than in the whole plant. Thus, most studies have been focused on the utilization of plant extracts. The methods of NP synthesis based on plants involve the mixing of a plant extract with an aqueous solution of metal salt. This process occurs at room temperature and takes from minutes to few hours to be completed (Rajan et al., 2015). The main mechanism considered to produce AgNPs is based on the reduction mediated by phytochemicals such as terpenoids, flavones, ketones, aldehydes, amines, and carboxylic acids. Flavones, organic acids and quinones are involved in the immediate reduction of Ag+ ions (Prabhu and Poulose, 2012). 3.3. Synthesis of AgNPs by templates In the last years, viruses have been exploited as templates to synthesize NPs because they offer confined cages, high symmetry, robust functional protein capsids and unique architecture structure, besides the easy manipulation (Slocik et al., 2005). Moreover, viral scaffolds can stimulate the nucleation and assembly of inorganic materials. The mineralization of Ag°, for example, was observed occurring within the hollow channel as result of pH manipulation and the electrostatic nature of the viral components (Slocik et al., 2005; Thakkar et al., 2010). Some examples of viral templates are tobacco mosaic virus (TMV) and cowpea chlorotic mottle virus (CCMV) (Slocik et al., 2005). DNA is also used as a template for NP synthesis. Davis and coworkers (2003) reported that a nucleoprotein filament from polymerizing RecA proteins on a single strand (ss)DNA probe was mixed with a long aldehyde-derived double strand (ds)DNA substrate. After this, the sample was exposed to AgNO3 ions, which binds to dsDNA wherever RecA proteins were absent and the aldehyde groups reduced the Ag+ specie to Ag° and form metallic aggregates (Davis et al., 2003). 4. Transformations of AgNPs AgNPs may alter their dissolution and agglomeration properties according to the location they are inserted (in the environment or in a biological medium). 4.1. Transformation of AgNPs in the environment The green synthesis of AgNPs can decrease the risk of contamination by toxic reagents, however, the risks arising from AgNPs release in the environment need to be well studied especially due to their transformations in the environment which modifies their properties such as toxicity (Levard et al., 2012). The primary process for AgNP transformation is the oxidation dissolution in order to form silver complexes such as Ag2S and AgCl. When exposed to oxygen, silver reacts to form a silver oxide (Ag2O) which adheres to the surface of AgNPs forming a core (AgNPs)-shell (Ag2O) structure. The Ag2O is dissolved in water and releases Ag+ ions (Eq. (1)) (Levard et al., 2012; Zhang et al., 2018).

2Ag (s) + ½O2(aq) + 2H+(aq) ⇌ 2Ag+(aq) + H2 O(1)

(1)

The dissolution is strongly dependent on the particle size. Due to the surface area, smaller AgNPs release more Ag+ ions than larger AgNPs (Levard et al., 2012; Zhang et al., 2018). Furthermore, the pH of the environment can enhance the dissolution, as shown in the Eq. (1). The AgNPs also form aggregates in the environment and ionic strength can affect this process. Under normal aquatic conditions, AgNPs are generally negatively charged. A higher concentration of

Fig. 2. Transformations in the environment impacting AgNP stability. 694

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(Murugan et al., 2016). Thereunto, the task of determining the real risk offered by NP release into the environment becomes difficult (Sabella et al., 2014). Besides the complexity of each organism affected, it should be considered that in solution these NPs tend to agglomerate in contact with biomolecules (Souza et al., 2016). Depending on the level of AgNP agglomeration, the physico-chemical properties related to their nanosize are lost and; consequently, their toxic potential is drastically changed. Moreover, AgNPs readily ionize in aqueous solution becoming highly reactive. Thus, when released into the environment, they may react with various compounds found in aquatic organic matter changing their size and reactiveness (Nason et al., 2012). AgNPs are applied in daily products mainly because they exhibit bactericidal effects. However, in association with certain types of ions, an opposite action is observed. The AgNP interaction with sulfide ion, for example, can induce microbial growth, which shows that AgNP toxicity can be modulated by unpredicted environmental specific conditions (Guo et al., 2017). However, depending on nature of the ions with which AgNPs are associated, these particles may not pose a real threat to the environment because they can form stable complexes that would decrease their toxicity. This finding is important for the creation of mechanisms to neutralize the toxicity of such NPs or to avoid this neutralization when their biocidal potential is required (Guo et al., 2017). Towards understanding the mechanisms of action of these NPs, the nature of their cyto- and genotoxicity should be uncovered (Franchi et al., 2012, 2015; Filho et al., 2014). In this context, the initial step is to determine if the size of AgNPs are directly associated to their cytotoxicity in different cell types (Franchi et al., 2012). In this sense, the investigation about how cells internalize AgNPs synthesized by distinct methods (chemical vs physical vs biological approaches) would clarify cytotoxic pathways activated in response to specific conditions. Cells can internalize particles by phagocytosis or pinocytosis. Pinocytosis is the most common internalization mechanism in eukaryotic cells and phagocytosis is performed mainly by immune cells, such as macrophages and monocytes (Kettler et al., 2016). In this context, Kettler and coworkers (2016) analyzed the uptake kinetics of different sizes of AgNPs and demonstrated that the monocytic cell line THP-1 preferentially incorporated the smaller ones (20 nm) (Kettler et al., 2016). However, there is no consensus about the relationship between AgNP size and its cytotoxicity yet. Our group, for example, observed a higher long-term cytotoxicity of large particles (100 nm) when compared to their smaller counterparts (10 nm) in CHO cell lines (Souza et al., 2016). Unfortunately, studies evaluating the relationship among AgNP size, their internalization rate, and their cyto- genotoxicity are still scarce (Kettler et al., 2016). The most widely accepted hypothesis to explain the cytotoxic effect of AgNPs is called “Trojan horse mechanism” (Kettler et al., 2016). In this mechanism, the NPs are internalized and high levels of toxic ions are released into the cytoplasm (Fig. 3). These ions act in the intracellular environment by depolarizing the mitochondrial membrane, inactivating enzymes from several cellular pathways and damaging lysosomes. As a consequence, an increase of reactive oxygen species (ROS) is observed, generating lesions in the cell membrane and DNA (Shrivastava et al., 2016). Depending on the concentration of AgNPs and their degree of ionization, these changes may culminate in the induction of cell death by apoptosis (Franchi et al., 2015; Li et al., 2016), necrosis (Kumar et al., 2015) or autophagy (Mao et al., 2016). The cytotoxicity of AgNPs can have therapy application such as in treatment of viral diseases, anti-inflammatory effects, and also in anticancer therapy which indicates a behavioral duality (toxic or beneficial) of the AgNPs depending on their application as illustrated in Fig. 4. The application of AgNPs in antiviral therapy was studied by Xiang et al. and they demonstrated that AgNPs might interfere in the

4.1.1. Transformation of AgNPs in biological medium As discussed in the Section 4.1, the ionic strength affects the AgNP stability. Due to the high ionic strength of the biological fluids, the AgNPs form aggregates as demonstrated by Stebounova and colleagues. In the simulated interstitial and lysosomal lung fluids, AgNPs coexist in the form of aggregates and dissolved single AgNPs and in the concentration range of 2–20 mg L−1 remains suspended (Stebounova et al., 2011). At the same time that agglomeration occurs in biological medium, the dissolution of AgNPs also is possible. In the biological medium DMEM/FCS, about 5.3% of AgNPs is dissolved, however, due to the presence of chloride ions, 2.2% can be re-precipitated in the form of solid silver chloride, while the 3.1% of the resultant silver remain dissolved (Loza and Epple, 2018). The behavior of AgNPs in biological medium also depends on the pH of the fluid. The strong acidity of stomach fluid, with the presence of HCl can induce transformations in the AgNPs which are different according to the size of these NPs. While small NPs (8 nm) are dissolved in HCl and form AgCl, larger NPs (> 1 µm) forms aggregates which release Ag+ ions. The oxidation and these ions can form AgCl in the surface of the aggregate (Kejlová et al., 2017). The presence of proteins in the biological fluid alters the surface of NPs due to their adsorption. This protein coating, called “protein corona” (PC) change the surface charge, hydrodynamic size and aggregation, which can be enhanced as observed with AgNPs and the protein pepsin by Kejlová and colleagues (Kejlová et al., 2017). These transformations are illustrated in Fig. 3. 5. Cyto- and genotoxicity of AgNPS Unfortunately, most literature data analyzing the dose-response toxicity of AgNPs with different physico-chemical characteristics only assess the toxic potential of these NPs after arbitrary exposure periods. Different lethal doses of AgNPs are found for different organisms: the minimum inhibitory concentration (MIC) for bacteria gram-positive (S. pneumoniae) and gram-negative (P. aeruginosa) were respectively 0.9 and 0.7 μg mL−1 as detected by Gurunathan and colleagues (Gurunathan et al., 2014). In case of organisms with higher complexity, the LC50 of AgNPs is higher, e.g. for the larvae and pupae stage of Aedes aegypti the LC50 detected were 3.496 and 17.700 mg L−1, respectively

Fig. 3. Transformation of AgNPs in biological medium. 695

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6.2. The toxic effects of AgNPs aggregation in the environment on toxicity The aggregation of AgNPs is a factor that can alter their biological effects by modifying their reactive surface area and the release of ions. In addition, AgNPs aggregation also affects the mode of cellular uptake and its subsequent biological responses (Hotze et al., 2010). It was observed that NPs measuring 20 nm deposit in the alveolar region, whereas NPs measuring 5–10 nm are deposited in tracheobronchial region, and NPs smaller than 10 nm accumulate in the upper respiratory tract (Hotze et al., 2010). In an environmental condition with high ionic strength, the aggregation can be enhanced. When the aggregation is enhanced, the surface area for dissolution decreases and therefore, less Ag+ ions are available which can decrease the toxicity. This behavior could be observed by comparing the toxicity of AgNP aggregates (micron-sized), Ag+ ions and AgNPs (in a range of 4.2–4.7 nm). The toxicity of AgNP micron-sized aggregates showed to be the lowest compared to Ag+ and AgNPs in the algae Pseudokirchneriella subcapitata (Angel et al., 2013). The lower toxicity of citrate-coated AgNPs aggregates to the nematode Caenorhabditis elegans was also reported by Yang and colleagues (Yang et al., 2012).

Fig. 4. The mechanism of action of AgNPs.

association of H3N2 influenza virus hemagglutinin to cellular receptors and then inhibit the viral infection. Literature data suggest that AgNPs interact with viral particles and destroy their morphological structures in a time-dependent manner (Xiang et al., 2013). Some studies have proposed that, probably, AgNPs inactive viruses by denaturing enzymes via reactions with amino, phosphate and imidazole groups (Lara et al., 2010, 2011a, 2011b). The anti-inflammatory effects of AgNPs have been investigated. One of them states that AgNPs are able to module the IL-6 and IL-10 cytokines expression. The AgNPs can act increasing the mRNA levels of IL10 and decreasing the pro-inflammatory cytokine IL-6 levels (Wong and Liu, 2010). Hebeish and colleagues tested the anti-inflammatory effects of AgNPs in rats and observed that both doses used (0.25 and 0.5 mL of a 250 mg L−1 solution of AgNPs) reduced the degree of rat bow oedema (Hebeish et al., 2014). AgNPs are also studied in anticancer therapy and they have been shown to display cytotoxicity to breast cancer cells. Franco-Molina and co-workers observed that the MCF-7 treated with colloidal silver significantly reduced the dehydrogenase activity, resulting in decreased NADH/NAD+ and caused the death of cells due to decreased mitochondrial membrane potential (Franco-molina et al., 2010).

6.3. The toxic effects of AgNPs adsorption in the environment on toxicity When NOM is adsorbed in AgNPs, the stability of these nanoparticles increases which extend their residence time and increase their exposure. The persistence of AgNPs in the environment can be dangerous for the organisms due to the Trojan-horse mechanism (Grillo et al., 2015; Zhang et al., 2018). Although the NOM contributes to AgNP persistence in the environment, it was reported the decrease of toxicity of AgNPs with NOM. The NOM adsorption on AgNPs reduces the Ag+ release in the environment by blocking the oxidation sites and due to the humic/fulvic acids, the NOM acts as a reducing agent in a reversible reaction of Ag+ formation from Ag0. In this way, decreasing the concentration of Ag+ ions, the toxicity can decrease (Souza et al., 2018). In addition, NOM can react with ROS and reduce the oxidative stress, which decreases the toxic effects of the AgNPs (Grillo et al., 2015). In this context, the AgNPs toxicity in the presence of NOM was reported by Seitz and colleagues. They observed the decrease of toxicity of AgNPs in Daphnia magna due to the formation of Ag-NOM complexes, which reduces the interaction of free Ag+ (Seitz et al., 2015). The toxicity of aged AgNPs is higher due to the higher release of Ag+, however, in the presence of NOM, their toxicity to Japanese medaka embryos can be reduced by Ag+ complexation, as demonstrated by Kim et al., (2013). The toxicity of aged AgNPs (5 mg L−1) decreased to 20% with 10 mg L−1 of humic acid (NOM) (Kim et al., 2013). It is well described that the mechanism of AgNP toxicity is mostly related to the formation of ROS. However, there is another factor that is important to consider: the surface charge of the NPs. The disruption of plasma-membrane integrity can occurs by the attractive electrostatic interactions between the cationic/anionic NPs and the cell membrane with opposite charge (Barbasz et al., 2017a). In view of this fact, the molecules adsorbed on the surface of NPs can play an important role in this interaction. This effect was observed in the study of Badawy et al. (2011). They reported that AgNPs coated with citrate have a negative surface charge and the cellular membrane of the bacillus species investigated (due to carboxyl, phosphate and amino groups) has also negative charge. This resulted in a high degree of repulsion between the negatively charged Citrate-AgNPs and the bacillus cells forming an electrostatic barrier that limits the cell-NPs interactions which decreases the toxicity. When the bacteria cells are exposed to AgNPs with positive surface charge (BPEI coating), the repulsion gives place to the attraction, which allow a higher degree of interaction and consequently higher toxicity (Badawy et al., 2011). Recently, Ahmed et al. (2017) also reported the influence of surface

6. AgNP transformation in the environment: a toxicity approach As described above, the AgNPs have toxic effects. However, these toxic effects can be enhanced or decreased due to the transformations of AgNPs in the environment. 6.1. The toxic effects of AgNPs dissolution in the environment The oxidation dissolution of AgNPs could increase the toxicological response of AgNPs in organisms due to the formation of Ag+ ions (as described in Section 6). Increasing the dissolution of AgNPs, Ag+ ions will be available to cause harmful effects in the environment and human health. The Ag+ ions are well known toxic agents: they interact with NADH dehydrogenase from respiratory chain resulting in the uncoupling of respiration from ATP synthesis, and they cause proton leakage and the collapse of the proton motive force due to their bind in the transport proteins (Jiravova et al., 2016). The Ag+ ions in low environmentally relevant concentrations can cause harmful effects to zebrafish according to Ašmonaite et al. (2016). High concentrations of Ag+ significantly suppressed locomotion which could lead to inactivity, and in lower concentrations, it was observed subordinate locomotive changes (hyperactivity) in developing fish (Ašmonaite et al., 2016). When Ag+ ions are in an environment with acid pH, their toxic effects can be enhanced. The hatchability of Japanese medaka embryos, for example, decreased to 18% and also their eye size decreased in pH 4 and Ag+ concentration of 0.06 mg L−1 (Kataoka et al., 2018). 696

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environment, they can be explored for therapeutic applications such as anticancer therapy. In this context, future studies should explore the synthesis methodologies and the desired physicochemical properties, as well as inactivate these properties when necessary. The adsorption of molecules in the surface of AgNPs is a topic that needs to be well understood because it modifies the surface charge of NPs and the interactions between cell-NPs. Furthermore, the use of AgNPs with protein corona as target delivery has not well explored and it has a great potential for therapeutic application. The elucidation of these issues will greatly contribute to the understanding of the multiple transformations of the nanoparticles in the environment avoiding possible damages to the environment as well as the use of these changes in the AgNPs for therapeutic applications.

charge in the internalization of AgNPs. The internalization of AgNPs by human liver carcinoma cells (HepG2) were higher for NPs with poly-Llysine (PLLA) coating (internalization higher than 80% for a concentration of 25 mg L−1 of Ag) due to their higher positively surface charge and the negatively charge of the cell membrane, which promotes this interaction (Ahmed et al., 2017). 6.4. The therapeutic application of the AgNPs transformed by dissolution, aggregation, and with adsorption of proteins In view of the transformations that the AgNPs can undergo in the biological environment, they can be used for therapeutic purposes. One example is the dissolution of AgNPs in the medium of tumor cells. It is known that the pH of tumor cells are slightly acidic than normal cells, due to this, the release of Ag+ ions in these tumor cells is higher when compared to normal cells. This higher release of Ag+ ions causes the death of tumor cells by formation of reactive oxygen species (ROS), which was not observed in normal cells (Mukherjee et al., 2014). Foldbjerg et al. (2009) reported the effects of Ag+ ions which caused a drastic increase in ROS levels after 6–24 h in THP-1 cells (a human monocytic cell line derived from an acute monocytic leukemia) (Foldbjerg et al., 2009). In the same way that Ag+ ions can be used, silver aggregates formed in biological medium can also be studied for therapeutic applications. Fröhlich et al. (2012) observed that aggregates of AgNPs are taken up by phagocytic cells (THP-1) in a higher degree than well dispersed AgNPs, which can trigger the Trojan-horse mechanism (described in Section 5) (Fröhlich, 2012). Furthermore, the silver agglomerates (or clusters) can be used for DNA detection, which is crucial in disease diagnostic due to their strong luminescence and excellent photostability (Tao et al., 2015). DNA-templated AgNPs display bright fluorescence in solution, i.e. the dark DNA–AgNPs could be converted into bright red/ green emitters when in close proximity to guanine-/thyminerich DNA. This characteristic can be applied for identify mutations associated with diseases such as sickle cell anaemia (Tao et al., 2015). The formation of protein corona in AgNPs represents the “way of the cells see the particle” which can enhance the interaction between the NPs and cellular surface receptors (Durán et al., 2015). The protein corona effect increase the stability of AgNPs decreasing the dissolution in Ag+ ions, however, while the stabilization of this NPs is increased, the cellular uptake is increased. After the internalization, the protein corona may be lost resulting in the dissolution of AgNPs releasing Ag+ ions (Shannahan et al., 2015; Corbo and Toledano, 2016). This behavior is important for their application as carriers, due to the release of Ag+ ions on the target cells.

CRediT authorship contribution statement Tiago Alves Jorge de Souza: Conceptualization, Investigation, Project administration, Supervision, Writing - original draft, Writing review & editing. Lilian Rodrigues Rosa Souza: Conceptualization, Investigation, Writing - original draft, Writing - review & editing. Leonardo Pereira Franchi: Conceptualization, Investigation, Writing original draft, Writing - review & editing. Acknowledgements Conceptualization and Investigation: TAJS, LRRS, LFP. Supervision: TAJS. Writing - original draft and review & editing: TAJS, LRRS, LFP. All authors read and approved the final manuscript. References Abou El-Nour, K.M.M., Eftaiha, A., Al-Warthan, A., Ammar, R.A.A., 2010. Synthesis and applications of silver nanoparticles. Arab J. Chem. 3, 135–140. https://doi.org/10. 1016/j.arabjc.2010.04.008. Ahmed, L.B., Milic, M., Pongrac, I.M., et al., 2017. Impact of surface functionalization on the uptake mechanism and toxicity effects of silver nanoparticles in HepG2 cells Lada Brki. Food Chem. Toxicol. 107, 349–361. https://doi.org/10.1016/j.fct.2017.07.016. Ahmed, S., Ahmad, M., Swami, B.L., Ikram, S., 2016. A review on plants extract mediated synthesis of silver nanoparticles for antimicrobial applications: a green expertise. J. Adv. Res. 7, 17–28. https://doi.org/10.1016/j.jare.2015.02.007. Al-Bahrani, R., Raman, J., Lakshmanan, H., et al., 2017. Green synthesis of silver nanoparticles using tree oyster mushroom Pleurotus ostreatus and its inhibitory activity against pathogenic bacteria. Mater. Lett. 186, 21–25. https://doi.org/10.1016/j. matlet.2016.09.069. Ali, M., Kim, B., Bel, K.D., et al., 2016. Green synthesis and characterization of silver nanoparticles using Artemisia absinthium aqueous extract — a comprehensive study. Mater. Sci. Eng. C 58, 359–365. https://doi.org/10.1016/j.msec.2015.08.045. Amerasan, D., Nataraj, T., Murugan, K., et al., 2016. Myco-synthesis of silver nanoparticles using Metarhizium anisopliae against the rural malaria vector Anopheles culicifacies Giles (Diptera: culicidae). J. Pest Sci. 89 (2004), 249–256. https://doi. org/10.1007/s10340-015-0675-x. Anastas, P., Eghbali, N., 2010. Green chemistry: principles and practice. Chem. Soc. Rev. 39, 301–312. https://doi.org/10.1039/b918763b. Anastas, P.T., Kirchhoff, M.M., 2002. Origins, current status, and future challenges of green chemistry. Acc. Chem. Res. 35, 686–694. https://doi.org/10.1021/ar010065m. Angel, B.M., Batley, G.E., Jarolimek, C.V., Rogers, N.J., 2013. The impact of size on the fate and toxicity of nanoparticulate silver in aquatic systems. Chemosphere 93, 359–365. https://doi.org/10.1016/j.chemosphere.2013.04.096. Ashok, D., Palanichamy, V., Mohana, S., 2014. Green synthesis of silver nanoparticles using Alternanthera dentata leaf extract at room temperature and their antimicrobial activity. Spectrochim. ACTA PART A Mol. Biomol. Spectrosc. 127, 168–171. https:// doi.org/10.1016/j.saa.2014.02.058. Ašmonaite, G., Boyer, S., de Souza, K.B., et al., 2016. Behavioural toxicity assessment of silver ions and nanoparticles on zebrafish using a locomotion profiling approach. Aquat. Toxicol. 173, 143–153. https://doi.org/10.1016/j.aquatox.2016.01.013. Badawy a, M.E., Luxton, T.P., Silva, R.G., et al., 2010. Impact of environmental conditions (pH, ionic strength,and electrolyte type) on the surface charge and aggregation of silver nanoparticle suspensions. Environ. Sci. Technol. 44, 1260–1266. https://doi. org/10.1021/es902240k. Badawy, A.M.E.L., Silva, R.G., Morris, B., et al., 2011. Surface charge-dependent toxicity of silver nanoparticles. Environ. Sci. Technol. 45, 283–287. Barbasz, A., Magdalena, O., Roman, M., 2017a. Toxicity of silver nanoparticles towards tumoral human cell lines. Colloids Surf. B Biointerfaces 156, 397–404. https://doi. org/10.1016/j.colsurfb.2017.05.027. Barbasz, A., Oćwieja, M., Roman, M., 2017b. Toxicity of silver nanoparticles towards tumoral human cell lines U-937 and HL-60. Colloids Surf. B Biointerfaces 156,

7. Final considerations AgNPs have been employed in a multitude of daily products and more recently are being used for therapeutic purposes. However, the environmental fate of these NPs can alter their properties due to the interaction with organic matter, cations, different pH, and oxygen. The consequence of AgNP interactions in the environment is the change of their surface properties which leads to release of Ag+ ions (by oxidation), aggregation (in an environment with high ionic strength) and also their stabilization (when the NPs interact with NOM). These transformations of the AgNPs lead to changes in their toxicity: enhancing the release of toxic Ag+ ions and consequently toxicity to organisms. However, agglomeration of AgNPs can modify their uptake characteristic by cells, and the interaction with NOM can decrease their toxicity by decreasing the Ag+ release. In addition, the transformations of the properties of AgNPs also changes in a biological medium. The interaction of AgNPs with proteins present in the biological medium promotes the formation of the protein corona, which changes their interaction with cells. Although these transformations may be dangerous for health and 697

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