Metallic and Metal Oxide Nanoparticles: History
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Contributor:
Nayrim B. Guerra
,
Jordana Bortoluz
,
Andressa R. Bystronski
,
Ana Elisa D. Maddalozzo
,
Danielle Restelatto
,
Mariana Roesch-Ely
,
Declan M. Devine
,
Marcelo Giovanela
,
Janaina S. Crespo

Diseases caused by infections are becoming harder to treat as the antibiotics used become less effective. A combination of strategies to develop active biomaterials that enhance antibacterial effects are desirable, especially ones that cause fewer side effects and promote healing properties. The development of new antimicrobial products is necessary to avoid the transmission of infection in healthcare environments. In this sense, metallic and metal oxide nanoparticles (NPs) have been gaining attention due to their unique size-dependent physical and chemical properties. The best known examples of this category are the NPs of elements such as silver, copper, gold, palladium, and platinum, which are used in varied areas of application (catalytic, biomedical, and electronic) as their properties are distinguished from those presented by the bulk. NPs are especially effective against Gram-negative and Gram-positive bacteria, such as Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. 

  • nanoparticles
  • nanotechnology
  • biomedical applications

1. Silver Nanoparticles

Traditionally, silver is known as a substance with antibacterial properties. The concentration of AgNPs added is proportionally responsible for the antibacterial action, as well as the size and shape of the NPs. Studies show that the minimum inhibitory concentration (MIC) of AgNPs against Gram-negative and Gram-positive bacterial strains depend strongly on the factors already mentioned, but these are approximately 1.0 and 1.5–2.0 μg mL−1, respectively [1]. Therefore, its NPs are currently being used in a wide variety of commercial products [2]. Silver nanoparticles (AgNPs) are used in the form of wound dressings, the coating of prostheses, and surgical utensils due to their antimicrobial properties against bacteria and protozoa, in addition to being effective in eliminating some fungi and viruses [3]. AgNPs are used in the coating of medical devices, the water and wastewater treatment industry, smart fabrics, wound dressings, and the food industry. They also have electrochemical and bioluminescent properties that enable their application in optical and biological nanosensors [4].
However, NPs can present cytotoxicity in addition to antibacterial activity; this is an effect that depends on factors such as the size, dose, and exposure time of NPs. The continued use of these NPs can lead to the development of diseases and their leaching into aquatic environments, polluting groundwater. In contact with water, NPs oxidize and form Ag(I) species, ions that are toxic to marine organisms and can return to the human body due to the food chain. It is not known exactly what effect of AgNPs will be generated by a prolonged exposure over time, but a series of in vitro tests observed toxicity in keratinocyte cells, liver cells, and colon cells, among others. In vivo tests with rodents have shown that AgNPs accumulate in the lung, spleen, and liver [1].

2. Copper Nanoparticles

Due to their high oxidative ability in contact with air, the use of copper nanoparticles (CuNPs) presents some challenges. The formation of copper oxide results in a loss in intensity of the antibacterial activity, so CuNPs must have high stabilization in the substrate to which they are added. To that end, chelates promote the stability of NPs, which will be surrounded by organic molecules. Chelates with amino acids showed antibacterial activity ten times higher than that presented by CuNPs. The use of different materials in these compounds will modify the antimicrobial activity, which may be superior to some bacteria in relation to others. In addition to the oxidation factor, CuNPs also suffer from agglomeration, which must be minimized. In this way, NPs will be more dispersed, offering a larger zone of interaction between particles and micro-organisms, leading to an increase in their toxicity [4].
In addition to antibacterial activity, it has been reported in the literature that CuNPs also have anticancer and cytotoxic properties. Cell death or the damage of cancer cells is caused by the generation of reactive oxygen species (ROS), which cause cellular lipid peroxidation, DNA damage, and protein oxidation [5].

3. Gold Nanoparticles

Gold nanoparticles (AuNPs) have a high biocompatibility and can therefore be used in different medical applications [6]. They can have different sizes, formats, and aggregation capabilities [7]. The size and shape of the NPs influence their physical–chemical, electrical, and optical properties [8]. The AuNPs have an average particle size smaller than AgNPs and they are less rough. A high roughness is important for a high antibacterial efficacy, as bacteria are attracted by irregular metal particles and are thus eliminated [9].
AuNPs have been the subject of many studies due to their applications in the development of new agents and because they are of stable, nontoxic in nature, inert, and controllable sizes [10]. In addition, they absorb light through the surface plasma resonance phenomenon, affecting the production of intracellular ROS [11]. However, AuNPs, despite their wide range of applications in electronics, biomedicine, and nanotechnology, have a feeble antibacterial property compared to other metallic NPs [12]. To increase the antibacterial capacity of AuNPs, several studies involving the synthesis of composite materials with other antibacterial agents have been carried out [9][13][14].

4. Metal Oxide Nanoparticles

Nanometer-sized metallic oxides have also attracted the attention of scientists, mainly due to the existence of a negative surface charge, or one that favors their functionalization with different molecules [15]. Metal oxides NPs have a high stability, the possibility of synthesis in different sizes, and ease of preparation and incorporation into hydrophobic and hydrophilic matrices [16]. They can be synthesized from metals or metal oxides, such as silver, gold, titanium, zinc, copper, magnesium, calcium, and iron [17]. In contrast, metallic oxide NPs tend to be less stable than metallic nanomaterials (composed of a single metallic element), and these are more susceptible to dissolution and the release of ions when inserted into a biological medium [18]. In this regard, a great deal of research is being carried out to assess the possible toxic effects, as well as the computational methods, to predict their toxicity [19][20].
Zinc oxide nanoparticles (ZnONPs), for example, have several applications in the engineering and biomedical fields. They offer new possibilities for biomedical applications, ranging from diagnosis to treatment [21]. Furthermore, they are responsible for speeding up the rate of wound healing, since zinc is an important trace element found in the muscles, bones, and skin [22]. In the rubber industry, ZnONPs are widely applied as they offer wear resistance of the rubber compound, improve its toughness, and prevent aging, amongst other functions [23]. At present, ZnONPs are being investigated as associates of antimicrobial agents, which is one of the most important reasons for their use [24]. Compared with other metal oxide NPs, ZnONPs are inexpensive and have a low toxicity [25].
Other metal oxide NPs used in the biomedical field are titanium oxide (TiO2NPs), which have high photocatalytic activity and thermo-stability, which makes them applicable for use in biomedical applications, such as in the treatment of cancer using phototherapy and for use against different bacterial contaminations [26][27]. Nanostructured TiO2 has a great potential for application due to its good biocompatibility, intrinsic properties, and different manufacturing techniques [28]. Furthermore, TiO2NPs have also presented antifungal activity against diverse species of fungus [29]. In these NPs, it is important to point out that mixed polymorphs of TiO2 (anatase and rutile) are more effective for biomedical applications than using only one crystalline phase [30].
Iron oxide magnetic nanoparticles (Fe3O4NPs) are also used in the biomedical field, specifically as a component of biosensors, in magnetic resonance studies and cancer cell treatment. However, their most discussed application is in targeted drug delivery, because of their unique magnetic properties, biodegradability, low toxicity, and excellent biocompatibility [31]. Despite the fact that these NPs have a highly reactive surface, there is only one piece of research that has used NRL as a stabilizing agent in the synthesis of magnetic Fe3O4NPs for biomedical applications [32].

5. Synthesis of NPs

The properties of NPs depend on the synthesis method used; therefore, different methods of synthesis of antimicrobial NPs are used depending on the final applications. The synthesis methods can be grouped into biological or green, chemical, and physical methods (Figure 1) [33].
Figure 1. Biological and physical–chemical methods of NPs synthesis.
In general, physical methods have a high energy consumption and high costs, whereas chemical synthesis methods produce a great number of NPs in short periods of time; however, there are several studies that indicate that in the use of toxic chemicals, the generated by-products are a disadvantage. For this reason, “green synthesis” methods have received special attention in recent years [34].

5.1. Physical Approach

The technique of physical vapor deposition (PVD) magnetron sputtering can be utilized in the manufacture of metallic NPs. The process is environmentally friendly and takes place inside a vacuum chamber, avoiding the occurrence of contaminants in the coating. The deposition occurs through a metallic target, which will be bombarded by ions resulting from the plasma with an inert gas, such as argon. A momentum transfer resulting from this collision will lead to the ejection of atoms from the target, which will be deposited on the sample surface, forming the NPs [35]. In this regard, Garcia et al. [36] demonstrated how AgNPs synthesized by sputtering led a latex substrate which demonstrated bacteriostatic activity against Staphylococcus aureus to be employed in the production of dressings for people with a healing deficiency, such as diabetics. These authors concluded that NPs at a concentration of 2.87 μg cm−2 did not show toxicity to human cells and presented a hydrophilic character to the polymeric matrix, a factor that can prevent bacterial growth [36].
Another widely used physical method is evaporation-condensation, which takes place in a tube furnace and allows the formation of NPs of varying sizes [37]. Inside the tube, there is the source of the metal to be synthesized, which is vaporized into the carrier gas [38]. However, this technique has some disadvantages, such as high energy consumption, a large occupied space, and the time it takes to acquire thermal stabilization [39].
A more modern method uses laser ablation to produce NPs by removing them from a solid target in a medium [37]. The control of the characteristics of the NPs depends on the period of radiation, laser fluency, wavelength, the nature of the material to be synthesized, and the medium used. Since there is no use of chemical reagents, the NPs produced by this technique are considered pure and/or without contamination [38]. The disadvantage is when there is the formation of many NPs in the medium, which will prevent the laser from passing through and will absorb its energy, instead of being absorbed by the target [40].
Metal oxide NPs have also been synthesized using distinct physical methods. Gunnarsson et al. [41] obtained TiO2NPs by hollow sputtering in an argon/oxygen atmosphere using high-power pulsation. In turn, Dreesen et al. [42] synthesized TiO2NPs with a high surface coverage using magnetron reactive direct current (DC) sputtering. This same technique was also employed by Kwoka et al. [43] to obtain ZnO nanostructures using a zinc target at an 80 W DC power.

5.2. Chemical Approach

One of the chemical methods for the generation of metallic and metal oxide NPs is the reduction of metallic salts by using a stabilizing agent to prevent their aggregation. The characteristics of the NPs generated depend on the type of stabilizer and reducing agent. Some of the chemical agents used in this process are hydrazine, amino-boranes, polyols, hydrochloric acid, oleylamine, citrate, and sodium borohydride (NaBH4) [32][38]. However, this technique has some restrictions, such as the toxicity of the reducing agent, its high cost, and the presence of impurities [40]. The Turkevich protocol, introduced in 1951, is the most popular chemical method, and it uses sodium citrate as a stabilizing and reducing agent [44].
In addition to the reduction method, another chemical approach technique is chemical vapor deposition (CVD), where the target material chemically reacts with gaseous molecules, leading to their release in the form of volatile molecules. The surface morphology is well controlled, but the precursor gases can be toxic, corrosive, and explosive [40]. Additionally, this method allows a satisfactory dispersion of NPs over the substrate, on both flat and 3D samples (as nanotubes) [45].
In this perspective, Danna et al. [46] projected research in which AgNPs were added into the NRL matrix. The purpose of the research was to create a biocompatible composite. To produce this material, NRL membranes were first generated by the casting method. Afterward, the films were submerged in silver nitrate (AgNO3) at a concentration of 3.0 × 10−5 M, which was kept in a sand bath at 80 °C for varying times. The scanning electron microscopy (SEM) analysis exhibited that NPs were dispersed through the polymeric matrix, and the existence of AgNPs was effectively confirmed by plasmon absorption and elemental analysis. The cell viability assay proved that the AgNPs caused no toxicity to CHO-K1 cells that were in contact with the extracts obtained from the samples for 24 h. With the increase in the reduction time, the intensity of the peak on the UV-Vis analysis was proportional to the AgNPs concentration and also likely to increase the size of the AgNPs in the polymer matrix.
In order to develop an antibacterial material capable of support in guided bone regeneration, Marques et al. [47] combined the properties of NRL and AgNPs in a composite. To produce the NPs, a chemical reduction method was used with AgNO3 (2.0 mM) and NaBH4 (4.0 mM). The solution was stirred for 12 h and was later added to the latex, reaching the final concentration of AgNPs of 0.4%. The final solution was located in a Petri dish (casting method) at 40 °C until it reached complete polymerization. The assays were promising, showing that the AgNPs were not cytotoxic to CDLH1 lineage cells and that they aided in a faster calcification, as seen in in vivo tests with Wistar rats.
Arsalani et al. [32] synthesized magnetic Fe3O4NPs using a co-precipitation method at 90 °C. The process was described as being fast, economical, and environmentally friendly. The NPs were synthesized from ferrous chloride tetrahydrate (FeCl2·4H2O) and ferric chloride hexahydrate (FeCl3·6H2O), dissolved in aqueous solution of hydrochloric acid (5.45 M) and added, under stirring, to a solution of ammonium hydroxide previously heated to 90 °C for 10 min. Afterwards, the solution was kept in an ultrasonic bath for 1 h and then separated by magnetic precipitation, rinsed with Milli-Q water, and dried in an oven at 32 °C. Fe3O4NPs of a spherical shape with a size of 12 nm were obtained. The results demonstrated that the NRL stabilized the magnetic NPs, and these are considered useful for biomedical applications.

5.3. Biological Approach

Natural products play an important role in the formation and transformation of substances at the nanoscale. These natural processes can be used to minimize the environmental impact of other methods, so biological techniques such as green synthesis have been increasingly used for the synthesis of metallic and metal oxide NPs. In this method of synthesis, chemicals derived from living organisms are used in place of the reducing agent and stabilizer that were previously used in the chemical approach, such as fungi, bacteria, algae, and plants [37]. This method is cost-effective, can be easily reproduced on a large scale, and is eco-friendly. Furthermore, there is no use of high pressure, temperature, energy, and toxic chemicals [40].
Plant extracts can be used as reducing agents and, as they are abundant in nature, they have the lowest cost. Several parts of plants can be applied as substrates, such as leaves, fruits, seeds, and roots. Plants that have been studied in the synthesis of NPs include magnolia, plane tree, banana, and peppermint [37]. NPs that can be produced with this technology are gold, silver, copper, and zinc [40]. Green synthesis using plants is considered to be of a great advantage for antimicrobial methods as they have an extensive spectrum of biological activity because of the presence of phytocompounds. In addition, they present a great cost benefit, quick synthesis, and also good stability [7].
The main plant compounds used are phenolic acids, flavonoids, terpenoids, and alkaloids, which have the function of reducing the metallic ion and leading to the formation of metallic and metal oxide NPs. These primary and secondary metabolites are involved in redox reactions, so they are used as reducing agents. Prior to NPs synthesis, the bio-reducing agent must be purified and then placed in contact with the aqueous solution containing the precursor metal. Spontaneous reactions will take place at room temperature, producing NPs [40]. In addition to plants, fungi can be utilized to synthesize metallic and metal oxide NPs, such as Humicula sp., Cryphonectria sp., Verticillium, Aspergillus flavus, and Fusarium oxysporum [37][48]. The enzymes and proteins of these fungi are the compounds used as reducing agents.
For some authors, the “green” syntheses of NPs mean those that use organic molecules, which interact with the particles and grant them stability against agglomeration and oxidation. In this scenario, polymeric molecules have been used due to the fact that their long chains offer many binding sites that can stabilize NPs. Among these biomolecules, the natural latex of Hevea brasiliensis, a tree native to the Amazon rainforest, stands out. The research developed by Guidelli et al. [49], for example, introduced the green synthesis of colloidal AgNPs using Hevea brasiliensis latex. The technique in question was simple, cheap, and ecologically correct. The resulting composite can be applied as a wound dressing that will aid the healing process due to latex angiogenesis and the antibacterial activity of AgNPs. In this work, a solution of latex and Milli-Q™ water was prepared, and later, AgNO3 was added. The final solution was heated at 100 °C for 1 h and the results showed that there was a greater formation of AgNPs as the amount of NRL and AgNO3 increased, and that the particle size was also dependent on these concentrations. The Fourier transform infrared spectroscopy results indicate that the amine groups present in ammonia were responsible for the Ag(I) reduction, and that the poly(cis-1,4-isoprene) molecules of the NRL act as a capping agent that prevents the agglomeration of NPs. According to the research, certain latex proteins are essential for the development and passivation of NPs. In this case, the carbonyl groups from the amino acid residues and the peptides of proteins have a robust affinity for metals, thus avoiding their agglomeration.
Using a similar procedure, Bakar et al. [50] synthesized AgNPs in the NRL matrix. For this, NRL was added to deionized water and 2.94 × 10−5 mol of AgNO3. The resulting mixture contained about 0.03% (v/v) silver based on dry rubber and was placed in an oven at 50 °C to complete the polymerization process. The results suggested that the proteins present in NRL play an important role in the stabilization and growth of NPs. The interface regions between rubber particles, where protein mixing occurs, contained AgNPs in significant concentrations.
In another study, Rathnayake et al. [51] synthesized AgNPs using green synthesis, where the NPs were reduced in situ by NRL. The NPs were reduced from AgNO3 (0.1 M) added directly to centrifuged latex, being mixed for 8 h at 60 °C. Next, the reaction was brought to room temperature and stirred slowly for another 24 h. Then, the mixture was stored in a closed amber glass and the modified NRLF with AgNPs was produced, which was yellowish in color. This method produced NPs smaller than 100 nm. AgNPs were reduced by substances present in the serum fraction of the centrifuged NRL, which have not been described in the present study, but it is believed that the proteins present in the NRL are of great importance for silver reduction. Moreover, the NRLF modified with AgNPs was tested for Escherichia coli, Staphylococcus epidermidis, and Staphylococcus aureus, obstructing bacterial growth [51].
In the studies conducted by Phinyocheep et al. [52], AgNPs were synthesized from AgNO3 by incorporating it into NRL, without the use of a reducing agent. AgNO3 was added to the NRL and kept at room temperature. After that, the mixture was heated to 60 °C and stirred for 8 h. With this green method, spherical-shaped NPs of sizes between 5 and 30 nm were obtained. In this work, the authors also concluded that the existing proteins in the NRL were responsible for the reduction, in situ, of silver. AgNPs were responsible for the antibacterial effect on the compound, which was tested for Escherichia coli and Staphylococcus aureus [52].
Another study performed by Guidelli et al. [53] presented the chemical reduction of AgNPs added to NRL to release the silver present in the dressings. The NPs were synthesized from AgNO3 using NaBH4. The reaction was stirred for 12 h and then added to NRL, which was dried at 40 °C. Spherical-shaped NPs were obtained with a size of 30 nm. The results demonstrated that NRL membranes provide an effective matrix for AgNPs release, promoting angiogenesis and providing the dressing with antimicrobial characteristics [53].
In the same work previously reported by Arsalani et al. [32], Fe3O4NPs were obtained using the green method. For this, different volumes of NRL (100 to 800 μL) were added to the aqueous ammonium hydroxide solution and stirred for 3 min. Then, a mixed solution of ferrous and ferric chloride was added to the NRL solutions, and the formation of a black precipitate was observed. The size distribution and average size of Fe3O4NPs was influenced by the amount of NRL (13 ± 2.8, 10.3 ± 2.2, and 7.9 ± 1.5 nm for 100 μL, 400 μL, and 800 μL of NRL, respectively). The authors concluded that this behavior occurs with an increase in the concentration of NRL, in which more NRL molecules were bound to the surface of the NPs, preventing agglomeration and decreasing their growth [32]. Table 1 summarizes the different routes of synthesis of metallic and metal oxide NPs reported in the literature.
Table 1. Reported methodologies of the metallic and metal oxide NPs synthesis.
Nanoparticle Synthesis Method Precursor Agent Reaction Time (min) Reaction Temperature (°C) Average Size
(nm)		 Shape Observation Reference
AgNPs Chemical method AgNO3 30 to 120 80 65 to 85 - - Danna et al. [46]
AgNPs Chemical method AgNO3/NaBH4 - - 10 to 20 Sphere NPs concentration
in NRL 0.4%		 Marques et al. [47]
AgNPs Physical method AgNO3/NaBH4 20 - 4 to 10 Sphere and aggregates UV power
light 250 W		 Bakar et al. [50]
AgNPs Green synthesis AgNO3 60 100 2 to 100 Sphere and aggregates 50 to 400 μL of NRL were tested Guidelli et al. [49]
AgNPs Chemical method AgNO3/NaBH4 5 40 30 Sphere and aggregates - Guidelli et al. [53]
Fe3O4NPs Chemical method FeCl3·6 H2O
FeCl2·4 H2O		 60 90 12 Sphere - Arsalani et al. [32]
Fe3O4NPs Green synthesis FeCl3·6 H2O
FeCl2·4 H2O		 70 90 7.9 to 13 Sphere 100 to 800 μL of NRL were tested Arsalani et al. [32]

6. Mechanism of Bactericidal Activity of NPs

There is still no consensus on the exact mechanism by which metallic and metal oxide NPs exert their antibacterial and cytotoxic functions. Among the possibilities to explain this phenomenon, the first one is related to the electrostatic attraction between the negatively charged microbial cells and the positive ions released by the NPs. The NPs form a complex with electron donors, such as oxygen, nitrogen, phosphorus, or sulfur, which are in the proteins present in the cell walls [54]. The ions will then bind to the cell surface, causing damage to the bacteria walls, inactivating proteins and enzymes. When incorporated by the cell, the ions will harm the mitochondria [55], leading to the formation of unwanted ROS and the interruption of the release of adenosine triphosphate (ATP). The ROS in question are, in turn, responsible for altering the DNA, and the ions may also be responsible for the malfunctioning of protein synthesis, denaturizing ribosomal cytoplasmic components [56]. It is necessary to emphasize that the characteristics of each classification of bacteria influence the activity of NPs. Gram-positive bacteria have a dense layer of peptidoglycan on their cell wall, whereas Gram-negative bacteria have a thin layer of peptidoglycan with an outer lipopolysaccharide membrane. For this reason, Gram-positive bacteria are more resistant to the bactericidal effect arising from NPs [54].
The second possibility to explain the antibacterial effect is related to the metallic and metal oxide NPs configuration, which are able to denature cell membranes by themselves. Furthermore, due to their reduced size, NPs have an ability to permeate the cell membrane and modify its arrangement. As a result of this activity, damage to organelles and cell lysis can occur [56]. NPs may also be involved in bacterial signal transduction, which is directly affected by the phosphorylation of protein substrates. Moreover, they can dephosphorylate tyrosine residues from peptide substrates. The interruption of transduction leads to cell apoptosis and to the end of the organism’s multiplication [57]. Despite representing a promising solution to the contamination by microorganisms and biofilm formation, metallic NPs have some disadvantages, which are outlined in Table 2.
Table 2. Summary of some disadvantages of metallic NPs.
Disadvantages Consequence/Examples
Cytotoxicity There are concerns about the cytotoxic effect of metallic NPs, as the mechanism of interaction of NPs with cells is still not fully understood [58]. This may occur because there is a large variation in the parameters in relation to NPs, such as their size, shape, and surface charge [59][60]. Extended exposure to AgNPs through oral and inhalation can lead to Argyria or Argyrosis, i.e., chronic disorders of skin microvessels and eyes in humans. In vitro cell culture studies have indicated the toxic effects of AgNPs in immortal human skin keratinocytes, human erythrocytes, human neuroblastoma cells, human embryonic kidney cells, human liver cells, and human colon cells. In vivo animal studies have revealed the toxic effects of AgNPs in rodents by accumulating in their liver, spleen, and lung [1].
Interactions for different cell lineages Different cell lineages exhibit distinct cytotoxic responses. Vero cells (African green monkey renal epithelial cells), for example, have been shown to be more susceptible to chitosan/pectin/AuNPs hydrogel than LLCMK2 cells (Macaca mulatta renal epithelial cells) [61]. We can also mention the case of the hydrogel dressing containing AgNPs, which exhibited a different level of toxicity in relation to immortal keratinocytes and primary keratinocytes [62]. Therefore, there is a certain challenge when choosing a cell line that is more suitable for biocompatibility testing in the study of a material containing NPs [59].
Migration of NPs to undesirable sites NPs cannot only be directly absorbed by the cells of exposed organs, but they can also be translocated to other organs, causing unwanted toxicity or other adverse effects [63]. The NPs leaching depends on the hydrodynamic conditions at the implantation site [64]. The material safety assessment should be extensively conducted in adjacent tissues and organs, and not limited to the site where the artifact will be implanted [59].
Resistance to NPs by bacteria Bacteria such as Bacillus subtilis have the ability to adapt to cellular oxidative stress produced by Ag(I) [65]. Bacteria can develop a resistance to AgNPs after a repeated exposure, and resistance evolves without any genetic change. Only phenotypic change is needed to reduce the stability of NPs and thus eliminate the antibacterial activity of AgNPs [66][67].
Nanoparticle aggregation process NPs tend to aggregate or flocculate and are not stable in aqueous solutions [68]. Aggregation affects the stability of NPs and limits their use as drug carriers. Particle collisions due to Brownian motion leads to aggregation and precipitation. Therefore, it is vital to obtain NPs that are well dispersed and stable in the solution phase (mainly in phosphate-buffered saline). A possible solution is to increase the repulsion between NPs, which increases their colloidal dispersion. However, in the case of NPs used in biomedical therapies, chemical stability in the biological environment is hard to obtain. For example, acidic conditions found in cancer cells can cause the aggregation of many NPs [69].
Pollution of riverbeds The extensive application and production of AgNPs can increase their release in aquatic environments such as rivers and lakes. For example, AgNPs can be released from antimicrobial fabrics into water during washing, thereby polluting groundwater. Once AgNPs enter the freshwater environment, they generally oxidize to Ag(I) ions that are toxic to aquatic organisms. Furthermore, ionic silver can stabilize into sparingly soluble salts. By accumulating in aquatic organisms, AgNPs can enter the human body through the food chain [1].

This entry is adapted from the peer-reviewed paper 10.3390/compounds3020023

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