Biomedical applications of green synthesized Nobel metal nanoparticles

Accepted Manuscript Biomedical applications of green synthesized Nobel metal nanoparticles

Zia Ul Haq Khan, Amjad Khan, Yong Mei Chen, Noor S. Shah, Nawshad Muhammad, Arif Ullah Khan, Kamran Tahir, Faheem Ullah Khan, Behzad Murtaza, Sadaf Ul Hassan, Saeed Ahmad Qaisrani, Pingyu Wan PII: DOI: Reference:

S1011-1344(17)30498-0 doi: 10.1016/j.jphotobiol.2017.05.034 JPB 10850

To appear in:

Journal of Photochemistry & Photobiology, B: Biology

Received date: Revised date: Accepted date:

13 April 2017 23 May 2017 23 May 2017

Please cite this article as: Zia Ul Haq Khan, Amjad Khan, Yong Mei Chen, Noor S. Shah, Nawshad Muhammad, Arif Ullah Khan, Kamran Tahir, Faheem Ullah Khan, Behzad Murtaza, Sadaf Ul Hassan, Saeed Ahmad Qaisrani, Pingyu Wan , Biomedical applications of green synthesized Nobel metal nanoparticles, Journal of Photochemistry & Photobiology, B: Biology (2017), doi: 10.1016/j.jphotobiol.2017.05.034

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ACCEPTED MANUSCRIPT Review Biomedical applications of Green Synthesized Nobel Metal Nanoparticles Zia Ul Haq Khan*a,b, Amjad Khanc, Yong Mei Chen*b, Noor S.Shaha, Nawshad Muhammadd, Arif Ullah Khanb Kamran Tahirf, Faheem Ullah Khanb, Behzad Murtazaa ,Sadaf Ul hassane and Saeed Ahmad Qaisrania, Pingyu Wanb* a

Department of Environmental Sciences, COMSATS Institute of Information Technology, Vehari 61100, Pakistan National Fundamental Research Laboratory of New Hazardous Chemicals Assessment & Accident Analysis, Institute of Applied Electrochemistry, Beijing University of Chemical Technology, Beijing 100029, China c The Research Center for Medical Genomics, College of Basic Medical Science, China Medical University, Shenyang 110122,PR China d Interdisciplinary Research Centre in Biomedical Materials, COMSATS Institute of Information Technology, Lahore 54000, Pakistan e State Key Laboratory of Rare Earth Materials Chemistry and Applications, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China. f institute of chemical science Gomal University DIK Pakistan

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Corresponding authors: [email protected], [email protected], [email protected], a

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Department of Environmental Sciences COMSATS Institute of Information Technology, Vehari 61100, Pakistan National Fundamental Research Laboratory of New Hazardous Chemicals Assessment & Accident Analysis, Institute of Applied Electrochemistry, Beijing University of Chemical Technology, Beijing, 100029, China

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Contents

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Abstract ......................................................................................................................................................... 2 Introduction ................................................................................................................................................... 2

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Applications of nano-technology impacting on human health ................................................................. 4 Drug delivery strategies using gold nano particle platforms .................................................................... 5

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Anticancer activity of AuNPs ................................................................................................................... 6 Hemolytic activity..................................................................................................................................... 6

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Enzymatic browning reduction ................................................................................................................. 6 Microscopic signs of apoptosis in gold nano-particle treated MCF-7 cells [75-81] ................................. 7 The cytotoxic activity of the biosynthesized AuNPs on MCF-7 cells ...................................................... 8 Observation of Morphological Changes by Light Microscopy................................................................. 9 SEM Analysis of Surface Characteristics of RBCs Following NP Exposure ......................................... 10 Physical method ...................................................................................................................................... 11 Synthesis of AgNPs by Chemical Method .............................................................................................. 11 Synthesis of silver nano-particles by reduction method.......................................................................... 11 Table 4: ...................................................................................................................................................... 12

ACCEPTED MANUSCRIPT Conclusions ............................................................................................................................................. 14 References:.............................................................................................................................................. 15 Table 4: Some important physical, chemical and photochemical methods for synthesizing and stabilizing silver NPs .................................................................................................................................................... 44

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Abstract

Synthesis of Nobel metal nanoparticles, play a key role in the field of medicine. Plants contain a

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substantial number of organic constituents, like phenolic compounds and various types of glycosides that help in synthesis of metal nanoparticles. Synthesis of metal nanoparticles by

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green method is one of the best and environment friendly methods. The major significance of the green synthesis is lack of toxic by-products produced during metal nanoparticle synthesis. The

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nanoparticles, synthesized by green method show various significant biological activities. Most of the research articles report the synthesized nanoparticles to be active against gram positive and

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gram negative bacteria. Some of these bacteria include Escherichia coli, Bacillus subtilis, Klebsiella pneumonia and Pseudomonas fluorescens. The synthesized nanoparticles also show

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significant antifungal activity against Trichophytonsimii, Trichophytonmentagrophytes and Trichophytonrubrum as well as different types of cancer cells such as breast cancer cell line.

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They also exhibit significant antioxidant activity. The activities of these Nobel metal nanoparticles mainly depend on the size and shape. The particles of small size with large surface area

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show good activity in the field of medicine. The synthesized nanoparticles are also active against leishmanial diseases. This research article explores in detail the green synthesis of the

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nanoparticles and their uses thereof. Keywords. Green synthesis; Nobel metals; nanoparticles; AgNPs; AuNPs

Introduction Different definitions for Nanotechnology are expressed in literature, but for the purposes of our current work, nanotechnology is observed to be the capability to work with materials ranging between 1-100 nm in size [1-3]. At nano scale, the materials synthesized have novel properties

ACCEPTED MANUSCRIPT with respect to other isolated and bulky materials. The applications mainly depend upon the size and morphology of synthesized nano-materials. Nano-technology is not specific and limited to a discipline, but it is interdisciplinary including natural science and engineering science [2] and most recently toxicology. The synthesis of nanomaterial at the dimensional scale are not new, but the entire natural, for example the life depending nano scale materials including proteins, enzymes, DNA and small size particles are

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occurring in nature. For the purposes of color, ceramic glazes and stained glass silver nano-

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particles (AgNPs) and gold-nano-particles (AuNPs) have been in use since 10th AD and 4th

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century [4-5].

There are many natural sources for nano-particles, included fires and volcanic bursts. Few

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biological examples include magnetite (usually occur in animals and cell), viruses and protein like ferritin. The interest of researchers in nano-technology has increased melodramatically to

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synthesized nanoparticles by straightforward way of combustion and simple industrialization methods. All the engines, power plants and others like welding gases release nano-particles into

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the environment [6]. The environment has been affected by the rapid step of industrialization. The rapid developments of nano-technology play a vital role in the environmental applications.

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The existence of organic pollutant in air and water present a great problem to humanity. In this field, nano- materials are excellent catalyst and good sensors because NPs show high reactivity

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and have specific surface area. The ratio of high surface area (HAS) and mass of NPs increases the adsorption capability of sorbent materials. Due to small and spherical size of nano-particles

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(NPs), develop exponentially for the similar density as the diameter shrinks. Furthermore, NPs agility in solution is approximately higher and the as whole liquid scanned quickly, because of

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small size and high surface area. Having these unique properties, NPs can be applied for degradations and scavenge of pollutant in water [7]. The organic pollutants absorbed on the surface of NPs and may remove by gravitational or magnetic force. The size, shape and morphology of NPs have significant role in natural environment [8, 12]. The distributions of NPs are mainly based on size, shape and reactive sites as well as the messy surface area. Furthermore, it is confirmed from natural science and engineering that NPs like chitosan, AgNPs, photo catalytic TiO3 and other carbon nanotube (CNT) have strong anti-microbial applications [10-17]. The NPs can be achieved by (1) crushing, and mechanically alloying techniques (2) deposition of vapors either by physical or chemical (3) sol-gel chemical synthesis procedure (GP) gas- phase

ACCEPTED MANUSCRIPT synthesis techniques like, flame paralysis, electro explosion, (5) by combustion methods or determination of layered materials [16-18]. To improve the morphology and surface area of nanoparticles usually fictionalization process is applied. The functionalization method is also applied in order to avoid aggregation and eliminate interaction between nano materials and in microbial activities. Nowadays the great challenges faced by researchers are chemotherapy developing drugs delivery [18-19]. The passive and

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active targeting methods have been used with nano carriers such dendrimers [20-21], liposomes

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[22], metal nano-particles (MNPs) [23], polymer micelles and vesicles [24, 25].The Drug

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Delivery system (DDS) has better distributions of the therapeutics for cancer treatment. The gold nanoparticles play vital role to improve rapidly DDs efficiency [16, 27]. The characteristic

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properties of gold nanoparticles make them a very auspicious vehicle for delivery of drugs. To control the size of various particles up to 1-150 nm limited disparity has been established [28-

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31], exhausting ligand place exchange reactions [29] multi-functional mono-layers can be fabricated. Variety of structures enables nano-particles size that comprises multiple pointing

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agents. The diverse application of AuNPs permits them for a different DDS projects. All the hydrophobic drugs can be encumbered onto gold nano-particles (AuNPs) by non-covalent

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interactions, demanding no structural modification to the drug statement [32]. Covalent conjugations to the gold nanoparticles by breaking link also be used to transfer pro-drugs to the

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cell and released outside [33] or inside [34-35] stimulation. Regardless of the approach used, the tunability of the AuNPs mono-layer is crucial for internal or external release mechanisms.

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Applications of nano-technology impacting on human health In many fields, the toxicology of Nobel metals (NMs) is unknown, but its applications and

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importance is well realized. The quantity of production in nano-particles is increasing day by day from multi-tone black productions and furious silica up to microgram quantities, especially for biological properties [36]. This range comes under the dominions of nano-medicine as the applications of nano-technology for the treatment of fictional diseases, analysis, nursing and control of biological system [37]. The synthesized mono- structured nano-particles can be intended to self-assembly and produce structure for tissue engineering, efficiently imitating mineralization methods [38]. Self-assembly peptide can direct mineralization of –OH apatite (hydroxyapatite) with development of collagen fibrils which is curiosity in mineralization tissue restoration [39]. Light irradiation of Au-coated silica spheres triggers the proclamations of heat

ACCEPTED MANUSCRIPT that can abolish cancer cell [40-42]. Disinfection of surface is likely using UV photo-catalytic oxidation with nano-crystalline TiO2 [43-44]. Synthetic mechanical red blood cells are impersonators for the O2 and CO2 carriage functions of red blood cells. The nano-materials deliver 236 times more O2 per unit volume (PUV) as compared with natural blood cell [45]. The antibodies adsorption on assemblies of single wall carbon nanotube procedures the origin of an amperometric immune sensor [46]. Carbon Nano Tubes (CNTs) behave to deliver drugs, gens

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and anti-gens have been used as new stage to sense antibodies related with human autoimmune

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diseases with high specificity [47]. Usually for free radical scavenger modified carboxy-fullerene

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carbon is used as drug target activities on human cell of resistant system and their mitochondria, for fortification against apoptosis [48]. The parent fullerene C60 and other plagiaristic have

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application as oxidants in contradiction of radical-included biological procedures [49]. Drugs can be ensnared physically within the hydrophobic centers of micelles, which are mainly depending

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upon the physicochemical properties of the drug. There is also small nano-sphere where the required medicine is absorbed, deceived, devoted or encapsulated throughout or maybe within a

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polymeric matrix [37]. The nanomaterials can be loaded with antigen and have various applications in vaccination process [50] in drugs distribution, across the blood- brain barrier

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(BBB) is possible [51-52]. Naturally occurring polymers like chitosan are usually used for the transfer of anti-cancer drugs, genes and vaccines [53-56]. The chitosan –DNA NPs also help in

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genes carriers [54]. The attractive nano-particles aerosols are also used for drug delivery, because of their bio-availability in bottomless lung tissue and ease of distribution [55]. Single

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Walled Carbon Nano-Tube (SWCNTs) is also good carrier of drugs and genes delivery [56] and functionalized Single Walled Carbon Nano-Tube (SWCNTs) with DNA involved amplified

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DNA and genes uptake is more as compared with free DNA [56-57].

Drug delivery strategies using gold nano particle platforms Drug transportation is one of the major factors for producing efficient Drug Delivery system (DDS). Loaded nano-particles with drugs by non-covalent bond interactions or maybe by conjugations [58] making pro-drugs, which is administrated by the cell [59]. The gold nanoparticles offer an exceptional pathway for DDS strategy due to purposeful adaptability of their monolayers. Figure 1

ACCEPTED MANUSCRIPT Anticancer activity of AuNPs Widely used MIT assay on MCF-7 cell is conducted to estimate anti-cancer applications of Gold nanoparticles at different doses. With the increase of dose of nano-particles from 6.25 - 100 μg mL-1 as shown in figure 2, the invitro cytotoxicity against human breast cancer cells MCF-7 increases [61, 62]. After optical microscopy examination of MCF-7 show morphological changes

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and conquest of cell growth and last clattering and death as shown in figure 3, because of At

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AuNPs. With the increase of nano-particles concentrations cells feasibility decreases.

concentration of 100μg /mL, the maximum cytotoxic effect (75%) was observed in MCF-7 cells

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Figure 2 Figure 3

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as evident from Fig. 3, where MCF-7 cells show 25% viability at this concentration.

Hemolytic activity

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The basic need of biogenically synthesized nano-materials must be biocompatibility and it should not produce any toxic effect. The biocompatibility is mainly related with the surface of

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the particle size and can be resolute based on the adversative host reaction concentration [62].

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The results of different concentrations of AuNPs at red blood cells (RBCs) are shown in table 1 [63]. From the results, it is clear that AuNPs have no hemolytic properties against red blood cells at different concentrations. Furthermore, it is known that AuNPs are non-toxic in nature, stable,

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inert and highly binding capability, so due to this reason gold nanoparticles are used for

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anticancer drug carrier [64].

Table 1

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Enzymatic browning reduction The silver nanoparticles (AgNPs) play vital role in biological fields. Different concentrations are used to show the elimination of browning in white cabbage as shown in figure 4 [65]. Different concentrations from 1 mg to 0.125 mg/g have been used. From the results, it is clear that AgNPs of browning units ranging from 3.3 to 8.41. From the value, it clear that higher the value, the enzymatic browning reduction will be stronger [65]. The results analysis show linear relationships between enzymatic browning reduction (EBR) and AgNPs concentration. The enzymatic browning reductions have direct relation with silver nanoparticles as shown in figure 4. About 95% of variability in EBR transversely concentration of silver nanoparticles. The

ACCEPTED MANUSCRIPT AgNPs and EBR show much correlation ((r2 = 0.9777, F = 113.3, p=0.001) [65]. The silver nanoparticles are used specially as reducing agents in food which oxidized by itself [65], thus help to avoid oxidative taste and color worsening. AgNPs are useful EBR, anti-microbial agent and act as anti-oxidants [65]. Figure 4

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Microscopic signs of apoptosis in gold nano-particle treated MCF-7 cells [75-81] The ability of gold nanoparticle to alter the morphology (an indication of apoptosis) of the cancer

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cell lines were assessed using Propidium Iodide (PI) staining (Figure. 5). After incubation for 24 h with AuNPs, the cells became round in appearance exhibited nuclear condensation and

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significant nucleus fragmentation indicating apoptosis.

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Figure 5 Different researchers used AuNPs for different purposes. Rotello et al [82] used AuNPs in photo cleavage pathway for cleavage of o-nitrobenzyle ester moiety that is associated with the light irradiation, depending the surface either positive or negative intracellular liberating adsorbed

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DNA [82]. The researchers also studied the absorbed light control statement of the drug-

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fluorouracil from gold nanoparticles as shown in figure 6 [83]. Improved solubility and incomplete cellular approval was accomplished using the zwitterion ligand. Using Ultra violet

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radiation of 365 nm the cleavage of ortho-nitrobenzyl occurred to the 5-fluorouracil from the gold nanoparticles. Observations showed IC50 value on particles basis for gold nanoparticles was

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0.7 µM. During photo-catalytic activity, it is observed that no cell death was observed without

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the use of gold nanoparticles

Figure 6

Persuading necrosis and apoptosis by reactive [O] types are a probable approach for therapeutic. Burda et al exploited this approach to improve a photodynamic therapy (PDT) with PE-Gylated AuNP-Pc4 [84-85]. The ligand of PEG has been used for multiple purposes. The function of PEG is first to constrain non-specific binding to biomolecules and avoid colloidal accumulation. The ligands as well, through Van der Waals relations, encapsulated the phatho-cyanine photosensitizing agent (figure 7A). An efficient delivery process was verified by monitoring the release of Pc4 from the nano-carrier in vitro in a two-phase solution system and in vivo in cancer-

ACCEPTED MANUSCRIPT bearing mice with enhanced accumulation of Pc4 in tumor sites. The AuNP-Pc4 conjugates decreased the time needed for photodynamic Therapy (PDT) from 2 days to 2 h versus the free drug (Fig. 7B). Figure 7 For conformation whether the initial cell death occur in HeLa and MCF-7 tumor cell visible to

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free MTX and MTX-CS-NP might be due to apoptosis, AO/EB staining was carried out and

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analyzed the sample under a fluorescence microscope. From Figure 8 important increases in the

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number of apoptotic cell in both cell line following behavior with free MTX and Methotrexateloaded chitosan nanoparticles (MTX-CS-NPs). Both the MTX-CS-NPs and free methotrexate

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(MTX) has been responsible for the effective doses. Moderate increase was studied in a number of cell undergoing late apoptosis or necrosis, but these results are not different from control cells. The remaining and un-treated HeLA and MCF-7 cells have been studied with complete

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nuclear structure as shown in figure (8c and f), but after free MTX or MTX-CS-NPs treatment, it was observed that the cell showing blebbing and nuclear margination as shown in fig 8d,

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chromatin condensation as shown in Figure 8e, orang nuclei with normal chromatin distribution

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as shown in figure 8g and apopatic apoptotic body separation and reddish-orange color as shown in figure 8h.

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Figure 8

The conformation whether the induced cytotoxic effect caused by synthesized silver

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nanoparticles using plant extract of Solanum triobatum, which involve apoptotic changes, the nuclear condensation was studied by propidium discoloration. Limited amount of propidium

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iodide positive cells remained detected as shown in figure (9a) [86-92]. On the other hand, large number of propidium iodide susceptible cells has been observed when 30µg/mL green synthesized silver nanoparticles are used as shown in figure 9c, after comparison of results with figure 9b. Figure 9

The cytotoxic activity of the biosynthesized AuNPs on MCF-7 cells The AuNPs consequence was assessed against cancer cell MCF-7 using different concentrations like 6, 3, 1.5, 0.75 and 0.375 µl/ mL. From figure 10, it is clear that the cancer cells gestated of 3

ACCEPTED MANUSCRIPT and 6 µl/ mL of the green synthesized AuNPs for two days has been rounded and stomped departed cells. At last the membrane is like swell appearance on its different points which is caused by necrosis. From the results, it is clear that about 50% of cell died at concentration of 1.5 µl/ mL of the green synthesized AuNPs as shown in figure 11 [93]. Furthermore, the cytotoxicity has direct relationship with the concentrations of synthesized gold nanoparticles which are indicated that 1.5 µl/ mL of AuNPs showed significant activity and the cell growth have been

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inhibited, while using the lower concentration of AuNPs.

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Figure 10 Figure 11 The nano-materials also showed anti-leishmanial activity. Different scientist used different plants extracts and found them to be active. Even at very low amount of concentrations, they show

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significant activity. The Noble metal NPs are able to create reactive oxygen species (ROS) that destroy micro-organisms by simple method called respiratory burst mechanism as shown in

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figure 12. It is observed that leishmania is extremely vulnerable to these O2 species and the medicine that could be generated, ROS will be effectual anti-leishmanial mediator. Macrophages

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are the distinctive resistant cells of human existences that can produce high concentrations of the ROS to extinguish the entered pathogens. The leishmanial organisms have the capability of

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preventing some enzyme of ROS creating path in macrophages and therefore, can live in the resistant cells. The uses of AuNPs as leishmanicidal mediator will perform as a greater reservoir

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of Au ions that will afford a nano enzymatic foundation of ROS and extinguish the entered organism. The reactions between electrons generated by AuNPs and O2 at the surface of nano-

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particles, generated ROS (O2, -OH) the radical generated during the reaction are responsible to

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destroy DNA and other cellular part of the species and finally lead to death. Figure 12

Observation of Morphological Changes by Light Microscopy Morphological study of abnormal RBCs provides understanding about the analysis of several remedial situations such as hemolytic anemia. Remaining RBCs in Dulbecco Ca2- and Mg2- Free phosphate buffered saline (DPBS) seem in a regular biconcave form as shown in (Fig. 13a) [99107]. Morphological aberrant forms appear for RBCs by the exposure of silver nanoparticles such as echinocyte as outcome the biconcavity was lost and RBCs seem distended as shown in

ACCEPTED MANUSCRIPT figure 13b.With the increase of Ag-starch concentrations number of ghost cells also increased as shown in figure 13c and also Ag-PVA, but the Red Blood Cell treatment with other nanoparticles did not show such activity. Up to 100mg mL-1 in Ag-PVA hemagglutination has been studied as shown in figure 13e and Au-PVA shown in figure 13f, did not show any morphological differences and hemagglutination. Treatment with Pt-PVA as shown in (fig.3e) and Au-PVA (fig.3f) did not exhibit any morphological variations and hemagglutination.

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Exposure of RBCs to a low concentration of reactants (Ag+ (fig, 3g) and NaBH4 (Fig.3h) did not

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result in any morphological changes.

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Figure 13

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SEM Analysis of Surface Characteristics of RBCs Following NP Exposure EM (electron micrographs) was taken after 90 minutes of nano-particles exposure to study the

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morphological changes at initial steps of hemolysis. No change and no abnormalities have been studied in the control RBCs as shown in figurer 14a [107-108]. But after treatment of AgNPs with RBCs resultant different numbers of superficial estimates and morphological differences,

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signifying a possible lethal effect of silver nanoparticles. Abnormal morphological forms of red

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blood cells were very less in silver-starch as shown in figure 14b as compared with Ag-PVA as shown in figure 14c preserved cell. No abnormalities have been studied by treatment of Au

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(figure 14d) Pt-NPs as shown in (fig.14e) and also starch and PVA (fig. 14f) show no abnormalities. Erythrocyte sedimentation rate (ESR) has not been changed in the presence of

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silver nano-particles as shown in table 2 [87-107]. RBCs visible to starch, poly vinyl alcohols (PVA, Pt-PVA) and Au-PVA display no haamagglutination though Ag-PVA and Ag-starch preserved cells displayed a concentration-dependent increase in haamagglutination starting from

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100 mg mL-1.

Figure 14 Table 2 Table 3

The reduced form of metals is highly reactive because it has exclusive antimicrobial activity, biosensor properties. Some of anti-microbial AgNPs are summarized in Table 4. Different types of physical and chemical methods used for the synthesis of silver nanoparticles are summarized in table 5 [112].

ACCEPTED MANUSCRIPT Physical method The mostly used physical approach is the evaporation and condensation process. The absence of solvent adulteration in the ready thin films and the consistency of NPs circulation are the compensations of physical synthesis approaches in judgment with chemical procedures. To synthesize silver nanoparticle in physical methods, have some disadvantages, like furnace are

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used for the synthesis and it occupies large space and great amount of energy are used while the

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temperature around increased. AgNPs synthesis is carried out via small ceramic heater with slowly heating [110-113]. Usually the ceramic material is used to evaporate the materials and

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cool the materials slowly. In these methods, larger amount of small nanoparticles are formed. The generation of small particles is very stable because the heater temperature does not vary with

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time. From the result, it is concluded that geometric diameter, deviation and NPs amount have direct relation with heater surface temperature. With the increase of the temperature, amount of

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NPs also increases. At higher temperature, spherical NPs with aggregation has been observed. Standard deviation and geometric mean diameter of AgNPs range from 1.23 to 1.88 and 6-2 to

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21-5 respectively. Laser ablation method is used for NPs synthesis of metallic bulk materials in solution [114-118]. The properties and efficiency of synthesized AgNPs mainly depends at

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many parameters included wavelength of the imposing metallic target [119-122]. The advantage of ablation techniques on comparison with other procedures is that metal colloids in the absence

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of other chemical reagent in the solution. By this method pure and colloidal metal can be synthesized for further application [123].

Silver nano-spheroids of 20 -25 nm has been

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synthesized using laser ablation in water with femto second laser pulses at 800 nm. It was investigated that the ablation competence for femtosecond ablation in water was minor as

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compared with air. For fabrication of AgNPs synthesis Tien and his group [124] by arc discharge method suspension in DW (deionized water) and with no surfactant. AgNPs was synthesized by Siegel and co-workers [125] by direct method sputtering in to liquid media.

Synthesis of AgNPs by Chemical Method Synthesis of silver nano-particles by reduction method

To synthesize AgNPs by chemical method usually organic or inorganic reagents are used. This is the widely used method. These reagents are responsible to reduce Ag+ and help in the formation of silver (Ag0) that followed by accumulation into oligomeric cluster. These clusters lead the

ACCEPTED MANUSCRIPT formation of metal AgNPs [126-128]. It is important to use protective agents to alleviated dispersion nanoparticles syntheses and also protects the NPs from absorption and aggregation [1128, 129]. Several results have been reported that polymeric constituents like poly hydroxyl compounds, poly ethylene glycol etc are effective protective agents for stabilization of AgNPs [31]. Some researchers report [130] the synthesis of NPs in spherical, controllable size and highly dispersion while using polyol process and modified injection technique [130]. During 100

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°C, the AgNPs with size 17-2 nm has been obtained while the injection rate was 2.5 mL/s. The

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injection method is good and useful for the synthesis of AgNPs with small and narrow size in

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very short time. Some scientists like Zhang and his group used hyper branch chain poly methylene for the synthesis of silver nanoparticles [131], while other used oleyamin-liquid

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paraffin for the synthesis of highly dispersed and small size AgNPs [131-132]. This method has been divided into three stages, growth, incubation and Ostwald ripening of AgNPs synthesis.

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Furthermore, the size of the colloidal AgNPs could be controlled not by changing the heat or growing time but also correcting the ratio of oleylamine to the silver predecessor. AgNPs can

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also be synthesized in the laboratory, simply by mixing corresponding metal ion with reducing and alleviating mediator. The possible concentrations used for the formation constant expressed

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in Equation (2) and (3) as function of NH3 as shown in figure 15. By decreasing the silver ion concentration in the presence of ammonia which show decreased rate of reduction of silver ion

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as shown in equation 1 which change the morphology of particle size. First the decrease of

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particles occurs and latter nuclei develop with large particle size [133-134].

Figure 15: Table 4: Table 5:

The average particle size of the synthesized AgNPs range from 25-450nm. The size totally depends on the amount of ammonia used and the type of reducing agent used during this

ACCEPTED MANUSCRIPT reaction. The effect of ammonia and several types of reducing agents and its effect are summarized in table 6 [133-134]. Table 6:

Dilution standard method (DSM) has been applied in execution. MIC of AgNPs and regulatory sample against gram positive and gram negative bacteria has been summarized in table 2. The

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used micro dilution method enables testing of antibacterial activity of samples diluted two times

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up to 128 times. Total amount of silver ion in the test colloidal and control sample are 108 µg

dilution [133-134].

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Table 7:

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/mL after synthesis. The final concentration of Ag from 54 to 0.84 µg/ mL that depend on

Using second reductive reagent the particles size distribution become narrower. The diameter of

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synthesized nano-particles decreases dramatically by using mixture of hydrazine and hydrazinesodium citrate [136, 137]. By doubling the concentration of sodium citrate the yield of particles

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increases about 17% as shown in table 8 [133-134].

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Table 8:

The incidence of NPs at a certain level decreased bacterial development by more than 90%. The

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diameter of inhibition zones (in millimeters) measured is shown in Table 9. [135]. The zone of the bacterial inhibition associated with anti-biotic for gram positive and gram negative bacteria, which is clear indication that when the increase of AgNPs concentration and zone of inhibition also increases, as

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shown in table 9, 10, 11 [135].

Table 9 Table 10 Table 11

The antimicrobial property has been screened for silver nanoparticles when modified by surfactants, as SDS, Tween 80, polymer and PVP [138]. The antimicrobial activities

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significantly in most cases by modifying AgNPs with SDS as shown in fig 16. The SDS provid more stability to Ag ion when compared to Tween. Due to the ionic surfactant of SDS, they have the ability to destroy the cell wall of gram positive bacterium [138,139]. The Tween 80 do not have ionic properties and it doesn’t have the ability to contact with the cell wall of the

ACCEPTED MANUSCRIPT bacterium and have fewer properties to diminish the cell wall of pathogen [138]. The PVP also play significant role in nanoparticles stabilization because polymer is effective and avoid the particles from aggregation [138]. Figure 16

The anti-fungal activity also depends directly upon the concentration of AgNPs. With the

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increase of concentration from 25 to 100 µg, the zone of inhibition also change from 12 to 17 nm

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for T. simii and 13 to 17 nm for T. mentagrophytes and 17~21 nm for T.rubrum. Fluconazole

Table 12

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was used as a positive control as shown in table 12.

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DPPH is good and well synthetic solid radical for evaluations of antioxidant potential of constituents. By accepting an electron, the DPPH has been reduced and reducing capability of

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Ag and AuNPs is quantified by spectrophotometer by changing the color to yellow. The percentage DPPH radical is indicated in Figure 17A. The silver nanoparticles show good activity as compared to Au, it may be due to that Ag act as a good oxidant can easily lose

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electrons [141, 143]. Ag and Pt exhibits the DPPH radical scavenging properties [144-147].

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Hydroxyl radical deoxyribose dilapidation inhibition by Au and AgNPs are shown in figure 17B. The NPs with larger size and spherical shape accept electron easily from hydroxyl radical. The

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AuNPs showed 68.8% larger size while AgNPs showed 50% less inhibition due to smaller surface area. The hydroxyl radical inhibition of selenium and Pt-NPs has been reported [148-

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149-150]. The Au and AgNPs radical inhibition is 47% and 52% as shown in figure 17C. The NO radical with high electronegativity show less stability, can easily accept an electron (en)

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from Au and AgNPs. The percent NO Griess substance radical inhibition of Au AgNPs were 25.42 > 31.41 > 39.44 > 47.97 and 25.14> 28.97>48.21>53.11at µg/mL, 10 µg/mL, 100 µg/mL and 250 µg/mL respectively Fig. 17D. Figure 17

Conclusions Nanotechnology is one of the new fields in science. The nanoparticles are used for different purposes like, sensing, detection of heavy metal and degradation of water soluble organic pollutant. Plants extract help in synthesis of nanoparticles and phenolic compounds act as reducing agent to stabilize the zero-valent metal. The reduced form of metals is highly reactive

ACCEPTED MANUSCRIPT and used in various field like in biological field, electrochemistry and in photochemistry. The activities of NPs mainly depend on the surface area and particles size. The small sized and highly dispersed NPs have various biomedical applications, especially used for cancer treatment. The NPs synthesized by green method show good activity against gram positive and gram negative bacteria. Noble metal nanoparticles are used against several types of parasitic infection like leishmaniasis. Green synthesis is one of the best and environment friendly method for the

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synthesis of noble metal nanoparticles. In the present review, we studied the green synthesis of

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nanoparticles and its applications in medicine. We found that the synthesized Noble metal

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nanoparticles are one of the cheap and easy methods to synthesize the required nanoparticles. We highly recommend the green method for the synthesis of nanoparticles.

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Acknowledgment The authors greatly appreciate the support from the National Natural Science Foundation of China [grant number 51374016].

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Kumar , K. Premkumar , C. Thirunavukkaras, A. Suyavaran. Colloids and Surfaces B: Biointerfaces 102 (2013) 808– 815

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145. J.P. Saikia, S. Paul, B.K. Konwar, S.K. Samdarshi, J. Colloid Surf. B (2010) 146-148. 146. B. Huang, J. Zhang, J. Hou, C. Chen, Free Radic. Biol. Med. 35 (2003) 805-813.

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147. A.Watanabe,M. Kajita, J. Kim, A. Kanayama, K. Takahashi, Y Miyamoto, Nanotechnology. 20

(2009) 455105–455114 148. X gao, J. zhang, I. zhang, Adv. Mater. 14 (2002) 290-293. 149. T. Hamasaki, T. Kashiwagi, T. Imada, N. Nakamichi, S. Aramaki, k. Toh, S. Mori- sawa, H.

Shimakoshi,Y. Hisaeda, S. Shirahata, Langmuir, 24 (2008) 7354-6364 150. J.M Dowding, T. Dosani, A. Kumar, S. Seal, W.T. Self, Chem. Commun. (Camb.) 48 (2012)

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Figure: 1 The size nanoparticles dependent pervasion of the tumor interstitial space. (A-C) historical sample were found for 20, 60, and 100 nm at eight post injection (HPI). (D) Image .J software was used to create contrastenhanced images for densitometry analysis. (E).Densitometry signal was enumerated at 10 µm detachment gone from blood vessel center 8HPI and was legalized to the single 0-10 µm.

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Figure 2: Cytotoxicity of gold nanoparticles in contradiction of human breast cancer cell line MCF-7 screening % of feasible at diverse conc: after 24 h of action, where inst (A) expressions the progressive alteration in color due to the number of viable cells

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Figure 3: Microscopy study of cytotoxicity of gold nanoparticles against human breast cancer line MCF-7 showing progressive decrease in the number of viable cells as well as morphological changes with increasing concentration of AuNPs

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Figure 4: Enzymatic browning reduction (EBR) index of AgNPs

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Figure 5: DNA Staining (Microscopic) after twenty four hour, Development of MCF-7 Treated against 200 µg/ml AuNPs with Control. Red fluorescence is due to Propedium Iodide staining and detected under green filter. Observations done at 200 x magnification

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Figure 6: (A) UV-hγ reaction (3665 nm) of Au_ PCFU and distribution of consignment to cell (B) Cytotoxicity of varied conc: of Au_ PCFU suffering and control environments.

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Figure 7: (A) Structure of the water-soluble AuNPs as a PDT drug delivery agent, Pc 4 structure (B) Fluorescence images of a tumor-bearing mouse after being injected with Au NP-Pc 4 conjugates in normal saline (0.9% NaCl, pH 7.2), (a) 1 min, (b) 30 min, and (c) 120 min after intravenous tail injection. Any bright signal is due to Pc 4 fluorescence. For comparison, a mouse that got only a Pc 4 formulation without the AuNP vector injected is shown in panel (d). No circulation of the drug in the body or into the tumor was detectable 2 h after injection without the AuNP as drug vector. Reprinted with permission from Ref. [84].

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Figure 8: [64]. Effect of MTX-CS-NPs and free MTX on apoptosis of (a) HeLa cells and (b) MCF-7 cells determined by fluorescence microscopy after AO/BE staining. Results are expressed as the percentage of viable, apoptotic and necrotic cells after 24 h treatment with 1, 10 or 50 mg/ml of MTX-CS-NPs or free MTX. Fluorescent micrographs of HeLa cells: (c) Untreated control cells, (d) 50 mg/ml free MTX, (e) 50 mg/ml MTX-CS-NPs and of MCF-7 cells: (f) Untreated control cells, (g) 50 mg/ml free MTX, (h) 50 mg/ml MTX-CS-NPs. Legends: (►) typical live nuclei, (▼)chromatin condensation (early apoptosis), (▲) blebbing and nuclear margination (early to moderate apoptosis), (*) necrosis, (**) late apoptosis. Statistical analyses were performed using ANOVA followed by Dunnett’s or Tukey’s multiple comparison tests. *p < 0.05 and **p < 0.005 denote significant differences from untreated control cells. a significantly different from free MTX (p < 0.05).

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Figure 9: Cytotoxic effect caused by synthesized silver nanoparticles using plant extract Solanum triobatum, showed good activity against Human breast cancer MCF-7 cell

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Figure 10: The Effects of Capped GNPs in Recipient MCF7 Cells. (a) MCF7 Cells were Treated with or without GNPs, for 48 h, and then Observed under Microscopy. (a): Microscopy Image of Normal MCF7 Cells, (b; c; d; e; f): Microscopy Image of MCF7 Cells Treated with GNPs at Concentrations of 0.375; 0.75; 1.5; 3 and 6 µl/ml, respectively.

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Figure 11: In vitro cytotoxic applications of the capped GNPs prepared using Corallina officinalis extract against human breast cancer (MCF7) cell line

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Figure 12: Microscopic view of parasites (a) in the control group (not exposed to AuNPs and (b) in the group visible to AuNPs in the dark for twenty four hour.

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Figure 13: Optical microscopy of NP-treated RBCs. Normal morphology of RBCs (a, control) with biconcave structure and smooth surface, Ag-starch treated (100 µgmL -1) RBCs (b) with numerous ghost cells and swollen RBCs, Ag-starch-treated (400 µgmL-1) RBCs showing heavy hemolysis, many ghost cells, and a few RBCs, indicating significant haemolysis (black arrows and circles). Ag-PVA-treated (100 µgmL-1) RBCs (d) showing haemagglutination (black arrow), Pt-PVA-treated (400 µgmL-1) RBCs (e) displaying normal morphology, Au-PVAtreated (400 mgmL-1) RBCs (f) showing normal morphology, Ag+- (g) and NaBH4 - exposed (h) RBCs showing no morphological deteriorations. Inset pictures shows magnified RBCs. Scale bar in inset pictures corresponds to 10 mm.

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Figure 14: Electron micrographs of untreated RBCs (a) showing smooth biconcave structure, Ag-starch treated RBCs (b) showing cells with ruffled membrane and spiky projections, Ag-PVA treated RBCs (c) showing multiple aberrant cells, Au-PVA treated RBCs (d) with normal morphology. Pt-PVA treated RBCs (e) showing normal membrane and shape, PVA treated (capping agent) RBCs (f) expressing normal morphology. All RBCs were treated with 400 µgmL-1 of either NPs or PVA. Images were captured after 1.5 h of NP exposure.

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Figure 15: Concentration of free Ag+ ions and silver-ammonia complex Vs the NH3 Concentrations. The total [Ag] = 0.001M

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Figure 16: A plot of MIC silver nanoparticles synthesized by modified Tollens 80 process with D-maltose and therefore modified by addition of SDS, Tween 80, and PVP 360 in concentration of 1% (w/w).

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Figure 17: The antioxidant applications of Ag and AuNPs and their respective salts. (A) DPPH antioxidant of Au & AgNPs (B) ·OH scavenging assay of Au and AgNPs (C) super Oxide radical scavenging assay of Au and AgNPs (D), Nitric Oxide radical scavenging assay of Au and AgNPs. Catechin was used as a reference

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List of tables Table 1: Hemolytic property of AuNPs on RBCs at different concentration

Hemolytic activity (%)(OD540 nm) 1.22±0.18 103 ±0.0 1.22±0.11 1.24±0.15 1.23±0.0 1.25±0.12 1.27±0.11 1.29±0.13

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Sample (n=3) Control 1% Triton X-100 AuNPs (12.5 µg) AuNPs (25 µg) AuNPs (50 µg) AuNPs (75 µg) AuNPs (100 µg) AuNPs (125 µg) a

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The experiment are repeated in triplicate and the results are presented ± as standard deviationOD540 nm is the optical density at 540 nm

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Table 2: ESR reading of control and Np-exposed blood samples Sample

Column height of plasma [mm] 12

Starch

16

PVA

12

Ag-Pva

17

Ag-starch

12

Pt-PVA

17

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Control

8

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ACCEPTED MANUSCRIPT Table 3: Antimicrobial activity of silver nanoparticles and silver nitrate against different bacterial species. Antimicrobial activity was calculated in terms of zone of incubations (mm). Bacillius subtilius, pseudomonas aeruginosa and E. coli were incubated with silver nanoparticles or silver nitrate for 24 hr. for standered Octadisic, combi IV from Himedia was used [109]. S.No

Bacteria species

Inhibition zone (mm) Standered (Himedia Octadisic, combi IV) Ag (nanoparticles)

AgNO 3 (salt) 1µg 10µg 100µg 1000µg

Bacillus subtilus

12

5

8

9

10

4

5

8

9

2

Pseudonas aeryginosa

16

3

9

10

11

2

6

8

10

3

E.Coli

15

4

9

10

12

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1µg 10µg 100µg 1000µg

1

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10

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ACCEPTED MANUSCRIPT Table 4: Some important physical, chemical and photochemical methods for synthesizing and stabilizing silver NPs Reducing agent

Stabilizer agent

Size (nm)

Chemical reduction

Silver precursor AgNO3

DMF

----

< 25

Chemical reduction

AgNO3

NaHB4

Ssurfactin( a lipopeptide

3-28

Method

biosurfactant) Chemical reduction

AgNO3

Trisodium citrate (initial) +

Trisodium citrate

T

SFS (secondary )

<50

AgNO3

Trisodium citrate

Trisodium citrate

30-60

Chemical reduction

AgNO3

Ascorbic acid

--

200-600

Chemical reduction

AgNO3

NaBH4

DDA

Chemical reduction

AgNO3

Paraffin

Chemical reduction

AgNO3

Destrose

AgNO3

Hydrazine

AgNO3

Glucose

AgNO3

Ethylene glycol

Chemical reduction

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(polyol process) AgNO3

(polyol process) Electrochemical

AgNO3

10-14

PVP

22±4.7

Electrolysis , cathode ,

--

2-10

Gluconic acid

40-80

PVP

5-25

PVP

50-115

PVP

~11

SDS

15-260

titanium anode

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Ethylene glycol

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Chemical reduction

~7

Oleylamine

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Chemical reduction

m-hydroxy- Benz aldehyde

Physical synthesis

Silver wire

Electrical discharge , water

--

~10

Physical synthesis

AgNO3

Electrical are discharge

Sodium citrate

14-27

Chemical reduction

AgNO3

Hydrazine hydrate

AOT

2-5

AgNO3

Hydrazine hydrate

AOT

<1.6

AgClO4

Ethylene glycol

--

17-70

(polyol process)

(Tollen)

AgNO3

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(microemulsion) Chemical reduction (microemulsion) Photochemical reduction plus radiolysis

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AgNO3

Ethylene glycol

PVP

5-10

AgNO3

UV light

--

4-10

Ag2SO4

X-ray

--

AgNO3

CMCTS,UV

reduction plus microrediation Photochemical reduction(Photoche mical reduction photoreduction ( X-

reduction( X-ray

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radiolysis)

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Plant

Fungi

Algae

Aeromonas sp,SH10

Aloe vera leaf

Nitrate reductases

Spirulina platensis (alga)

(bacterium)

(plant)

(from fusarium

Klebsiella pneumonia

Azadiracha

Phaeneroechaete

(bacterium)

indica(plant)

chrysosprium (fungus)

Lactobacillus strain

Cinnamomum

Verticllium sp (Fungus)

(bacterium)

camphora (plant)

Oxysporum) Oscillatoria willei( alga)

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Gelidiella

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Aspergillus fumigatus

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graveolens

(fungus)

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Fusarium oxysporium

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Enterobacter clocaca

leaves

Fusarium semiectum

(plant)

(fungus)

Pinus eldarica

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DMF; N.N-dimethylformaamide, NaHB4; Sodium borohydrate, SFS: sodium formaldehyde sulphoxylate, DDA: Dodecanoic acid, PVP: polyvinyle pyrrolidone,SDS: sodium dodecyle sulphate, AOT; Bis(2-ethylehexyl) sulfosuccinate, CMCTS; carboxymethylated chitosan

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0.01d/hw

0.02d/hw

0.035d/hw

0.05d/hw

0.1d/hw

0.20d/hw

52/18

52/20

304/140

318/138

394/546

453/246

57/24

63/28

87/49

-/-

270/133

302/156

336/150

Glucose

50/15

50/16

53/19

54/22

58/26

314/170

343/181

Maltose

25/8

30/9

32/10

290/95

286/99

213/75

262/91

47/13

68/36

116/57

-/-

239/112

328/167

352/158

35/11

41/12

41/13

286/96

282/106

168/59

186/63

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glucose

maltose

lactose

control

d

control e

-c

--

13.5

54.00

6.75

-c

6.75

54.00

6.75

6.75

6.75

-c

Echerichia coili CCM 3954

27.00

--

3.38

27.00

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Bacteria

1.69

-c

Pseudomonas aeruginosa CCM

27.00

--

6.75

13.5

0.84

-c

Pseudomonas arruginosa

13.5

27.00

3.38

13.5

0.84

-c

Staphylococcus epidermisa

13.5

6.75

1.69

6.75

0.84

-c

Staphylococcus epidermisb

6.75

54.00

1.69

6.75

1.69

-c

Staphylococcus aureus MRSA

27.00

54.00

6.75

27.0

6.75

-c

Enterococcus aureus (VRE)

-c

-c

13.5

54.0

3.38

-c

Klebsiella pneumonia (ESBL-

27.0

-c

6.75

54.0

3.38

-c

Enterococcus faecalis CCM 4224 Staphylococcus aureus CCM

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Methicillin-susceptible, b Methicillin-resistant. Growth inhibition of bacteria unsubstantiated. Control sample containing all initial reaction components without reducing saccharides. e Control sample containing all initial all initial reaction components without silver nitrate, MIC and BMC of silver sols had same value

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Sample

Mean diameter (nm) 9±2 14±5

yield (%)

406 405

65.77 82.51

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SHC-1 SHC-2 1. 1 mM AgNO3

ƛ (nm)

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SHC-1

SHC-2

SHS-1

SHCS-1

9±1.0

10±1.0

32±0.7

26±0.5

Pseudomonas aerueus CCM 3953

9±0.5

11±0.3

29±1.0

19±0.6

Staphylococcus aureus CCM 3953

12±0.4

11±0.6

34±0.5

31±1.0

Staphylococcus aureus MRSA

11±0.6

11±1.0

40±0.3

29±0.5

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Escherichia coli

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Minimum inhibitory concentration (µg/mL) SHC-1 14.38 14.38

SHC-2 28.77 28.77

14.38 14.38

28.77 28.77

SHS-1 258.89 6.74 258.89 258.89

SHCS-1 215.74 215.74 215.74 215.74

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Escherichia coli CCM3954 Pseudomonas aeruginosa CCM 3955 Staphylococcus aureus CCM3953 Staphylococcus aureus MRSA

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Silver concentration in the final rinsing solution (mg/L) 1.05 0.89 0.66 1.19

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SHC-1 SHC-2 SHS-1 SHCS-1

Initial silver concentration (mg/L) 116.28 112.72 621.33 595.44

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positive control Fluconazole 100µg/well

Test organism 25µg

50µg

100µg

Trichophyton simii

12

21

27

22

2

Trichophyton mentagogrophytes

13

20

26

21

3

Trichophyton rubrum

--

17

21

29

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Biological applications

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Physical and chemical method to nanoparticle synthesis

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Anti-cancer properties of green synthesis nanoparticles

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