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Silver nanoparticles are nanoparticles of silver of between 1 nm and 100 nm in size. While frequently described as being 'silver' some are composed of a large percentage of silver oxide due to their large ratio of surface-to-bulk silver atoms. Numerous shapes of nanoparticles can be constructed depending on the application at hand. Commonly used are spherical silver nanoparticles but diamond, octagonal and thin sheets are also popular.
Silver nanoparticles may eventually offer treatment of various diseases. Their extremely large surface area permits the coordination of a vast number of ligands. The properties of silver nanoparticles applicable to human treatments are under investigation in laboratory and animal studies, assessing potential efficacy, toxicity, and costs.
Ion implantation has been used to create silver nanoparticles embedded in glass, polyurethane, silicone, polyethylene, and polymethylmethacrylate.The particles grow in the substrate with the bombardment of ions. The existence of nanoparticles is proven with optical absorbance, though the exact nature of the particles created with this method is not known.
Wet chemical methods for creating silver nanoparticles typicall involve the reduction of a silver salt such as silver nitrate with a reducing agent like sodium borohydride in the presence of colloidal stabilizer. Sodium borohydride has been used with polyvinyl alcohol, poly(vinylpyrrolidone), bovine serum albumin (BSA), citrate and cellulose as stabilizing agents. In the case of BSA, the sulfur-, oxygen- and nitrogen-bearing groups mitigate the high surface energy of the nanoparticles during the reduction. The hydroxyl groups on the cellulose are reported to help stabilize the particles. Polydopamine-coated magnetic-bacterial cellulose contains multifunctional groups, which acts as a reducing agent for in situ preparation of reusable antibacterial Ag-nanocomposites. Citrate and cellulose have been used to create silver nanoparticles independent of a reducing agent as well. An additional novel wet chemistry method used to create silver nanoparticles took advantage of D-glucose as a reducing sugar and a starch as the stabilizer and also cellulose molecular chain is applied to employ the reducing and stabilizing features of cellulose to synthesize nano silver. A one-pot synthesis of crystalline silver nanoparticles was recently reported.
Coating with silica
In this method, polyvinylpyrrolidone (PVP) is dissolved in water by sonication and mixed with silver colloid particles. Active stirring ensures the PVP has adsorbed to the nanoparticle surface. Centrifuging separates the PVP coated nanoparticles which are then transferred to a solution of ethanol to be centrifuged further and placed in a solution of ammonia, ethanol and Si(OEt4) (TES). Stirring for twelve hours results in the silica shell being formed consisting of a surrounding layer of silicon oxide with an ether linkage available to add functionality. Varying the amount of TES allows for different thicknesses of shells formed. This technique is popular due to the ability to add a variety of functionality to the exposed silica surface.
The biological synthesis of nanoparticles has provided a means for improved techniques and methods in the medicinal field. Biogenic methods can be used to make nanoparticles of different chemical compositions, sizes, and shapes without the use of toxic ingredients as used currently in synthetic protocols. In addition, precise control over shape and size is vital during nanoparticle synthesis since the NPs therapeutic properties are intimately dependent on such factors. Hence, the primary focus of research in biogenic synthesis is in developing methods that consistently reproduce NPs with precise properties.
Interestingly, an alternate method of synthesizing silver nanoparticles comes from the extracts of plant material, commonly referred to as “green synthesis”. Extracts from flowers such as germanium and many pepper species have been used as the initial reducing agent of Ag+ in the first step of nanoparticle synthesis. The extract can be mixed with silver nitrite and treated with distilled water, acetone and ethanol to crystallize the colloid suspension. The resultant silver nanoparticles are synthesized without the use of harmful reagents such as sodium borohydride and sodium citrate.
Bacterial and fungal synthesis of nanoparticles is practical because bacteria and fungi are easy to handle and can be modified genetically with ease. This provides a means to develop biomolecules that can synthesize AgNPs of varying shapes and sizes in high yield, which is at the forefront of current challenges in nanoparticle synthesis. Fungal strains such as Verticillium and bacterial strains such as K. pneumoniae can be used in the synthesis of silver nanoparticles. When the fungus/bacteria is added to solution, protein biomass is released into the solution. Electron donating residues such as tryptophan and tyrosine reduce silver ions in solution contributed by silver nitrate. This again causes colloid crystallization and thus the formation of nanoparticles similar to the previous methods.
Silver nanoparticles have long been known for their antibacterial, antifungal, anti-viral and anti-inflammatory properties.[medical citation needed] Recently, researchers have extend their use into chemotherapy as a device for delivering various payloads such as small drug molecules or large biomolecules to specific targets. Once the AgNP has had sufficient time to reach its target, release of the payload could be triggered by internal or external stimulus. The targeting and accumulation of nanoparticles to a designated area ensures high drug concentration at specific sites and thus minimizes side effects.
The introduction of nanotechnology into medicine is expected to advance diagnostic cancer imaging and the standards for therapeutic drug design. Nanotechnology may uncover insight about the structure, function and organizational level of the biosystem at the nanoscale.
Silver nanoparticles can undergo coating techniques that offer a uniform functionalized surface to which substrates can be added. When the nanoparticle is coated, for example, in silica the surface exists as silicic acid. Substrates can thus be added through stable ether and ester linkages that are not degraded immediately by natural metabolic enzymes. Recent chemotherapeutic applications have designed anti cancer drugs with a photo cleavable linker, such as an ortho-nitrobenzyl bridge, attaching it to the substrate on the nanoparticle surface. The low toxicity nanoparticle complex can remain viable under metabolic attack for the time necessary to be distributed throughout the bodies systems. If a cancerous tumor is being targeted for treatment, ultraviolet light can be introduced over the tumor region. The electromagnetic energy of the light causes the photo responsive linker to break between the drug and the nanoparticle substrate. The drug is now cleaved and released in an unaltered active form to act on the cancerous tumor cells. Advantages anticipated for this method is that the drug is transported without highly toxic compounds, the drug is released without harmful radiation or relying on a specific chemical reaction to occur and the drug can be selectively released at a target tissue.
A second approach is to attach a chemotherapeutic drug directly to the functionalized surface of the silver nanoparticle combined with a nucelophilic species to undergo a displacement reaction. For example once the nanoparticle drug complex enters or is in the vicinity of the target tissue or cells, a glutathione monoester can be administered to the site. The nucleophilic ester oxygen will attach to the functionalized surface of the nanoparticle through a new ester linkage while the drug is released to its surroundings. The drug is now active and can exert its biological function on the cells immediate to its surroundings limiting non-desirable interactions with other tissues.
Multiple drug resistance
Nanoparticles can provide a means to overcome MDR. In general, when using a targeting agent to deliver nanocarriers to cancer cells, it is imperative that the agent binds with high selectivity to molecules that are uniquely expressed on the cell surface. Hence NPs can be designed with proteins that specifically detect drug resistant cells with overexpressed transporter proteins on their surface. A pitfall of the commonly used nano-drug delivery systems is that free drugs that are released from the nanocarriers into the cytosol get exposed to the MDR transporters once again, and are exported. To solve this, 8 nm nano crystalline silver particles were modified by the addition of trans-activating transcriptional activator (TAT), derived from the HIV-1 virus, which acts as a cell penetrating peptide (CPP). Generally, AgNP effectiveness is limited due to the lack of efficient cellular uptake; however, CPP-modification has become one of the most efficient methods for improving intracellular delivery of nanoparticles. Once ingested, the export of the AgNP is prevented based on a size exclusion. The concept is simple: the nanoparticles are too large to be effluxed by the MDR transporters, because the efflux function is strictly subjected to the size of its substrates, which is generally limited to a range of 300-2000 Da. Thereby the nanoparticulates remain insusceptible to the efflux, providing a means to accumulate in high concentrations.
Introduction of silver into bacterial cells induces a high degree of structural and morphological changes, which can lead to cell death. As the silver nano particles come in contact with the bacteria, they adhere to the cell wall and cell membrane. Once bound, some of the silver passes through to the inside, and interacts with phosphate-containing compounds like DNA and RNA, while another portion adheres to the sulphur-containing proteins on the membrane. The silver-sulphur interactions at the membrane cause the cell wall to undergo structural changes, like the formation of pits and pores. Through these pores, cellular components are released into the extracellular fluid, simply due to the osmotic difference. Within the cell, the integration of silver creates a low molecular weight region where the DNA then condenses. Having DNA in a condensed state inhibits the cell’s replication proteins contact with the DNA. Thus the introduction of silver nanoparticles inhibits replication and is sufficient to cause the death of the cell. Further increasing their effect, when silver comes in contact with fluids, it tends to ionize which increases the nanoparticles bactericidal activity. This has been correlated to the suppression of enzymes and inhibited expression of proteins that relate to the cell’s ability to produce ATP.
Although it varies for every type of cell proposed, as their cell membrane composition varies greatly, It has been seen that in general, silver nano particles with an average size of 10 nm or less show electronic effects that greatly increase their bactericidal activity. This could also be partly due to the fact that as particle size decreases, reactivity increases due to the surface area to volume ratio increasing.
It has been noted that the introduction of silver nano particles has shown to have synergistic activity with common antibiotics already used today, such as; penicillin G, ampicillin, erythromycin, clindamycin, and vancomycin against E. coli and S. aureus. In medical equipment, it has been shown that silver nano particles drastically lower the bacterial count on devices used. However, the problem arises when the procedure is over and a new one must be done. In the process of washing the instruments a large portion of the silver anno particles become less effective due to the loss of silver ions. They are more commonly used in skin grafts for burn victims as the silver nano particles embedded with the graft provide better antimicrobial activity and result in significantly less scarring of the victim. They also show promising application as water treatment method form clean potable water.
During a storage period of several days at room temperature coated silver nanoparticles can undergo dissolution releasing toxic free silver ions.  Cultured human mesenchymal stem cells showed 70% decreased viability on being exposed to silver nanoparticles aged for three days; complete cell death was observed with a one-month storage period. Freshly prepared silver nanoparticles were used as a control for each trial. The toxicity of silver ions arises from unfavorable binding interactions with DNA/ nucleic acids, mitochondrion, cell wall components and nucleophilic enzyme active site residues. The binding of silver ions to electron rich DNA species can cause double strand breaks. This renders the DNA unable to repair the strands leading to chromosome abnormalities. Dysfunctional cell cycles for replication and division are also exhibited as a result of DNA damage.
The electron transport chain and ATP synthesis takes place within the mitochondrion of the cell. Silver ions can act to block the transport chain or transfer electrons to gaseous oxygen molecules to form toxic superoxides and free radicals. If the electron transport chain is inhibited, the production of ATP is also inhibited. ATP is involved in the mechanisms that repair DNA damage as well as cell cycle checkpoints. Whether DNA is damaged from silver ions or through random mutations, inhibiting ATP synthesis renders the cell unable to repair or replicate its DNA.
Protein channels and nuclear membrane pores can often be in the size range of 9 nm to 10 nm in diameter. Small silver nanoparticles constructed of this size have the ability to not only pass through the membrane to interact with internal structures but also to be become lodged within the membrane. Silver nanoparticle depositions in the membrane can impact regulation of solutes, exchange of proteins and cell recognition. In the cell cytosol, an array of enzymes can be the potential target for free silver ions. Silver ions act as lewis acids, accepting electrons from nucleophilic active sites of enzymes. Coordination from a silver ion or multiple silver ions in the enzyme active can hinder the ability for the enzyme to accept its natural substrate and catalyze important biochemical reactions. Exposure to silver nanoparticles has been associated with "inflammatory, oxidative, genotoxic, and cytotoxic consequences"; the silver particulates primarily accumulate in the liver. but have also been shown to be toxic in other organs including the brain. Nano-silver applied to tissue-cultured human cells leads to the formation of free radicals, raising concerns of potential health risks.
- Allergic reaction: While there is anecdotal evidence suggesting the possibility of a silver allergy, an extensive review of the medical literature does not lend any credence to this possibility. Some silver alloys that include nickel do elicit an allergic reaction.
- Argyria and staining: Ingested silver or silver compounds, including colloidal silver, can cause a condition called argyria, a discoloration of the skin and organs.In 2006, there was a case study of a 17-year-old man, who sustained burns to 30% of his body, and experienced a temporary bluish-grey hue after several days of treatment with Acticoat, a brand of wound dressing containing silver nanoparticles. Argyria is the deposition of silver in deep tissues, a condition that cannot happen on a temporary basis, raising the question of whether the cause of the man’s discoloration was argyria or even a result of the silver treatment. Silver dressings are known to cause a “transient discoloration” that dissipates in 2–14 days, but not a permanent discoloration.
- Silzone heart valve: St. Jude Medical released a mechanical heart valve with a silver coated sewing cuff (coated using ion beam-assisted deposition) in 1997. The valve was designed to reduce the instances of endocarditis. The valve was approved for sale in Canada, Europe, the United States, and most other markets around the world. In a post-commercialization study, researchers showed that the valve prevented tissue ingrowth, created paravalvular leakage, valve loosening, and in the worst cases explantation. After 3 years on the market and 36,000 implants, St. Jude discontinued and voluntarily recalled the valve.
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