green synthesis of silver nanoparticles: an approach to overcome toxicity
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e n v i r o n m e n t a l t o x i c o l o g y a n d p h a r m a c o l o g y 3 6 ( 2 0 1 3 ) 807–812
Available online at www.sciencedirect.com
jo ur nal homepage: www.elsev ier .com/ locate /e tap
ini-review
reen synthesis of silver nanoparticles:n approach to overcome toxicity
idhija Roy, Archana Gaur, Aditi Jain,usinjan Bhattacharya, Vibha Rani ∗
epartment of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida 201307, Uttarradesh, India
r t i c l e i n f o
rticle history:
eceived 18 December 2012
eceived in revised form 4 July 2013
ccepted 11 July 2013
vailable online 20 July 2013
eywords:
a b s t r a c t
Nanotechnology, with its advent, has made deep inroads into therapeutics. It has revo-
lutionized conventional approaches in drug designing and delivery systems by creating
a large array of nanoparticles that can pass even through relatively impermeable mem-
branes such as blood brain barrier. Like the two sides of a coin, nanotechnology too has
its own share of disadvantages which in this scenario is the toxicology of these nanoparti-
cles. Numerous studies have discussed the toxicity of various nanoparticles and the recent
advancements done in the field of nanotechnology is to make it less toxic. “Green synthesis”
anotechnology
oxicology
reen synthesis
anoparticle toxicity
ilver nanoparticles
of nanoparticles is one such approach. The review summarizes the toxicity associated with
the nanoparticles and the advancement of “green” nanomaterials to resolve the toxicity
issues.
© 2013 Elsevier B.V. All rights reserved.
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ontents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Toxicology of nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3. Green synthesis of silver nanoparticles . . . . . . . . . . . . . . . . . .
4. Biotemplates used for the green synthesis of silver nan5. Applications of green synthesized silver nanoparticles.
6. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
∗ Corresponding author. Tel.: +91 120 2594210; fax: +91 120 2400986.E-mail address: [email protected] (V. Rani).
382-6689/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.etap.2013.07.005
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808 e n v i r o n m e n t a l t o x i c o l o g y a n1. Introduction
The revolutionary field of nanotechnology has become a majorthrust in scientific research. Nanotechnology has adapteditself to various field of science and technology includingphysics, chemistry, etc. It is expanding and continues tochange the way we perceive and execute things and has apronounced effect on therapeutics and shaping the ever evolv-ing society and influencing our daily lives (Chakraborty et al.,2011).
Nanomedicine has become a leading research field. Scien-tists are involved in synthesizing safe, effective, and most of allcheaper and less toxic drugs to combat diseases like cancer,epilepsy, etc. These nanoparticles have a site specific actiondue to which only a safe and a prescribed dosage of drugmolecules need to be administered and thus helps in reduc-ing the undesired toxicity. These nanoparticles due to theirtargeted action increase the efficacy of the drug. Their smallsize gives them an edge while evading the immune responsesand also gives them the ability to cross relatively impermeablemembranes (Uchegbu and Schatzlein, 2010).
2. Toxicology of nanoparticles
The flip side of the nanoparticles is its toxicity. The nanopar-ticles of various origins react differently in administeredenvironments (Kurek et al., 2011). Society of Toxicology definestoxicology as “the study of the adverse effects of chemical,physical, and biological agents on people, animals and theenvironment”.
Toxicity studies generally involve experiments where num-ber of cells and organs are subjected to varied doses ofchemicals and their response are taken into account over aperiod of time. These dose related responses are importantbecause they help in determining the appropriate amountof drug that is to be administered, lethal dose (LD50) andmedian toxicity (MD50) and the limit of its exposure to pre-vent any side effects. In traditional toxicological studies viacytotoxic assays, the focus is mainly on soluble chemicalsthat upon administration exhibit cellular toxicity, whereasin nanoparticles, it is based on the specific sizes, shapesand their density. This causes nanoparticles to aggregate andagglomerate at specific sites in the target cells or organs bydiffusing through the membranes leading to a colorimetricresult. Hence traditional in vitro assays on nanoparticles leadto misrepresentation of cellular uptake data and the resultsobtained make them less dependable. The structurally vary-ing nanoparticles are considered important in toxicologicalstudies because of their unique properties, for example, thecarbon nanotubes are known for their unusual mechanicaland electrical properties. These nanoparticles are consideredpotentially toxic due to their resemblance to asbestos andcarcinogenic fibers; they are also graphitic and are thereforeexpected to be biologically persistent in the body. Their fibrous
structure makes them toxic even in the occupational envi-ronment (Nature Nanotech Editorial, 2011). Then there arethe magnetic nanoparticles, which are widely used for track-ing and tagging of cells in vivo. And also have recently beena r m a c o l o g y 3 6 ( 2 0 1 3 ) 807–812
considered of a therapeutic value in regenerative medicinein the form of SPIONs (superparamagnetic iron oxide) whichare coated with dextran to make them biocompatible (Solankiet al., 2008). But, these become toxic if overdosed as they havethe ability to aggregate due to their shape and size (Markideset al., 2012).
The in vitro testing methods have revealed the gen-eral and biological properties of known materials as theyacquire nanoscale structure and result in the formation ofnanoparticles, thereby leading to tremendous applicationsin therapeutics. Nanoparticles can cross membrane barriersthrough transcytosis, which facilitates the drug to be function-alized onto these nanoparticles using hydrophilic surfactantslike Tween-80 for the targeted action (Sun et al., 2004). Thesestudies have also shown that exposure of nanoparticles oncells results in DNA damage, causing cancer and develop-mental toxicity which further leads to growth retardation,malformation or death in embryos. It is also shown to haveprovoking oxidative stress and inflammatory responses asthey travel along the dendrites and the axons (Durnev, 2007).Toxicology studies showed deleterious effects on people whocame in contact with nanoparticles as a result of their occu-pation, mainly by ultrafine particle inhalation, which is dueto its large surface area and its reactivity or intrinsic toxicity(Poma and Di Giorgio, 2008). Numerous in vivo experimentson intravascular or intracavitary drug delivery systems, tumorchemotherapy or antiangiogenic therapy were carried outusing nanoparticles with magnetic properties. Experimentsconducted on mice have shown nanoparticle aggregates inthe brain tissues but no disturbance or apparent toxicity hasbeen observed (Kim et al., 2009). A problem would arise ifthe magnetic nanoparticle aggregates start corroding after aperiod of time, which would lead to toxicity in neural tis-sues causing them to degenerate or cause hemorrhages ortumors. Coating with biocompatible and less toxic copoly-mers like polyethyleneoxide triblock copolymers of 15 kDacan prevent the aggregation of these magnetic nanoparticles(Hafeli et al., 2009).
Some of the reasons for toxicity are the surface chemistryof nanoparticles and the gap junctions present in the cells thatallow transmission of ions and molecules into the cell. Theoxidative stress is the result of the free radicals generated fromthe reactive surface of nanoparticles and the DNA damage byATP transmission through the gap junctions (Vijayaraghavanet al., 2010). A therapeutic profiling of the nanoparticles isdone to measure their toxicity. One such theoretical avenue isthe Pre-clinical Safety Assessment (PSA) system that has notbeen explored practically yet. The existing PSA runs a seriesof in vivo tests on the administered nanoparticles to deter-mine the toxicity of their chemical properties. Every individualhas a different genetic makeup that causes the bioavailabilityand the kinetics of the drugs to vary from person to person,thereby causing varied impact on the toxicity of the admin-istered nanoparticles (Oberdorster et al., 2005). The defects inthe existing PSA system are seen in the documented studies ofcytogenetic effects of the chrysolite asbestos fibers and zeoliteparticles. The routine method is ineffective in determining the
genetic defects caused by these particles. Experiments doneusing larger particles (2–10 �) have shown similar toxic mech-anisms involving oxidative stress and pro-oxidant effects.
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he genotoxicity and general toxicity is based on differentarameters like dosage, size, and route of administrationnd the persistence of these particles in the organism whichauses corpuscular mutagenensis.
The genetic variance among human beings makes theano-drug therapeutic profiling difficult because of theidespread genetic polymorphisms present in some part of
he population. This hypothesis agrees with the data of theole of oxidative stress, due to the toxicity of the nanoparti-les and the heterogeneity of the antioxidant system whichs genetically determined. This brings forth the necessity forhe early sensitivity prognosis based on the genetic dispar-ty of the significant persons involved with the nanoparticles,nvironmentally or professionally, and development of theethods to tackle this problem (Zasukhina, 2005). As these
ests are time-consuming and require utilization of vastesources, scientists have developed computational analy-is like Quantitative Structure–Activity Relationship (QSAR).n this model, parameters like descriptors are used that areelated to the steric and electronic properties of the com-ound, which in turn helps in determining the cytotoxicity ofarious metal oxide nanoparticles (Burello and Worth, 2011).s more nanoparticles are being developed over the course of
ime, it is evident that their therapeutic roles in treatment willlso increase, as shown in Table 1.
The conventional approaches of nanoparticle synthesis useighly toxic chemicals which result in toxic side effects upondministration. Hence, an alternative method is required tovercome these toxic effects. Green synthesis is one suchpproach which not only ensures the safety and effective-ess of the nanoparticles being created but also provides us
ith the availability of cheaper, non-toxic nanoparticles. Thisesearch is currently being applied extensively in the case ofilver nanoparticles (AgNPs).
Table 1 – Composition, application and toxicity data of therapeu
Particle Characteristics
Carbon nanotube Single-walled carbonnanotubes, multi-walledcarbon nanotube
Bieltissc
Polypropylenimine dendrimer Polymeric molecules madeup of multiple branchedmonomers radially exudingfrom a central core
Drve
Gold nanoparticles Suspension ofsub-micrometer-sizedparticles of gold in a fluid
Dechat
Magnetic nanoparticles Magnetic materials Imdean
Quantum dots Semiconductornanocrystals made of aCdSe core capped with ZnSto increase quantum yield
Flfode
m a c o l o g y 3 6 ( 2 0 1 3 ) 807–812 809
The colloidal silver particles are known for their exten-sive bactericidal applications. The salts and derivatives ofAgNPs exhibit a strong toxicity toward a wide range ofmicro-organisms and have been used since a long time in ther-apeutics for treating burns and variety of infections (Sharmaet al., 2009). AgNPs are very efficient in disrupting the bacte-rial membrane and thereby causing production of free radicalsincluding reactive oxidant species (ROS). The production ofROS is also one of the reasons for the toxicity as it causesoxidative stress, inflammation and damages DNA and pro-teins. The emergence of resistant bacterial strains toward theknown antibiotics is a huge problem that promotes a strongincentive to look for other ways to create more bactericides.
The nanoparticles are comparatively much more chemi-cally reactive than their bulky counterparts. The uptake ofnanoparticles via different body routes like lung, skin, etc. canlead to DNA damage and inflammation which can further leadto tissue damage and other subsequent systemic effects (Choiand Hu, 2008). AgNPs are known for their uses in wound dress-ings, catheters and also in various processes involved withantimicrobial potential and hence the size dependent toxicityof AgNPs is an expanding field of research. The size depend-ency of AgNPs is decided on the basis of its biomedical use.For example, the cytotoxic effects of AgNPs were determinedin several cell lines including MC3T3-E1 and PC12, and AgNPsof size 10 nm were observed to have induced cellular deathgreater than the AgNPs of size 50–100 nm (Kim et al., 2009).AgNPs toxicity studies when were carried out for the abilityof the Drosophila eggs to palpate when exposed upon expo-sure to AgNPs, and it was observed that the AgNPs of largersize, 20–30 nm size, exhibited comparatively lesser toxicity as
compared to the AgNPs of higher size, 500–1200 nm. This sug-gested that the nanoscale silver particles (<100 nm) are lesstoxic to Drosophila eggs than silver particles of conventionaltic nanoparticles.
Applications Toxicity
osensors andectronic devices,sue-engineeredaffolds, drug delivery
Anti-proliferative effects, decreasedcell adhesion, apoptosis, necrosis andoxidative stress (Chui et al., 2005)
ug delivery, non-viralctor for nucleic acids
Inadvertent change in geneexpression and apoptosis in humancarcinomas cells (Omidi et al., 2003)
tects conformationalanges in the proteinstached with DNA
Contrasting results about toxicityfrom different studies are toxic tomammalian and bacterial cells; littlecytotoxicity (Goodman et al., 2004;Shukla et al., 2005; Connor et al., 2005)
munoassays, druglivery, gene transferd tissue repair
If corrosion occurs it gets toxic as ithas a tendency to aggregate in cell
uorescent propertiesr imaging andtection in diagnostics
Fluorescent labels for cellular labeling,intracellular sensors, deep-tissue andtumor imaging agents, sensitizers forphotodynamic therapy and alsovectors for studying nanoparticlemediated drug delivery (Delehantyet al., 2009)
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810 e n v i r o n m e n t a l t o x i c o l o g y a nsize (>100 nm) (Gorth et al., 2011). Another size-dependentcellular interactions based study of known biologically activesilver nanoparticles (Ag-15 nm, Ag-30 nm, and Ag-55 nm) wasdone in alveolar macrophages and a significant increase ofROS and other inflammatory response were observed with Ag-15 nm nanoparticles suggesting the important role played bythe size of the nanoparticles (Carlson et al., 2008). However, instudies with human hepatoma HepG2 cells, the cytotoxicitygenerated by silica particles strongly depended on the particlesize, and smaller silica particle possessed higher toxic effect(Li et al., 2011).
Interaction of metal nanoparticles with viruses has beenstudied and it was observed that AgNPs undergo a size-dependent interaction with HIV-1, where only AgNPs with1–10 nm size can attach to the virus (Elechiguerra et al., 2005).In addition, AgNPs were found to be completely cytotoxic toEscherichia coli for surface concentrations as low as 8 �g ofAg/cm2 (Baker et al., 2005). The surface area dimensions andsurface energy might be important properties that contributein some way to toxicity. Therefore, it would not be unrea-sonable as suggested by other investigators to hypothesizethat the toxicity of AgNPs could be based on the availableexposed surface for reaction with the cell, which increaseswith decreasing nanoparticle size or increasing concentrationof individual AgNPs per volume (Oberdorster et al., 2005).
3. Green synthesis of silver nanoparticles
Green synthesis of nanoparticles is the field of nanoparticlesynthesis and assembly by utilization of biological systemssuch as yeast, fungi, bacteria and plant extracts. Generally alot of colloidal metal nanoparticles like platinum (PtNPs), gold(AuNPs), etc. are synthesized using this technique but in thisreview we have focused more on silver nanoparticles becauseof their known bacteriocidal properties. The development ofsilver nanoparticles using green synthesis technique has rev-olutionized the whole world of nanoparticles synthesis. Thistechnique is popular these days because of its vast reservesof plants that are easily accessible, widely distributed, safeto handle, availability of wide range of metabolites and mini-mizes the waste and energy costs.
The green synthesis of AgNPs includes selection of solventmedium, reducing agent and non-toxic stabilizing com-pound/material, also termed as capping agent, preventsaggregation of the nanoparticles. As these nanoparticles resultin significantly low toxicity on adoption of this technique,it can be used for encapsulation of drug molecules. Furtherresearch in the field of nanomedicine with respect to AgNPs isgoing on worldwide.
4. Biotemplates used for the greensynthesis of silver nanoparticles
Bacterial strains, both gram positive and gram negative,
have been employed in the non-enzymatic production ofAgNPs through the interaction of silver ions with the organiccompounds present on the bacterial cells. For example, Lac-tobacillus, Enterococcus, Pediococcus pentosaceus and Enterococcusa r m a c o l o g y 3 6 ( 2 0 1 3 ) 807–812
faecium reduce silver ions in alkaline conditions (Ahmad et al.,2003). AgNPs synthesized by Plectonema boryanum precipitatesspherical AgNPs of size 200 nm. Bacillus subtilis yields AgNPsof 5–60 nm on microwave irradiation. Bio-reduced diamine sil-ver complexes of Corynebacterium strain, SH09, results in silvernanoparticles of size ranging between 10 and 15 nm (Merinet al., 2010). Spirulina platensis is also used for the extra cel-lular synthesis of nanoparticles. AgNPs of size 7–16 nm andgold nanoparticles of size 6–10 nm are obtained at optimumconditions, i.e. 37 ◦C, 120 h and pH 5.6 (Sintubin et al., 2009).
Fungi have been immensely used for the green synthesis ofnanoparticles. AgNPs are known to be excellent antimicrobialand anti-inflammatory agents and are thus used to enhancewound healing. Compared to bacteria, fungi have been knownto secrete much higher amounts of bioactive substances andso fungi are considered more suitable for large-scale pro-duction. Fusarium oxysporum synthesizes bioactive substanceextracellularly by reducing silver nitrate. The process includesstabilization of AgNPs in a solution with the help of proteinsecreted by the fungal strain and the metal ions producedare reduced by nitrate-dependant reductase and quinine shut-tle. The AgNPs thus produced are tested for their bactericidaleffect against S. aureus on cotton and silk cloth (Fu et al.,2006).
Algae are employed for the synthesis of nanoparticleswhich reduces the Ag+ ions by means of proteins released bythem and these proteins reduce the nanoparticles and helpin maintaining AgNP’s stability. In Chorella vulgaris, the pro-teins in the extract have dual function of Ag+ ion reduction,and shape controlled synthesis of NPs. The Ag nano plates areobtained at room temperature. Reduction of Ag+ ions is doneby the hydroxyl groups in Tyr residues and carboxyl groupsin Asp/Glu residues. This is responsible for the anisotropicgrowth of Ag nanoplates which yields rod-like particles witha mean length of 44 nm and width of 16–24 nm. The metabo-lites of marine algae like Chaetoceros calcitrans, Chlorella salina,Isochrysis galbana and Tetraselmis gracilis can also reduce the sil-ver ions and thereby synthesize the AgNPs (Govindaraju et al.,2008).
Plant varieties are also used widely for the synthesis ofAgNPs. Jatropha Curcas is a widely used plant for the synthe-sis of AgNPs. Seed extracts of the plant are taken where thelatex of J. curcas acts as a reducing agent as well as a cap-ping agent. Spherical AgNPs of the size range 15–50 nm areobtained (Bar et al., 2009). Clove extract is also being usedwhich reduces an aqueous solution of AgNO3 for synthesiz-ing AgNPs. Brassica juncea plant is hydroponically grown in asolution of AgNO3, Na3Ag(S2O3)2 and Ag(NH3)2NO3 to obtainAgNPs of 2–35 nm. Sun dried biomass of Cinnamomum camphoraleaf produces triangular or spherical shaped AgNPs whentreated with aqueous silver precursors at ambient tempera-ture. The protective and reductive biomolecules present in theplant are responsible for the shape control. The polyol compo-nent and the water soluble heterocyclic components presentin C. camphora are responsible for reduction and stabilizationof Ag and chloroaurate ions in nanoparticles (Huang et al.,2007). Treatment of silver ions with the leaf extracts of Cap-
sicum annum synthesizes AgNPs. The amine groups presentin the proteins of C. annum acts as controlling and reduc-ing agents in the formation of silver nanoparticles (Li et al.,
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007). Pleurotus florida is used for reduction of silver ions to sil-er on treatment with aqueous 10−3 M silver nitrate solutionBhat et al., 2011). Nelumbo nucifera extracts on treatment withqueous 1 mM silver nitrate solution results in formation ofgNPs (Santhoshkumar et al., 2010).
Bioproducts like oils, enzymes, etc. can also be used in thereen synthesis of nanoparticles. For example, coconut oil issed for synthesizing AgNPs of size 4–6 nm using laser abla-ion technique. The virgin coconut oil controls the particle sizend also does not allow the ablated nanoparticles to agglom-rate (Zamiri et al., 2011). Lysozyme in the presence of silvercetate forms AgNPs of size 8–12 nm where silver acetate actss both a nucleating agent as well as a reducing agent. Theilver ions are reduced into nanostructures by the glutamiccid and aspartic acid peptides present on the surface of theeasts (Darroudi et al., 2011). Tea polyphenols and starch alsoields stable AgNPs on treatment with 0.1 N AgNO3 solutionMoulton et al., 2010).
. Applications of green synthesized silveranoparticles
gNPs have a wide range of applications, characterized bycores of medical and technological properties. These includehe new antibacterial agents that have revolutionized thepplied medicine. They are used in healing wounds and ulcers,sually in the form of dressings and creams and also uti-
ized to coat medical devices such as catheters, dentures, orurgical masks (Cortivo et al., 2010; Li et al., 2006). In theextile industry, non-toxic nanoparticles possessing antimi-robial properties are used in making sterile hospital clotheshat prevent or minimize infection with pathogenic bacte-ia such as S. aureus (Duran et al., 2007). They are also usedn the production of antimicrobial nanopaints. Recently, atudy revealed the potential cytoprotective activity of AgNPsoward HIV-1 infected cells. AgNPs might inhibit the repli-ation in Hut/CCR5 cells causing HIV-associated apoptosis.urthermore, AgNPs are utilized for the preparation of antibac-erial water filter. The use of ROS as a scavenger and Ag+ ion as
neutralizing agent suggested a role of ROS in the strong bac-ericidal activity of carbon filter supporting silver (Sun et al.,005).
. Conclusion
he synthesis of nanoparticles without knowing or testingheir toxic effects on the human body has followed a nega-ive trend in the therapeutics which should be discontinuedt the earliest. More emphasis should be laid on the creation ofanodrugs that use natural biological pathways making themore bio-compatible with the body.
onflict of interest statement
othing declared.
m a c o l o g y 3 6 ( 2 0 1 3 ) 807–812 811
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