- Synthesis of silver nanoparticles
- Polyol method
- Different shapes of AgNPs
- Therapeutic applications
- Conclusions and further perspectives
In the past years, nanoparticles (NPs), mainly those of noble metals, like silver (Ag) or gold (Au) have been the focus of research due to their definite properties:
- physical ones.
Due to these properties, they can be used in a large area of applications: biomedicine, health care, food industry, textiles etc. .
Among the noble metals, excellent biocompatibility and antibacterial properties have made silver a considerable interest as nanoparticles for biomedical applications. Extensive research has gone into synthesizing and characterizing silver nanoparticles because the size, shape and composition of AgNPs can have significant effect on their efficacy .
Research on silver nanoparticles has clearly demonstrated that the shape, size, and size distribution, which can be varied by using different methods, reducing agents, and stabilizers, influence their optical, electromagnetic, and catalytic properties. New approaches in sensing and imaging applications have been possible due to the valuable optical properties of AgNPs, leading to surface-enhanced Raman scattering techniques, at extremely low detection limits .
In the environment and in living organism, silver has several forms like metallic, ionic, complexes, and colloidal. Small size and large surface to volume ratios are characteristic to silver nanoparticles. In comparison with their bulk counterparts, these characteristics can lead to both chemical and physical differences in their properties. These differences include mechanical, and biological properties, catalytic activity, thermal and electrical conductivity, optical absorption, and melting point .
Extensive investigations have been made on AgNPs and their associated nanostructures because of their great potential applications in plasmonic, antibacterial materials, sensing, and spectroscopy. For example, silver nanoparticles have been used as antibacterial agents in burn and wound therapy. Surface plasmon resonance (SPR) effect and strong bacterial resistance to antibiotics are exhibited by AgNPs, making them ideal for biotechnological applications .
Examples of several applications in which silver nanoparticles are used:
- antibacterial agents
- medical device coatings
- wound healing dressings
- drug delivery
- anticancer agents
- optical sensors
- health care product
- cosmetics and pharmaceutical industry
- food industry
- textiles .
Their large area of applications is due to their unique physical and chemical properties such as optical, catalytic, electrical, and thermal, high electrical conductivity .
Due to their broad-spectrum antimicrobial activities, silver nanoparticles have become the most commercialized engineered nanomaterials. AgNPs can enhance the healing of wounds. Also, they have anti-fungi, anti-virus, anti-biofilm, anti-inflammation, and anti-thrombosis effect. Silver nanoparticles have been explored as nanoprobes for the detection and imaging of tumors, vectors for drug delivery, as well as inhibitors to suppress angiogenesis and tumor growth. Furthermore, several studies have reported that AgNPs induced the cytotoxic effect against leukemic cells, such as THP-1, Jurkat and K562 cells, mainly through elevating reactive oxygen species (ROS). These particles could also display a synergistic effect against leukemic cells with chemotherapeutic drugs, such as cyclophosphamide .
2. Synthesis of silver nanoparticles
There are various methods of synthesis for silver nanoparticles. Normally three different approaches are used to obtain silver nanoparticles: physical, chemical, and biological methods .
Conventional physical methods include evaporation-condensation, spark discharging, pyrolysis, laser ablation, which have the advantages that they do not use toxic chemicals, they have speed and the use radiation as reducing agents. Their disadvantages are low yield and high energy consumption, solvent contamination, and lack of uniform distribution .
Chemical methods use water or organic solvents to prepare the silver nanoparticles and this process usually employs three main components: metal precursors, reducing agents, and stabilizing/capping agents. The major advantages of chemical methods are high yield, contrary to physical methods, which have low yield, ease of production, and low cost. The surfaces of the manufactured particles are sedimented with chemicals, so they are not of expected purity and is very difficult to prepare AgNPs with a well-defined size .
Biological methods have emerged as viable options, to overcome the shortcomings of chemical and physical methods. Studies of biological synthesis of silver nanoparticles have shown that this method is simple, cost effective, dependable, and environmentally friendly. Bacteria, fungi, plant extracts, and small biomolecules like vitamins and amino acids represent distinct systems from which AgNPs, of defined size, can be obtained .
2.1 Polyol method
The primary reaction of this process involves the reduction of an inorganic salt (the precursor) by the high temperature polyol method. PVP (poly-vinylpyrrolidone) is added as a stabilizer to prevent agglomeration of colloidal particles. The reasons for the popularity and versatility of this method are: the ability to dissolve many precursor salts (and ions), the reducing power which depends on a high temperature, the boiling points which are relatively high. This high temperature on which the polyol reduction power depends, makes this method ideal for the synthesis of colloidal particles in a variety of different shapes and sizes .
The polyol method for obtaining silver nanoparticles uses ethylene glycol (EG), which is a good solvent for both AgNO3 and PVP. At high temperatures, ethylene glycol can reduce Ag+ ions into Ag atoms, and thus induce nucleation and growth of silver nanostructures in the solution phase .
Obtaining silver nanoparticles using the polyol method implies: ethylene glycol (EG) was heated at 160° C for one hour, solutions of AgNO3 and PVP dissolved in EG were injected simultaneously into the EG solution. The solution gradually became yellow as AgNO3 and PVP were added, indicating the formation of silver nanoparticles .
Changing the molar ratio of PVP:AgNO3, AgNO3 concentration or growth time can lead to the formation of silver nanoparticles in distinct shapes. Thus, silver nanoparticles can be obtained in the form of:
- triangular nanoplates .
2.1.1 Different shapes of AgNPs
Figure 2.1 TEM and SEM images of silver nanocubes 
Figure 2.2 TEM and SEM images of silver nanowires 
Figure 2.3 TEM image of silver nanospheres 
Figure 2.4 TEM image of silver triangular nanoplates 
Silver nanoparticles have attracted an increased interest due to unusual optical, electronic and chemical properties that depend on their size, shape, composition, crystallinity and structure. AgNPs have been extensively exploited for use as microelectronic, antibacterial, anti-inflammatory, anti-tumor, catalytic and sensor materials due to these unique properties .
Silver nanoparticles represent a new class of materials with remarkably different physicochemical characteristics, such as increased optical, electromagnetic and catalytic properties, the ability to generate reactive oxygen species (ROS). The surface of silver nanoparticles is also chemically reactive, allowing for easy functionalization with different biological stabilizing agents, biomolecules and chemotherapeutic agents , .
Silver in the form of nanoparticles may be more reactive due to its high catalytic properties and could become more toxic than its bulk counterpart. Furthermore, toxicity is assumed to be size and shape dependent, because small-sized nanoparticles can pass through cell membranes, and the accumulation of intracellular nanoparticles may lead to cellular dysfunctions .
Silver nanoparticles are among the most studied subjects today because of their special properties. Out of all of them, their antibacterial activity seems to attract the greatest interest .
The antimicrobial effects of silver can be increased by manipulating nano-scale dimensions. Due to changes in physicochemical properties, silver nanoparticles have appeared as antimicrobial agents. Silver nanoparticles measuring between 10-100 nm present a strong bactericidal potential against Gram-positive and Gram-negative bacteria .
The antibacterial activity of silver nanoparticles against multidrug-resistant (MDRs) and drug susceptible pathogens, has been studied for a long time and AgNPs have been shown to be powerful weapons against MDRs, such as: Pseudomonas aeruginosa, Escherichia coli (ampicillin-resistant), Streptococcus pyogenes (erythromycin-resistant), Staphylococcus aureus (methicillin-resistant and vancomycin-resistant) (Figure 3.1) .
Figure 3.1 Antibacterial activity of silver nanoparticles against various microorganisms 
Silver nanoparticles have the ability to attach to the bacterial cell wall and then penetrate it, causing structural changes in the cell membrane: it affects the permeability of the cell membrane and leads to cell death. Dips/holes are formed on the surface of the cell and there the nanoparticles will accumulate. The formation of free radicals by silver nanoparticles can be considered another mechanism that leads to cell death. There are studies suggesting that these free radicals are formed when silver nanoparticles encounter bacteria. The free radicals obtained can destroy the cell membrane, making it porous, which ultimately leads to cell death .
The physicochemical properties of silver nanoparticles can enhance the bioavailability of therapeutic agents after both systemic and local administration. The cellular uptake, biological distribution, penetration into biological barriers, and resultant therapeutic effects can also be affected. Therefore, the development of silver nanoparticles with controlled structures that are uniform in size, morphology (nanocubes, nanowires, nanospheres, triangular nanoplates), and functionality are essential for various biomedical applications .
The morphology, or overall shape of silver nanoparticles, can play a central role in their general physical, chemical, and biological characteristics. In these nanomaterials, the morphological effects in phenomena such as optical, electronic, magnetic, and catalytic behavior have been widely studied. Different shapes of silver nanoparticles have attracted special interest in optics, surface-enhanced Raman spectroscopy, and biological labeling and diagnosis applications .
Figure 3.2 Properties of silver nanoparticles 
4. Therapeutic applications
Due to their unique properties, silver nanoparticles can be used in a large area of applications such as: biosensing, drug delivery, nanodevice fabrication, cancer therapy, wound healing dressings, medical imaging, dental instruments, diagnostic applications, improved Raman spectroscopy, optics, biosensor materials, electronic components, optics, food industry (Figure 4.1) , , .
Figure 4.1 Silver nanoparticles applications , , 
Although all of these are important applications of silver nanoparticles, they are particularly desirable in the medical field. The antimicrobial nature of silver nanoparticles is the most exploited in the medical field, but anti-inflammatory is also considered very useful. Silver nanoparticles are used in bone cements, which are used as artificial replacements for joints. Polymethylmethacrylate loaded with silver nanoparticles can be used because AgNPs induce antimicrobial activity. High molecular weight polyethylene has been the preferred choice for making inserts for the total replacement parts of the joints, but is susceptible to tearing and wear, which is a major disadvantage. In order to overcome this, silver nanoparticles were added, and their presence drastically reduced polymer breakage .
The methods currently used to prevent surgical infections include antibiotics and antiseptics. Surgical nets are used to bind large wounds and repair tissues. Although they are effective, they are susceptible to microbial infections. A silver nanoparticle coated polypropylene mesh is considered to have good antimicrobial activity and can be considered an ideal candidate for surgical nets .
Due to the antimicrobial, anti-inflammatory, antifungal properties of AgNPs, it is also believed that most medical treatments such as intravenous catheters, endotracheal tubes, wound dressings, bone cements, and dental fillings can be used to prevent microbial infections .
Also, silver nanoparticles have the ability to be used in biosensing. The plasmonic properties of AgNPs are dictated, depending on the dielectric shape, size, and environment surrounding them. Biosensors containing AgNPs can effectively detect a large number of proteins that normal biosensors find difficult to detect. This unique advantage of these nanoparticles can be used to detect various anomalies and diseases in the human body, including cancer .
Cancer is a complex disease which has the characteristic feature of the uncontrolled growth and spread of abnormal cells. Cancer can be caused by several factors, including a combination of several factors, such as: internal, external, genetic, and environmental factors. This disease is treated by various treatments including:
- hormone therapy
- immune therapy
- targeted therapy.
Effective, cost-effective, and sensitive lead molecules that have cell-targeted specificity and increase the sensitivity, are the ones that are being researched. Recently, AgNPs have been shown much interest because of their therapeutic applications in cancer as anticancer agents, in diagnostics, and in probing .
The application of AgNPs in cancer is divided into diagnostic and therapeutic purposes. Silver nanoparticles are used in therapy as nanocarriers for targeted delivery, chemotherapeutic agents, and as enhancers for radiation and photodynamic therapy .
The anticancer property of AgNPs was studied in normal human lung fibroblast cells (IMR-90) and human glioblastoma cells (U251). Increased production of reactive oxygen species (ROS), which ended with DNA damage, alterations in the metabolic activity and increased oxidative stress are induced by silver nanoparticles. U251 cells showed more sensitivity than IMR-90. The same group also demonstrated that the cellular uptake of AgNPs occurred mainly through endocytosis .
The morphology analysis of cancer cells suggests that biologically synthesized AgNPs could induce cell death very significantly .
Silver nanoparticles has been intensively used in several applications, including diagnosis and treatment of cancer and as drug carriers .
Silver nanoparticles are used in active implantable medical devices, along with vanadium oxide in battery cell components to improve the battery performance. Recently, silver nanoparticles have been used to develop silver-based biosensors for the clinical detection of serum p53 in head and neck squamous cell carcinoma. In addition, it has been used to find the location of cancer cells and can absorb light and selectively destroy targeted cancer cells through photothermal therapy .
Wound healing dressings play a major role in wound management, especially for burn injuries. Lately, the development of resistant pathogens has become a major problem. Designing new dressings has provided breakthrough for the treatment of infections and injuries. The antibacterial properties and toxicity of silver nanoparticles against microorganisms are well known and are therefore used in various types of formulations, such as surface coating agents, wound dressings, etc. Wound dressings containing silver nanoparticles use delivery systems that release silver in various concentrations. Various factors, such as the distribution of silver in the dressing, its chemical and physical form, the affinity of dressing to moisture also influence the destruction of microorganisms .
Hydrogels have become very popular due to their unique properties, such as high-water content (80-90%), flexibility and biocompatibility. Natural and synthetic hydrophilic polymers can be physically or chemically crosslinked to produce hydrogels. Their resemblance to living tissue offers opportunities for a wide range of biomedical applications. Currently, hydrogels are used for the manufacture of contact lenses, hygiene products, tissue engineering scaffolds, controlled drug delivery systems and wound dressings. There are a number of both natural: collagen, chitosan, alginate and synthetic polymers: polyvinyl alcohol (PVA), polylactic acid (PLA) which can serve as biomedical hydrogels , .
Studies have shown that silver nanoparticles in various shapes such as nanocubes, nanowires, nanospheres, and triangular nanoplates, can have a different antibacterial activity. Silver triangular nanoplates and nanospheres are the ones that presented the best antimicrobial activity against several microorganisms like Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus. This indicates that the antimicrobial activity of AgNPs depends on their morphology .
5. Conclusions and further perspectives
Shape-controlled synthesis of silver nanoparticles has the potential to provide an unprecedented level of control over both nanoscale and bulk material properties, for example the antimicrobial activity of AgNPs is based on their morphology .
The high efficiency of AgNPs has been proved to be important mainly because of their antimicrobial properties. Various studies have further investigated the mechanistic aspects of antimicrobial, antiviral, and anti-inflammatory effects of these NPs. Research into the science and engineering of such NPs has to combine all of these attributes into practical systems. A major effort toward successful AgNPs-based therapeutics will be to avoid immunosuppressive reactions or side effects once administered into the body .
The possibility of using AgNPs as a next-generation anticancer therapeutic agent, has been the focus of research, due to the conventional side effects of chemo- and radiation therapy. To obtain good result, several factors need to be considered:
- the synthesis method
- controlled release
- cell-specific targeting
- toxicological issues to human beings.
Using AgNPs in cancer treatment and other angiogenesis-related diseases, can lead to the improvement of poor delivery and the problem of drug resistance .
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