Therapeutic applications of green-synthesized silver nanoparticles

CHAPTER

Therapeutic applications of green-synthesized silver nanoparticles

16

Rajesh Kotcherlakota⁎,†, Sourav Das⁎,†, Chitta Ranjan Patra⁎,†

Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India⁎ Academy of Scientific and Innovative Research (AcSIR), Chennai, India†

­C HAPTER OUTLINE 1 Background.......................................................................................................... 391 1.1  History of Metal Nanoparticles............................................................... 391 1.2  Nanomedicine for Disease Therapy......................................................... 391 1.3  Significance of Metals and Metal Nanoparticles in Biology and Medicine... 392 2  Green Chemistry.................................................................................................... 393 2.1  Synthetic Strategies of Silver Nanoparticles............................................ 393 2.2  Characterization of Biosynthesized Silver Nanoparticles............................ 395 2.3  Mechanism of Biosynthesized Silver Nanoparticle Formation.................... 395 2.4  Biological Sources of Silver Nanoparticle Synthesis................................. 397 3  Therapeutic Applications of Biosynthesized Silver Nanoparticles............................. 400 3.1  Anticancer Properties............................................................................ 401 3.2  Drug Delivery Applications..................................................................... 403 3.3  Antiangiogenic Therapy......................................................................... 404 3.4  Antimicrobial Activity............................................................................ 405 3.5  Neuroregenerative Therapy.................................................................... 407 3.6  Antidiabetic Activity.............................................................................. 410 3.7  Antiinflammatory Activity...................................................................... 411 3.8  Wound Healing..................................................................................... 413 3.9  Anticoagulating Activity......................................................................... 414 4  Diagnostic Applications of Biosynthesized Silver Nanoparticles............................... 415 4.1  Bioimaging Applications........................................................................ 415 4.2  Biosensing Applications........................................................................ 417 5  Limitations of Biosynthesized Nanoparticles........................................................... 418 6  Toxicity of Biosynthesized Silver Nanoparticles...................................................... 419 7  Conclusions and Future Prospects.......................................................................... 419 Acknowledgments..................................................................................................... 420 References............................................................................................................... 420

Green Synthesis, Characterization and Applications of Nanoparticles. https://doi.org/10.1016/B978-0-08-102579-6.00017-4 © 2019 Elsevier Inc. All rights reserved.

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­ABBREVIATIONS ABTS AgNO3 AgNPs Ag-PL NPs AKT AuNPs b-AgNPs BSA CAM COX DDS DLS DPPH E. coli EDAX ERK FDA FT-IR GPC H2O2 HaCaT HCT-15 HeLa Hep-G2 HMSNP HPAEC HRTEM ICP-MS IL1α IL1β IL-6 iNOS LOD LSH MDA-MB-231 MHB MIC NB NF-κB NMR P38 MAPK PBMC

2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) silver nitrate silver nanoparticles silver (protein-lipid) nanoparticles protein kinase B gold nanoparticles biologically synthesized silver nanoparticles bovine serum albumin chick chorioalantoic membrane cyclooxygenase drug delivery system dynamic light scattering 1,1-diphenyl-2-picrylhydrazyl Escherichia coli energy dispersive X-ray spectroscopy extracellular signal-regulated kinases Food and Drug Administration Fourier transform infrared spectroscopy gel permeation chromatography hydrogen peroxide nonmalignant epithelial cell line (human keratinocyte cells) human colon cancer cell line cervical adenocarcinoma epithelial cells human epithelial liver carcinoma cells herbal-mediated silver nanoparticles high-performance anion exchange chromatography high-resolution transmission electron microscopy inductively coupled plasma mass spectroscopy Interleukin 1 alpha Interleukin 1 beta Interleukin 6 nitric oxide synthase limit of detection linseed hydrogel human adenocarcinoma breast cancer cell line Mueller-Hinton broth minimum inhibitory concentrations nutrient broth nuclear factor kappa-light-chain-enhancer of activated B cells nuclear magnetic resonance P38 mitogen-activated protein kinases human peripheral blood mononuclear cells

1 ­Background

PRECs PVA RAW264.7 RNAi ROS S. aureus SEM SPR TEM XPS XRD

porcine retinal endothelial cells polyvinyl alcohol mouse macrophage cell line ribonucleic acid interference reactive oxygen species Staphylococcus aureus scanning electron microscope surface plasmon resonance transmission electron microscopy X-ray photoelectron spectroscopy X-ray diffraction

1 ­BACKGROUND 1.1 ­HISTORY OF METAL NANOPARTICLES Since ancient times, different inorganic metals/metal ions have been used for the treatment of various diseases and other biomedical applications [1–5]. For instance, gold is predominant in biological uses. The history of civilization shows the extensive use of gold in disease therapy [6]. Indian ayurvedic medicine uses gold as “Swarna Bhasma” for old age rejuvenation and revitalization [7]. Silver is another noble metal used extensively for various biological applications. Ancient Greeks and early Americans used silver as a sterilizing agent to store liquids [8]. Gold and silver were used in the form of “bhasma” (swarna and rajat; nothing but nanoparticles) for asthma, anemia, chronic fever, cough, sleeplessness, weak digestion, and muscle weakness [9, 10]. Paracelsus, who was the father of pharmacology, used silver as a wound healing agent in 1520 [11]. Readers interested in learning more about metalbased nanoparticles and their applications can consult various books and articles [12–15].

1.2 ­NANOMEDICINE FOR DISEASE THERAPY The branch of medicine that uses nanotechnology tools and proficiency to prevent and treat disease is called nanomedicine. Nanomedicine is a vast developing area of science offering alternative treatment methods over conventional approaches for disease therapy and diagnosis, and aids in understanding complex biological systems [16]. The cellular machinery, including proteins (~10 nm), nucleic acids (~2 nm), and viruses (~50 nm), is in the nanoscale range. The dimension of man-made nanoparticles is comparable with these biological components. Therefore, n­ anoparticles can easily interact with cellular components, nucleic acids, and proteins after internalization into the cells, and can be used for therapeutic and diagnostic purposes [17]. Blood circulation in a living system allows the flow of 20-nm-sized particles, which could distribute into the different organs to monitor biological systems. Additionally, the nonspecific uptake of chemotherapeutic agents is a major challenge in cancer

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treatment [18]. Hence, nanotechnology plays an important role in the targeted delivery of therapeutic agents, thereby reducing their toxic effects [13]. A large number of metal nanoparticle applications have been studied in various disease therapies such as angiogenesis, microbial infections, diabetes, neuroregenerative therapy, and disease diagnosis. The vast biological applications of metal nanoparticles have been discussed in previous chapters [12, 13]. Nanomedicine is categorized into three areas of application: (1) therapeutic nanomedicine, (2) diagnostic nanomedicine, and (3) theranostic nanomedicine [19]. In therapeutic nanomedicine, nanoparticles are used for disease therapy without need of drugs. Several investigators, including our group, developed nanoparticles that exhibited therapeutic effects as anticancer, antimicrobial, and angiogenesis agents [20]. Similarly, nanoparticles were employed as vehicles to deliver therapeutic agents (drugs, nucleic acids, proteins) either by passive or active targeting strategies [21]. Diagnostic nanomedicine, on the other hand, assists in early identification of diseases either noninvasively way or by measurement of disease biomarkers [19]. An advanced nanomedicine that performs therapy and diagnosis at the same time is called theranostic nanomedicine. Nanoparticles having both a therapeutic effect (like anticancer, antimicrobial) and imaging efficacy (having fluorescence, luminescence, etc.,) fall under this category [22]. Biosynthesized silver nanoparticles also possess both therapeutic and diagnostic potential, which will be explained in detail in later sections.

1.3 ­SIGNIFICANCE OF METALS AND METAL NANOPARTICLES IN BIOLOGY AND MEDICINE Every living system needs metal ions to perform various biological activities governed by the metal ions in the body for their survival. This has been a matter of discussion and examintion for quite some time. Several limitations in using bulk materials motivated scientists to work more on nanosized materials [23]. In the last few decades, researchers have engaged in various projects involving the use of inorganic metal nanoparticles, compared to bulk materials, due to their unique physicochemical properties that could be exploited in divergent diagnostic and therapeutic applications [24, 25]. The eventual discovery of nanotechnology has been a boon to human society, paving the path toward the development of new nanoparticles with divergent applications. Intensive research has yielded different nanoparticles of controlled size and shape, and has evaluated their applications (imaging agents, sensors, biomarkers, and therapeutic as well as diagnostic tools). Generally, metal nanoparticles comprised of gold, silver, platinum, iron, silica, copper, zinc, and some lanthanides are used as carriers of different biomolecules, specifically drugs, nucleic acids, peptides, and antibodies. They can act as diagnostic and therapeutic agents of various disease models including cancer, microbial infections, cardiovascular disease, and neurodegenerative disease [26]. As nanomedicine could play a remarkable role because of its various advantages such as better half-life, therapeutic efficacy, bioavailability, and reduced toxicity, the nanomedical approach can extend its arm toward fruitful

2 ­Green chemistry

biological applications [27]. Because numerous applications of metal nanoparticles are available in the literature, this chapter focuses on medicinal applications of silver nanoparticles, specifically, biosynthesized silver nanoparticles.

2 ­GREEN CHEMISTRY According to the literature, there are 12 basic principles of green chemistry: (1) prevention, (2) atomic economy, (3) less hazardous chemical syntheses, (4) designing safer chemicals, (5) safer solvents and auxiliaries, (6) design for energy efficiency, (7) use of renewable feedstocks, (8) reduced derivatives, (9) catalysis, (10) design for degradation, (11) real-time analysis for pollution prevention, and (12) inherently safer chemistry for accident prevention, which are mentioned by Paul Anastas and John Warner [28, 29]. The field of green chemistry is a newly evolving area that has drawn the attention of investigators to develop various nanomaterials for numerous applications [30]. Notably, biological resources (such as microbes and plants) can produce those nanoparticles that display various properties such as anticancer, antibacterial, and antidiabetic abilities. The biological constituents participate in the reduction process to make nanoparticles [31]. During the synthesis process, the active ingredients from biological sources (such as anticancer molecules, fluorescent pigments, or proteins) can attach on to the surface of the nanoparticles, which helps in the formation of in-situ delivery systems. This type of biosynthesized nanoparticle exhibits many more therapeutic benefits than the chemically synthesized nanoparticles. Among various nanoparticles, silver nanoparticles produced through biological methods have exhibited tremendous biomedical applications. The following sections will describe the recent progress toward and various biological properties of biosynthesized silver nanoparticles.

2.1 ­SYNTHETIC STRATEGIES OF SILVER NANOPARTICLES The eco-friendly methods in chemistry and chemical technologies developed out of concern for environmental problems [32]. Silver nanoparticles are highly commercialized materials, with 500 tons produced every year, and are expected to increase next year. Silver is one of the most commercialized nanomaterials, with increased silver nanoparticle production reported every year [33]. Hence, an ideal route for silver nanoparticle synthesis that provides a simple, cost-effective, eco-friendly method is required. Currently, there are several methods available to synthesize silver nanoparticles: (i) Physical method. (ii) Chemical method. (iii) Biological method [34]. i. Physical method Different physical methods are generally applied to fabricate nanoparticles. There are two subdivisions of these methods: (1) mechanical, which includes high energy ball milling and melt mixing, and (2) vapor, which includes physical vapor deposition, laser ablation, electric arc deposition, ion implantation, and sputter deposition

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[35–39]. The major drawbacks of these techniques are the introduction of structural defects and surface contamination during synthesis, as well as their use of sophisticated instruments, which increases the cost of production. ii. Chemical method Chemical methods are also used to synthesize nanoparticles. It encompasses various methods such as coprecipitation, chemical reduction, electrochemical, microemulsion, pyrolysis, phytochemical, sonochemical, and microwave-assisted synthesis [40–42]. For example, colloidal nanoparticles are synthesized using a chemical method. The sol-gel method of forming nanoparticles also falls into this category [43]. The chemical method has several advantages such as using inexpensive instruments, doping of foreign materials, high yield, the possibility of obtaining a variety of sizes and shapes, and a potential for self-assembly and patterning. However, these first two methods require hazardous chemicals, which may have toxic effects upon biological systems. Therefore, alternative, eco-friendly, cost-effective methods are urgently required to prepare silver nanoparticles. However, chemical and physical methods are not under the scope of this chapter. Hence, we will explain recent advancements in biosynthesis methods for silver nanoparticle preparation (Scheme 1). iii. Biological method Recent advancement in green chemistry approaches for silver nanoparticles synthesis has proven its potential in all biomedical applications. Synthesis of silver nanoparticles using different biosources has always been an exciting task for scientists due to their versatile applications. Various researchers have used different biological sources for the synthesis of silver nanoparticles including microbial sources (like bacteria, fungi, and their culture media) and plant sources (extracts of leaves, root, flowers, seeds, stems, and fruits). Some recent literature describing the utilization of biological sources for silver nanoparticle preparation will be discussed in the following sections. Silver nanoparticles

Physical method

Microbes • •

Extracellular Intracellular

Biological method

Chemical method

Plants

Algae • • • • •

Leaves Stems Flowers Seeds Fruits

SCHEME 1 Synthesis strategies for synthesis of silver nanoparticles.

Others • • • •

Algae Leishmania Lysozymes Egg whites

2 ­Green chemistry

2.2 ­CHARACTERIZATION OF BIOSYNTHESIZED SILVER NANOPARTICLES Characterization is an important step after the synthesis of nanoparticles. There are several physiochemical methods currently available to characterize nanomaterials to understand their crystallinity, size, shape, hydrodynamic radii, charge, and surface functional groups. Detailed characterization of nanomaterials using various analytical methods lets us understand their biological fate when introduced into the body. Currently, various analytical methods are used to assess nanomaterial properties, including UV-visible spectroscopy (to detect SPR spectra), XRD (for surface crystallinity), TEM (to understand the size), SEM (to analyze the shape), DLS (to assess the size and charge), FTIR (to detect the functional groups), XPS (to analyze elemental composition), and ICP-MS (to detect metal concentration). In recent years, various research groups, including ours, synthesized biosynthesized silver nanoparticles and characterized them using the previously mentioned analytical tools. For example, Ramalingam et al. synthesized silver nanoparticles using cell-free protein of Rhizopus oryzae and characterized them by various analytical techniques including UV-visible spectroscopy, HRTEM, DLS, and FTIR (Fig. 1) [44]. The as-synthesized AgNPs displayed an SPR band at 420 nm, whereas the DLS study of AgNPs exhibited size of 9.1 ± 1.6 nm and charge −17.1 ± 1.2 mV. The HRTEM analysis demonstrated that the size of the AgNPs was 7.1 ± 1.2 nm, which supported the formation of AgNPs. Meanwhile, the FTIR analysis proved the in-situ conjugation of protein molecules with AgNPs evidenced from the shifting of the –NH/OH stretching vibrations (Fig. 1) [44]. Similarly, Fei et al. synthesized silver nanoparticles using Bombyx mori silk fibroin and employed TEM as their nanoparticle characterization method, which showed that the particles were 12.0 ± 2.1 nm in size (Fig. 2) [45]. The as-synthesized AgNPs showed an SPR band at 440 nm along with a small hump at 347 nm, suggesting the presence of different morphologies and sizes. The HRTEM of the AgNPs measured the d-spacing of individual nanoparticles, which fell in the range of 0.23 nm, which were comparable with the (111) lattice plane of Ag (Fig. 2). Balashanmugam et al. employed the EDAX method to confirm the presence of silver ions in silver nanoparticles synthesized from Cassia roxburghii DC aqueous extract [46]. For instance, our group also used the DLS method in our study to determine the size of silver nanoparticles prepared from Olax scandens. The authors found that the biosynthesized silver nanoparticles exhibited sizes of 55–85 nm and negative charge from −10.1 ± 0.7 to −15.2 ± 0.5 [47].

2.3 ­MECHANISM OF BIOSYNTHESIZED SILVER NANOPARTICLE FORMATION The exact mechanism of silver nanoparticle formation from biological sources is not completely understood. However, researchers have explained that plant extracts act as reducing and stabilizing agents in the formation of silver nanoparticles. According to the literature, the presence of polyphenolic/alcoholic compounds or aldehydes/ketones and protein molecules is responsible for the reduction of AgNO3

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Cell free protein AgNO3

(B) AgNPs

Absorbance (a.u)

AgNPs

AgNO3

Protein

3

2

24 h 20 h 16 h 12 h 8h 4h 1 min

1

0 300

400 500 600 Wavelength (nm)

700

800

10 nm

50 nm

25

(F)

(G) % Transmittance

20 Count (%)

396

15 10 5 0

AgNPs Protein extract

2

4

6 8 10 Particle size (nm)

12

14

4000

3000

2000

1000

Wavenumber (cm–1)

FIG. 1 Color photograph (A) and UV-vis spectra (B) of AgNPs synthesized using cell-free protein of R. oryzae. Low- (C) and high-resolution (D) TEM images and corresponding SAED pattern (E) of the synthesized AgNPs. Histogram particle size distribution (F) of the synthesized AgNPs and FTIR spectra (G) of the control cell-free protein and biosynthesized AgNPs. Reproduced with permission from Ramalingam B, Parandhaman T, Das SK. Antibacterial effects of biosynthesized silver nanoparticles on surface ultrastructure and nanomechanical properties of gram-negative bacteria viz. Escherichia coli and Pseudomonas aeruginosa. ACS Appl Mater Interf 2016;8:4963–76, Copyright © 2016 American Chemical Society.

to form ­silver nanoparticles. On the other hand, low and high molecular weight proteins also may participate in the synthesis of silver nanoparticles. Our group has studied the synthesis of silver nanoparticles using Butea monosperma plant extract where the mechanism of nanoparticle formation was proposed to have occurred through redox reaction (Fig.  3) [48]. This can be understood by ­comparing the

2 ­Green chemistry

FIG. 2 UV-vis spectra (A) and TEM (B−D) images of the synthesized RSF-AgNPs composites ([RSF] = 1 wt%, [AgNO3] = 4 mg/mL). Reproduced with permission from Fei X, Jia M, Du X, Yang Y, Zhang R, Shao Z, et al. Green synthesis of silk fibroin-silver nanoparticle composites with effective antibacterial and biofilm-disrupting properties. Biomacromolecules. 2013;14:4483–8, Copyright © 2013 American Chemical Society.

r­ eduction potential values of Au3+/Au0 (E0Au3+/Au0) and Ag+/Ag0 (E0Ag+/Ag0) (1.50 V and 0.80 V, ­respectively) with reduction potentials for aldehyde/alcohol, acid/aldehyde, quinone/phenol, and proteins ([E0] 0.80 V). This suggests the role of plant active components in the formation of metal nanoparticles. Apart from this explanation, researchers also found that microbial enzymes also participate in the reduction of silver ions. For example, Ahmad et al. identified a NADPH-dependant reductase enzyme responsible for synthesis of silver nanoparticles in Fusarium oxysporum fungus [49, 50].

2.4 ­BIOLOGICAL SOURCES OF SILVER NANOPARTICLE SYNTHESIS The aptitude of biological sources (microorganisms, culture media, and plant extracts) to reduce metals into nanoparticles has opened eco-friendly approaches in the advancement of green chemistry [51]. Several medicinally important

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FIG. 3 The plausible mechanism for the formation and stabilization of biosynthesized gold and silver nanoparticles from HAuCl4 and AgNO3 solution using Butea monosperma extract. Reproduced with permission from Patra S, Mukherjee S, Barui AK, Ganguly A, Sreedhar B, Patra CR. Green synthesis, characterization of gold and silver nanoparticles and their potential application for cancer therapeutics. Mater Sci Eng C 2015;53:298–309, Copyright © 2015 Elsevier Inc. All rights reserved.

b­ iomolecules from biological sources including alkaloids, proteins, phenols, saponins, tannins, enzymes, tannins, and terpinoids participate in the reduction and stabilization of nanoparticles [52]. Several research groups, including ours, synthesized silver nanoparticles using various biological sources [48]. The following sections will discuss the ability of various biological sources for the synthesis of silver nanoparticles.

2.4.1 ­From bacteria

Microorganisms can make nanoparticles through enzymes generated by their cellular activities either in the extra- or intracellular environment. For example, Gurunathan et al. prepared AgNPs from the culture supernatant of Bacillus funiculus. The authors confirmed the formation of nanoparticles by using different analytical techniques (UV-Vis, DLS, and TEM) [53]. Likewise, Das et al. reported the extracellular synthesis of silver nanoparticles (42–92 nm range) using Bacillus strain CS 11 obtained from an industrialized area. Using UV-vis spectroscopy, the authors confirmed the formation of silver nanoparticles, that exhibited the absorption peak at 450 nm [54]. Similarly, Garmasheva et  al. synthesized silver nanoparticles from Lactobacillus strains as an eco-friendly alternative method to chemical synthesis, demonstrating their antibacterial effects [55].

2 ­Green chemistry

2.4.2 ­From fungi

Fungus-mediated synthesis of silver nanoparticles also has more importance in biological applications. For instance, Husseiny et al. prepared size-controlled sphericalshaped silver nanoparticles from Fusarium oxysporum fungus [56]. On the other hand, Gurunathan et al. prepared water-soluble AgNPs using the mycelia of G. neojaponicum (Ganoderma neo-japonicum Imazeki) aqueous extract. The authors described synthesized AgNPs as potential cytotoxic agents against the breast cancer cell line (MDA-MB-231), which was confirmed through different biological assays (cell viability, lactate dehydrogenase leakage, caspase 3, ROS generation assay, TUNEL assay, etc.) [57]. Similarly, Xue et al. synthesized silver nanoparticles from soil-isolated Arthroderma fulvum fungal species and demonstrated their antifungal activities [58]. Recently, Gudikandula et  al. successfully synthesized AgNPs from white rot fungi with sizes ranging from 15 to 25 nm and demonstrated their antifungal effects [59].

2.4.3 ­From culture media

Silver nanoparticles can also be synthesized using microbial culture media, which generally refers to extracellular synthesis. Many of the microbial cultures secrete several proteins and sugars into the growth media that can help in the reduction process of nanoparticles. Various research groups have demonstrated the efficacy of the microbial culture media as a source in silver nanoparticles synthesis. For instance, Müller et al. studied culture media effects of Klebsiella pneumoniae UVHC5, Escherichia coli ATCC 8739, and Pseudomonas jessinii UVKS19 bacterial strains on silver nanoparticle synthesis [60]. The culture media also plays a crucial role in the size and shape of the silver nanoparticles. For example, Luo et al. studied the effect silver nanoparticle synthesis has in different culture media and found that nutrient broth (NB) and Mueller-Hinton broth (MHB) can significantly participate in the reduction of silver nanoparticles [61].

2.4.4 ­From plants

Whole plants or plants’ individual parts (stems, leaves, roots, flowers, and fruits) can be employed to synthesize silver nanoparticles. For example, Jang et al. synthesized AgNPs by using the flower extract of the Lonicera hypoglauca, which acted as a capping agent as well as reducing agent [62]. Lu et al. developed “one-pot” synthesis for AgNPs using freshly extracted egg white with the ability to reduce the Ag + ion. The authors also described that stability and dispersity of the particles depended on the proteins present in the egg white [63]. Rajasekhar et al. developed a one-step, eco-friendly method for the development of core-shell silver-(protein-lipid) nanoparticles (Ag-PL NPs) from the seed extract of Indian Almond tree, Sterculia foetida (L.) (Sterculiaceae), which were characterized through several physicochemical processes. The group suggested that the size of the core and shell of AgNPs depended on the reaction temperature [64]. Reddy et al. synthesized stabilized AgNPs (PLAgNPs) using the aqueous extract of Piper longum fruit (PLFE), which was b­ elieved to be

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stabilized through the phytoconstituents (polyphenols) present in fruit [65]. On the other hand, Sukirtha et al. developed a bio-green method for the synthesis of AgNPs using Melia azedarach. The author described the formation of silver nanoparticles (AgNPs) by several physicochemical processes [66]. Recently, Deyá et al. synthesized silver nanoparticles from plant extracts of Aloysia triphylla (cedrón), Laurelia sempervirens (laurel), and Ruta chalepensis (ruda), which were used in antimicrobial coatings to control indoor fungal pathogens [67]. Altogether, the different bio-green sources for synthesis are favored because of their low toxic effects on the environment promptly making them eligible for copious applications in the biomedical and industrial field.

3 ­THERAPEUTIC APPLICATIONS OF BIOSYNTHESIZED SILVER NANOPARTICLES Silver nanoparticles have tremendous biological applications including as anticancer, antibacterial, and antidiabetic agents, and in, bioimaging and biosensing, as already discussed in this section. The outline of the uses for silver nanoparticles in the biomedical field has been shown in the diagram (Scheme 2). The vast applications of silver nanoparticles led to the development of biosynthesized silver nanoparticles with more therapeutic effect due to previously m ­ entioned reasons such as the attachment of biological constituents with therapeutic potential.

Anticoagulating

Anticancer

Bioimaging

Antiangiogenic

Wound healing Silver nanoparticles

Biosensing

Antiinflammatory

Antidiabetic

Neuroregenerative

Antimicrobial

SCHEME 2 Applications of biosynthesized silver nanoparticles for disease therapy and diagnosis.

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

Moreover, the cost-effectiveness, bioavailability, and eco-friendly nature of nanoparticles leads us to focus more on green synthesis methods for the preparation of silver nanoparticles. Recent literature demonstrated that biosynthesized silver nanoparticles exhibited anticancer, antimicrobial, antiangiogenesis, wound healing, bioimaging, biosensing, neuroregenerative, antidiabetic, antiinflammatory, and anticoagulating activities. The following sections will demonstrate the various therapeutic applications of biosynthesized silver nanoparticles.

3.1 ­ANTICANCER PROPERTIES Increasing drug resistance, poor bioavailability, and the nonspecific toxic nature of chemotherapeutic agents limits their treatment effects. Hence, alternative treatment strategies are in high demand to cure cancer. Recent literature on the anticancer effect of biosynthesized silver nanoparticles suggests their future role as therapeutic agents to combat cancer. Several research studies proved that biosynthesized silver nanoparticles show effective anticancer properties. For example, Gurunathan et al. fabricated AgNPs using Bacillus funiculus culture supernatant, which exhibited antiproliferative activity in MDA-MB-231 (human breast cancer) cells through generation of ROS (reactive oxygen species), leading to apoptosis [53]. Similarly, Fageria et al. synthesized protein-capped silver nanoparticles using Penicillium shearii AJP05 fungus and demonstrated its anticancer effect on epithelial (hepatoma) and mesenchymal (osteosarcoma) cells. Generation of ROS was found to be the major reason for the cytotoxic effect of biosynthesized silver nanoparticles. The authors also claimed that these biosynthesized silver nanoparticles sensitize the cancer cells, making them cisplatin-resistant (Fig. 4) [69]. Likewise, Firdhouse et al. synthesized AgNPs from the plant extract of Alternanthera sessilis, which exhibited significant cytotoxic activity toward prostate cancer cells (PC-3) [68]. Scientists also found dual activity of the biologically synthesized AgNPs as both an antibacterial and anticancer agent. For example, Sankar et al. synthesized AgNPs using a bio-green route from the aqueous extract of Origanum vulgare (oregano), which was found to be useful for both antibacterial and anticancer activity. The research group described the dose-dependent efficacy of AgNPs toward the pathogens as well as human lung cancer cells (A549) [70]. Similarly, Rajasekharreddy et al. biofabricated AgNPs using Sterculia foetida L. seed extract, which exhibited enhanced killing ability toward human cervical cancer cell lines (HeLa). The researchers also found an application toward the antiangiogenic activity of the biosynthesized AgNPs [64]. Our group has already demonstrated the synthesis of silver nanoparticles using Olax scandens plant extract. The as-synthesized silver nanoparticles exhibited four applications as (i) biocompatible, (ii) imaging agent, (iii) anticancer, and (iv) antibacterial agents (Fig. 5). Generation of ROS and activation of p53 were found to be the nanoparticles’ anticancer mechanisms [47]. Ramar et al. developed biosynthesized AgNPs using ethanolic extract of rose (Rosa indica) petals, which demonstrated anticancer activity toward human colon cancer cells (HCT-15). The as-synthesized eco-friendly AgNPs mitigated toxicity levels while still retaining their anticancer activity [71].

401

FIG. 4 bAgNPs induce autophagy as a survival strategy. (A) Protein expression of autophagy marker LC3B-II was studied by immunoblotting after bAgNP treatment. Densitometric analysis of scanned immunoblots was performed by Image J software. β-actin served as a loading control. [The * symbol represents a significant difference (P < .05) as compared to that in untreated cells.] (B) For further confirmation of autophagy, MDC fluorescence staining was performed after 6 h and 24 h of bAgNP treatment in OS cells and green punctate bodies indicative of autophagosomes were monitored by fluorescence microscopy. The scale bar represents 100 μm. (C) Fluorimetric estimation of MDC activity was performed following bAgNP treatment (IC50 and high dose, 40 μg mL − 1) for 24 h in OS cells. [The * symbol represents a significant difference (P < .05) as compared to that in untreated cells.] (D) The cytotoxic effect of bAgNPs in OS cells was measured by the MTT assay after 24 h of bAgNP treatment in the presence or absence of the autophagy inhibitor (10 μM CQDP). The inhibitor was added 2 h before the treatment. [The (*) symbol represents a significant difference (P < .05) as compared to that in bAgNP-treated cells.] (E) Morphological changes observed in OS cells after bAgNP treatment in the presence or absence of the autophagy inhibitor are analyzed by phase contrast microscopy. The scale bar represents 20 μm. (F) ROS levels were measured after autophagy inhibition by CQDP in bAgNP-treated cells by DCFH-DA. ROS levels in untreated cells were taken as arbitrary unit “1”. [The * symbol represents a statistically significant difference (P < .05) as compared to that in only bAgNp treatment. Reproduced with permission from Fageria L, Pareek V, Dilip RV, Bhargava A, Pasha SS, Laskar IR, et al. Biosynthesized protein-capped silver nanoparticles induce ros-dependent proapoptotic signals and prosurvival autophagy in cancer cells. ACS Omega 2017;2:1489–504, Copyright © 2017 American Chemical Society (Open access).

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

FIG. 5 Overall presentation for synthesis, characterization, and biomedical applications (diagnostic, anticancer, antibacterial applications) of biosynthesized silver nanoparticles (b-AgNPs) using Olax scandens leaf extract. Reproduced from Mukherjee S, Chowdhury D, Kotcherlakota R, Patra S, B V, Bhadra MP, et al. Potential theranostics application of bio-synthesized silver nanoparticles (4-in-1 system). Theranostics 2014;4:316–35 (Open Acess Journal).

3.2 ­DRUG DELIVERY APPLICATIONS Drug delivery with metal nanoparticles is an efficient strategy in medicine to treat various diseases [72]. Slow and sustained release of drugs and delivery in targeted sites are the two major criteria for efficient drug delivery systems [73]. These two criteria can be achieved through active or passive delivery methods [74]. The recent literature demonstrates the potential of various metal nanoparticles for drug delivery applications [75]. Among various metal nanoparticles, silver nanoparticle-based drug delivery is well studied for cancer therapy [48]. However, there are only a few reports available for drug delivery with biosynthesized silver nanoparticles. For instance, our group developed a cancer drug delivery system using silver nanoparticles synthesized from Butea monosperma plant extract. These silver nanoparticles were loaded with the FDA-approved chemotherapeutic drug doxorubicin to prepare drug delivery system (DDS) and demonstrated anticancer efficacy in various cancer cells in  vitro (Fig.  6) [48]. The DDS system efficiently delivered the doxorubicin into cancer cells and exhibited more cytotoxicity than a pristine drug. These findings

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FIG. 6 Overall schematic representation for the green synthesis and characterization of biosynthesized b-AuNPs and b-AgNPs, and their probable applications in drug delivery. Reproduced with permission from Mukherjee S, Barui AK, Ganguly A, Sreedhar B, Patra CR. Green synthesis, characterization of gold and silver nanoparticles and their potential application for cancer therapeutics. Mater Sci Eng C 2015;53:298–309, Copyright © 2015 Elsevier Inc. All rights reserved.

suggest that biosynthesized silver nanoparticles could be employed for designing drug delivery systems for cancer therapeutics. Similarly, Kumar et al. synthesized silver nanoparticles using Delftia sp. strain KCM-006 culture supernatant and demonstrated delivery of antifungal drug miconazole. The authors claimed that the drugloaded silver nanoparticles efficiently inhibited ergosterol biosynthesis and biofilm formation of fungus [76].

3.3 ­ANTIANGIOGENIC THERAPY Angiogenesis, a process for the establishment of new blood vessels from preexisting blood vessels (i.e., sprouting of vascular network), is essential for organ growth and repair, and has now become a major focus of research in the scientific community. It involves endothelial cell growth, differentiation, proliferation, migration, and invasion procedures [77]. In the process of embryonic development, and in the etiology of various pathologies including cancer, the formation of new blood vessels through angiogenesis has a pivotal role. The concept of antiangiogenesis was first proposed by Dr. Judah Folkman in the 1970s [78]. The antiangiogenic drug molecules suppress cell proliferation, tube formation, and migration of cells through the downregulation of different cytokines levels, which are associated with angiogenesis factors.

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

Of the different nanomaterials that researchers recently investigated, the antiangiogenic properties of green-synthesized silver nanoparticles are briefly described in this section. Sheikpranbabu et al. developed a procedure for the synthesis of AgNPs through Bacillus licheniformis biomass that demonstrated antiangiogenic properties by inhibition of IL-1β molecules and VEGF in porcine retinal endothelial cells (PRECs), leading to a reduction of the level of vascular permeability [79]. The group also revealed that the biosynthesized AgNPs suppressed the cell permeability in PRECs, which was induced by advanced glycation end products decorated bovine serum albumin (AGE-BSA) through stimulation of intracellular adhesion molecule-1 (ICAM1). The authors described the enhancement of tight junction protein (occludins and ZO-1) expression, as well as the controlling of Src signaling pathway by the usage of AgNPs [79]. On the other hand, Baharara et al. synthesized the AgNPs using Salvia officinalis plant extract, which exhibited antiangiogenic activity in chick chorio alantoic membrane (CAM) by reducing the hemoglobin content in the blood (total hemoglobin content was symbolized as blood vessel formation) [80]. Similarly, the same group also explored the antiangiogenic nature of biosynthesized AgNPs (using Achillea biebersteinii flowers extract) by employing the rat aortic ring model. The researchers demonstrated a reduction in the number as well as the length of blood vessels, which is indicative of antiangiogenic activity [81]. Gurunathan et  al. defined the antiangiogenic nature of AgNPs in bovine retinal endothelial cells (BRECs) by decreasing the VEGF-mediated cell proliferation, tube formation, and migration through inhibition of PI3K/Akt signaling pathway [82].

3.4 ­ANTIMICROBIAL ACTIVITY Pathogenic microorganisms have become the major threat to human health [83]. Several antibiotics are currently available to treat microbial infections. However, the emergence of antibiotic resistance and their toxicity limits their use in clinics. In this regard, nanotechnology promises an alternative treatment method to cure microbial infections. In particular, silver nanoparticles have become potent antimicrobial agents due to their effectiveness, which is superior to that of the antibiotics used in clinics. Recently, several investigators reported the antimicrobial effects of silver nanoparticles. In particular, biogenic silver nanoparticles demonstrated their remarkable antibacterial effects as shown in the recent literature. For example, Singh et  al. synthesized silver nanoparticles using culture supernatant of endophytic fungus (Raphanus sativus) and demonstrated their antibacterial effect on Gram-positive (methicillin-resistant Bacillus subtilis, MTCC 441, Staphylococcus aureus, MTCC 740) and Gram-negative (Escherichia coli, MTCC 443, and Serratia marcescens, MTCC 97) bacterial pathogens [84]. The authors claim that disruption of cell membrane and DNA is the major reason for the antibacterial effect of silver nanoparticles [84]. In another study, Abalkhil et al. prepared silver nanoparticles using Aloe vera, Portulaca oleracea, and Cynodon dactylon, and investigated their antibacterial effect against human pathogens. Using SEM analysis, the authors were shown that cell wall damage was the major event occuring during the antibacterial effect of silver

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nanoparticles [85]. Similarly, Karunagaran, et al. described the antibacterial effects of silver oxide nanoparticles synthesized through culture supernatant of Bacillus thuringiensis SSV1 [86]. Our group has already illustrated the antibacterial activity of silver nanoparticles prepared using Olax scandens plant extract. These nanoparticles displayed the potent antibacterial effect in a growth curve experiment and inhibited colony formation in bacteria. The results of the study further suggested that biosynthesized silver nanoparticles damage the cell walls of the bacteria (as observed in SEM) and disturb the cellular catalase enzyme levels by inducing cell death (Fig. 7) [47].

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FIG. 7 Study of antibacterial activities: (A) liquid growth inhibition kinetics of E. coli using different concentrations of b-AgNPs. b-AgNP-30 (at 30 μM) shows almost 100% growth inhibition. Ampicillin has been used as a positive control (PC) and NC: negative control or untreated E. coli. The number indicates the concentration of b-AgNPs in μM, (B–E) optical images of bacterial colonies formed by E. coli cells, that is, colony counting assay (after 24 h): B: control, C: ampicillin (100 μg/mL), D: b-AgNPs (18 μM), E: b-AgNPs (30 μM) and (F–H) SEM images of E. coli cells (F) without being treated (control), (G) treated with Olax for 1 h, (H) treated with b-AgNPs (30 μM) for 1 h. The SEM images show the silver nanoparticles damage the bacterial cell membrane (marked by blue arrow), whereas, the bacterial membranes of untreated and treated E. coli with Olax are intact. Reproduced from Mukherjee S, Chowdhury D, Kotcherlakota R, Patra S, B V, Bhadra MP, et al. Potential theranostics application of bio-synthesized silver nanoparticles (4-in-1 system). Theranostics 2014;4:316–35 (Open Acess Journal).

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

Biosynthesized silver nanoparticles can also synergize with antibiotics. For instance, Railean-Plugaru et  al. synthesized silver nanoparticles using Actinobacteria CGG 11n bacteria and evaluated the antibacterial activity in combination with kanamycin, ampicillin, neomycin, and streptomycin. Enhanced antibacterial effect was seen with a combination of biogenic silver nanoparticles and antibiotics [87]. Formation of biofilms that contain drug-resistant bacteria is the major challenge for conventional treatments. Fei et al. prepared biogenic silver nanoparticles using Bombyx mori silk fibroin and demonstrated the antibacterial effect in bacterial biofilms [45]. Using SEM and confocal microscopy, the authors have nicely demonstrated the antibacterial effect of synthesized silver nanoparticles. The results clearly indicate the damage of the bacterial films after treatment with biogenic silver nanoparticles (Fig.  8) [45]. Nanda et al. synthesized silver nanoparticles using Staphylococcus aureus culture supernatant and evaluated their antibacterial effect on methicillin-resistant S. aureus, Staphylococcus epidermidis, and Streptococcus pyogenes as well as on Salmonella typhi and Klebsiella pneumoniae [88]. The silver nanoparticles synthesized using plant extract also exhibit a potent antibacterial effect. When silver nanoparticles were synthesized by medicinally important plants, the antibacterial activity was especially high. For example, Singhal et al. synthesized silver nanoparticles (4–30 nm) prepared using Ocimum sanctum (Tulsi) leaf extract and assessed their antibacterial effect on Gram-negative E. coli and Gram-positive S. aureus [89]. Krishnaraj et al. also prepared silver nanoparticles using Acalypha indica leaf extracts and characterized them thoroughly. The results suggested that biosynthesized silver nanoparticles exhibited an antibacterial effect against waterborne pathogens, viz., Escherichia coli and Vibrio cholera [90]. Shaik et al. prepared silver nanoparticles using Salvadora persica L. root extract and demonstrated their antibacterial effect in bacterial strains in both Gramnegative and Gram-positive bacteria (Fig. 9) [91]. Similarly, Kaviya et al. prepared silver nanoparticles using Citrus sinensis peel extract and evaluated their antibacterial effect on Gram-negative Escherichia coli and Pseudomonas aeruginosa, and Grampositive Staphylococcus aureus bacteria. The authors claimed that biosynthesized silver nanoparticles were more potent for antibacterial effects [92].

3.5 ­NEUROREGENERATIVE THERAPY In neurodegenerative diseases, maintenance of neuronal activity is very i­mportant [93]. Neuroprotection, which actually relies on the preservation of the neuronal integrity, is hampered by different neurodegenerative diseases such as stroke, Parkinson’s disease, and spinal cord and brain injury [94]. To protect from such ongoing insults, or to slow down the process of degeneration, regeneration therapy is needed. Generally, regeneration is nothing more than conservation of neuronal activity, which includes growth, maintenance of a number of neuronal cells, etc. [95]. Here, we discuss the neuroregenerative activity of biologically synthesized silver nanoparticles. Dayem et  al. biologically synthesized spherical silver nanoparticles (AgNPs) using the bacterial E. coli-based templating method [96]. The group mentioned that the average size of the particles was 30 nm and the particles could

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FIG. 8 SEM (small magnification, A1−D1; large magnification, A2−D2) and CSLM images (A3−D3, with the same magnification of A1−D1) of maturely formed MASA biofilm after contact with RSF-AgNPs composite with different concentration at 37°C for 24 h (A1−A3, MIC; B1−B3, MBC; C1−C3, 2 × MBC; D1−D3, 5 × MBC). In the CSLM image, the live MASA emit green light, whereas the dead MASA emit red light. Reproduced with permission of Fei X, Jia M, Du X, Yang Y, Zhang R, Shao Z, et al. Green synthesis of silk fibroin-silver nanoparticle composites with effective antibacterial and biofilm-disrupting properties. Biomacromolecules. 2013;14:4483–8, Copyright © 2013 American Chemical Society.

be ­useful for differentiation of human neuroblastoma cells (SH-SY5Y), which are ideal for neurogenesis study of the in-vitro system. The authors showed that, with treatment of the AgNPs, there was a remarkable increment in length of neurite and enhancement of the divergent neuronal markers like β-tubulin III, neurogenin-1, synaptophysin, Drd-2, Gap-43, and Map2 expression. The authors described that, after

Graphical representation of green and chemical syntheses of silver nanoparticles (Ag-NPs) using S. persica L. RE and trisodium citrate, respectively, and evaluation of their microbicidal activities against various bacterial strains. Reproduced from Shaik RM, Albalawi G, Khan S, Khan M, Adil S, Kuniyil M, et al. “Miswak” based green synthesis of silver nanoparticles: evaluation and comparison of their microbicidal activities with the chemical synthesis. Molecules 2016;21:1478 (Open Acess Journal).

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exposure with the AgNPs, there was also stimulation of the kinases such as AKT and ERK. Following that, the group further observed the downregulation of dualspecificity phosphatases (DUSPs) with an elevation of intracellular reactive oxygen species (ROS). Meanwhile, these AgNPs not only regulated different signaling pathways, but also differentiated the neuron. Overall, the authors accentuated the utility of the biologically evaluated AgNPs on neuronal regenerative therapy for future use [96].

3.6 ­ANTIDIABETIC ACTIVITY Diabetes (a group of diseases) occurs due to metabolic disorder; when there is an increase in blood sugar levels due to insufficient production of insulin, the cells do not reciprocate toward insulin, or both. So, diabetes can be insulin-dependent or independent. There are several enzymes involved with this complicated disease; α-glucosidase and α-amylase are two of the key regulators among them. Green-synthesized silver nanoparticles are now being extensively used for antidiabetic therapy, which acts upon the suppression of the secretary level of enzymes. Here, we discuss a few such examples. Balan et al. followed a green synthesis approach for the synthesis of AgNPs from aqueous leaf extract of Lonicera japonica [97]. The synthesized AgNPs were characterized using different physicochemical techniques such as UV-vis, XRD, FTIR, and HR-TEM. The researchers mentioned that the spherical and hexagonal-shaped nanoparticles were stable with a size of 53 nm, charge of −35.6 mV, and absorption band at 435 nm owing to their surface plasmon resonance. Furthermore, the nanoparticles demonstrated effective antidiabetic activity against α-amylase (IC50 = 54.56 μg/mL) and α-glucosidase (IC50 = 37.86 μg/mL) carbohydrate digestive enzymes for diabetes. The authors also found out that AgNPs underwent reversible noncompetitive inhibitory activity with Ki values of 24.6 and 25.9 for α-glucosidase and α-amylase, respectively, which reflected the remarkable antidiabetic activity of AgNPs [97]. Prabhu et al. synthesized AgNPs using a green route from the aqueous leaf extract of Pouteria sapota. Spectroscopic method, XRD, and SEM confirmed the formation of the nanoparticles. The inhibitory effect on α-amylase and the nonenzymatic glycosylation of hemoglobin and uptake study of glucose solution by yeast cells on 5 or 10 mmol/L concentrations confirmed the antidiabetic activity of AgNPs. Meanwhile, the antidiabetic activity in an in-vivo model was evaluated in streptozotocin-induced rats for a 28-day duration. The authors mentioned that there was a significant reduction in blood sugar levels in rats by the treatment of leaf extract (100 mg/kg) or AgNPs (10 mg/kg). Finally, the authors emphasized the potential application of the green-synthesized AgNPs’ antidiabetic activity [98]. Dhivya et al. synthesized AgNPs following the green-synthetic approach using Momordica charantia extract. The UV-vis, FT-IR, SEM, etc., were generally used to characterize the nanoparticles. Synthesized AgNPs exhibited a remarkable inhibitory effect against enzymes such as α-amylase (one of the key enzymes for diabetes). The researchers utilized Acarbose as a standard drug that showed more IC50 value (88.3 μg/mL) compared to AgNPs prepared from bitter gourd extract (IC50 value, 49.86 μg/mL). Overall, the current investigation highlighted the green-synthetic approach of silver nanoparticles, which ultimately showed ­notable inhibitory effect on diabetic ­regulatory enzyme amylase. Saratale et al. explored a green synthetic method for the synthesis of AgNPs from

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

leaf extract of Argyreia nervosa (ANE) [99]. Surface plasmon resonance (λmax = 435 nm), FTIR, and HRTEM (average size, 15 nm) were used to characterize the ANE-AgNPs. The nanoparticles demonstrated the in-vitro antioxidant activity of ANE-AgNPs based on the free radical scavenging properties of DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2′-azino-bis[3-ethylbenzothiazoline-­6-sulphonic acid]). Meanwhile, the authors explained the efficacy of ANE-AgNPs as an antidiabetic agent through the suppressing effect against digestive enzymes α-glucosidase (EC50 = 51.7 μg/mL) and α-amylase (EC50 = 55.5 μg/mL). So, the authors accentuated the green synthetic approach for the synthesis of AgNPs, which acted as a multifunctional agent for antibacterial, antioxidant, and antidiabetic effect [99]. Saratale et al. reported for the first time a novel synthesis of silver nanoparticles (AgNPs) using leaf extract of Punica granatum (PGE) [100]. The synthesized PGE-AgNPs were characterized through UV-vis, XRD, DLS, XPS, and HRTEM. The researchers mentioned that PEG-AgNPs were spherical (size ranging from ~35–60 nm), highly negative (−26.6 mV), and crystalline in nature. The antidiabetic activity of PGE-AgNPs was observed through its effective inhibitory effect on α-glucosidase and α-amylase (IC50; 53.8 μg/mL, 65.2 μg/mL), respectively. Overall, the authors emphasized the multifunctional applications of PGE-AgNPs, which could be used as future medicine applications and in industrial and biomedical applications [100].

3.7 ­ ANTIINFLAMMATORY ACTIVITY Inflammation, a defense mechanism, is a critical process where the body responds to external stimuli, which can be pathogens, irritants, or damaged cells. The complicated process involves different cells including variant molecular mediators, immune cells, and blood cells [101]. On the other hand, inflammation sometimes causes harm greater than its beneficial activity and can persist for a longer time. The search for compounds that can prevent perpetual inflammation could be useful for health [102]. Here, the antiinflammation activity of green-synthesized silver nanoparticles is discussed. Moldovan et al. synthesized silver nanoparticles (AgNPs) by using the European cranberry bush (Viburnum opulus L.) fruit extract where the polyphenols (ascorbic acid, l-malic acid, and carotenoids) present acted as a strong antioxidant. The synthesized AgNPs were characterized through several techniques like UV-vis, FTIR, TEM, and XRD. The smaller size nanoparticles (size ~25 nm) showed antiinflammatory activity on the HaCaT cell line in vitro. The authors mentioned that there was a significant release of IL-1α triggered by the irradiation of keratinocytes (with UVB, 100 mJ/cm2) for treated cells compared to control cells in the culture media at 24 h and 48 h duration, which proved the antiinflammation activity caused by the AgNPs. The authors further extended the work by doing an in-vivo study in carrageenan-induced hind paw edema, where they moderated the cytokine release from the skin of Wister rats within 2 h of injection with AgNPs. The AgNPs exhibited inhibitory activity on cyclooxygenase (COX), which is one of the major factors for inflammation. Overall, the authors explained the activity of synthesized AgNPs as a beneficial therapeutic tool for treatment of inflammation [103]. Similarly, the same group led by David synthesized AgNPs (ranging from 20 to 80 nm) using the

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bio-green method from European cranberry bush (Sambucus nigra–SN, Adoxaceae family) fruit extract. The AgNPs demonstrated antiinflammatory activity on HaCaT cells that were exposed to UVB radiation and, by reduction of the inflammatory cytokines, in an in-vivo model. The authors shed light on the therapeutic application of eco-friendly AgNPs on psoriasis lesions of mice [104]. Likewise, Sriramulu et al. prepared AgNPs at room temperature as well as at 60°C from the forest mushroom (Ganoderm alucidum) and edible mushroom (Agaricus bisporus) extract where the extracts acted as reducing agents [105]. The synthesized AgNPs were characterized by various physicochemical techniques (UV-vis, FTIR, XRD, SEM). The authors demonstrated the nanoparticles’ antiinflammatory, antioxidant, and antibacterial activity against Staphylococcus aureus and Escherichia coli species. The researchers attested that the antiinflammatory activity of EHT (AgNPs prepared from edible mushroom) was much more than other prepared AgNPs with a protection activity (84% ± 0.25%) compared to standards such as aceclofenac antibiotic. Finally, the authors emphasized the nontoxicity of AgNPs prepared through the bio-green method, which certainly had potential multifunctional activity [105]. Mani et al. synthesized AgNPs by using the unripe fruit aqueous extract of Piper nigrum; the nanoparticles were characterized through techniques like AAS, SEM, FTIR, and HPTLC [106]. The group evaluated the antiinflammatory activity of synthesized AgNPs (size 40– 100 nm), which was believed to be coated with piperine. The authors demonstrated the inhibitory effect by LPS-induced expression of inflammatory cytokines IL-1β and IL-6 in human peripheral blood mononuclear cells (PBMC) by RT-PCR assay. The activity was compared with the commercially available AgNPs and the studied NPs were found to more active at 10–20 μg/mL concentration. Finally, the authors explained the enhanced antiinflammatory activity as a synergism between silver ions with extract [106]. Singh et al. developed green-synthesized AgNPs (P-AgNPs) and AuNPs (P-AuNPs) from fresh fruit extract of P. serrulata in an efficient and rapid manner. Both types of the synthesized nanoparticles were thoroughly characterized using several techniques such as XRD, DLS, EDX, and FE-TEM, which confirmed their stable crystalline monodispersed structures. The group explored the antiinflammatory activities of synthesized nanoparticles. The nanoparticles in macrophages (RAW264.7) inhibited the downstream NF-κB signaling via p38 MAPK molecule and reduced the expression of prostaglandin E2 (PEG2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), along with mediators like nitric oxide (NO). Overall, the authors shed light on the antiinflammatory activities of the nanoparticles and emphasized the potential utility of eco-friendly, bio-green AuNPs and AgNPs as alternative therapeutic agents in the near future [107]. David et al. described the synthesis of AgNPs using European black elderberry (Sambucus nigra–SN, Adoxaceae family) fruit extracts that exhibited significant antiinflammatory effect upon in-vitro administration of the AgNPs on UVB radiation-exposed HaCaT cells (in vitro), on an acute inflammation model (in vivo), and on psoriasis lesions in humans. The group demonstrated decreased cytokine levels and edema in paw tissues in an in-vivo model. The authors shed light on the future application of AgNPs as a treatment for psoriasis lesions [104].

3 ­ Therapeutic applications of biosynthesized silver nanoparticles

3.8 ­WOUND HEALING Wound healing is an important biological process involving many cell types (endothelial, epidermal, and fibroblast) and can be considered a restorative operation of tissue injuries. Any cut or blow to the body can be referred to as a wound [108, 109]. The complex wound-healing process is generally disturbed by many physiological processes like diabetes, blood loss, etc., and it needs to be taken care of very delicately [110]. To heal wounds, angiogenesis plays a pivotal role, involving various growth factors and cytokines to expedite the process [111]. Meanwhile, to augment the process, scientists explored various polymeric and synthetic materials that have several limitations. To overcome the drawbacks, scientists incorporated nanomaterials into wound healing and synthesized different nanoparticles (silver, gold, graphene oxide, zinc oxide) that stimulate the wound healing process. In this regard, the following session only concentrates on green-synthesized silver nanoparticles in wound healing applications. Shankar et al. synthesized silver nanoparticles (AgNPs) from Lansium domesticum fruit peel extract, which were believed to be a potential wound healing material because of their antibacterial and antifungal activities. To potentiate the activity of the synthesized nanomaterials, the group incorporated Pluronic F127 gels as a delivery vehicle,which was observed through the increment of wound tensile strength (33.41 ± 2.38 N/cm2), hydroxyl proline content (2.39 ± 0.28 g/mL), and wound closure time. No inflammation was observed under histopathological and biomedical analysis, which was further corroborated with the high amount of collagen production in the treated groups compared to other groups [112]. Garg et al. synthesized AgNPs hydrogel using the Arnebia nobilis root extract for use as a wound healing agent. The synthesized nanoparticles were thoroughly characterized using the UV-visible spectra, XRD, TEM, SEM, and FTIR. Authors explained that the synthesized AgNP hydrogel exhibited significant wound healing ability in excision wound models in animals owing to their antibacterial property. The epithelialization and the contraction of the wound area indicated the enhancement of cell proliferation, migration of epithelial cells, and the incrementation in action of myofibroblasts, which demonstrated the wound healing potential of the hydrogel nanoparticles. The authors also suggested the lack of side effects of the eco-friendly, bio-green synthesis of AgNPs hydrogels could make them useful as an alternative wound healing agent [113]. Muhammad et al. followed a bio-green route for the synthesis of silver nanoparticles (AgNPs) under diffused sunlight using glucuronoxylan (GX) isolated from the seeds of Mimosa pudica (MP), which acted as a stabilizing or capping agent [114]. The prepared GX-impregnated AgNPs were characterized by UV-is, SEM equipped with STEM, and EDS. The nanoparticles demonstrated significant antimicrobial action against different bacteria: Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Aspergillus niger, Penicillium notatum, Rhizopus stolonifer, and Actinomyces odontolyticus. The authors explained the astounding wound healing ability of the nanoparticles in rabbits and the excellent storage ability of the nanoparticles in the formed thin films made of GX for about 6 months [114]. Haseeb et al. developed a novel method for synthesis of AgNPs using linseed hydrogel (LSH) working as a template in diffused

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sunlight confirmed through color change over 10 h [115]. The synthesized AgNPs was found to be within 10–35 nm in TEM and exhibited fcc structure under powder XRD spectrum. The authors explained the excellent storage ability of AgNPs as a LSH thin film observed by UV-vis spectrum after 6 months. The LSH-impregnated AgNPs exhibited remarkable wound healing properties as an antimicrobial dressing [115]. Wen et al. developed AgNPs using a fungus (endophytic) of a Chinese herb (Orchidantha chinensis) having medicinal properties [116]. The authors suggested that the protein produced by the endocytic fungus (having antimicrobial as well as antiinflammatory activity) acted as a capping and stabilizing agent to AgNPs. The AgNPs demonstrated superior antibacterial properties and wound healing abilities. Altogether, the authors shed light on the eco-friendly and simple development of AgNPs as an antibacterial wound healing substance [116].

3.9 ­ANTICOAGULATING ACTIVITY Coagulation is a natural process in which the blood in a living system changes from liquid to gel, forming clots wherever there is a cut or wound. It is a complex process with involvement of fibrin maturation and deposition along with the activation, adhesion, and aggregation of platelets [117]. The coagulation cascade can be abnormal, causing harm that goes against its ad hoc protective nature. The anticoagulation process is also required for different diseases such as cardiovascular disorders, allergic responses, and injuries where there are malfunctions in coagulation. Recent literature suggests that green-synthesized silver nanoparticles possess anticoagulating activity. Lateef et al. synthesized silver nanoparticles (AgNPs) using bio-green method, that is, extracting the cell-free extract of Bacillus safensis LAU 13 (GenBank accession number KJ461434), which acted as a blood anticoagulant and thrombolytic agent [118]. The synthesized nanoparticles were characterized through different techniques (UV-vis spectroscopy, FTIR, TEM, EDX). The synthesized AgNPs (5– 95 nm as measured by TEM) showed an inhibitory effect on Candida albicans with MIC 40 μg/mL and prevented the coagulation of human blood [118]. Kalishwaralal et al. demonstrated the synthesis of silver and gold nanoparticles using a bacterium Brevibacterium casei biomass (isolated from dairy industrial waste), which acted as both a reducing and stabilizing agent for the formation of nanoparticles [119]. The observed surface plasmon absorbances were 420 and 540 nm for AgNPs and AuNPs, respectively. The synthesized particles were characterized by XRD and FTIR, and measured by TEM (10–50 nm). The researchers provoked great excitement by evaluating its biological application on the human system, which confirmed their anticoagulant effects. The authors also explained the utility and benefits of this ecofriendly synthesis for large-scale production and commercial viability [119]. Singh et al. prepared AuNPs and AgNPs from the medicinal plant Panax ginseng [120]. The hydrothermal eco-friendly synthesis of AuNPs and AgNPs by simple reduction of auric chloride and silver nitrate was rapid and facile. The particles synthesized were characterized through UV-vis, XRD, and EDX, and measured by FE-SEM (10– 20 nm for AuNPs and 5–10 nm for AgNPs). These silver nanoparticles manifested

4 ­Diagnostic applications of biosynthesized silver nanoparticles

antimicrobial activity toward several pathogenic strains like Salmonella enterica, Staphylococcus aureus, Vibrio parahaemolyticus, Bacillus anthracis, Escherichia coli, etc., at a 3-μg dose. Potential anticoagulant activity and inhibition of biofilm formation was observed using these silver nanoparticles [120]. Similarly, Jeyaraj et  al. described the green synthesis of AgNPs by using the culture supernatant of Pseudomonas aeruginosa (GS1 strain). The authors characterized the synthesized AgNPs using UV-vis spectra, DLS, and SEM (size measured, 80 nm) physicochemical techniques. The nanoparticles exhibited excellent anticoagulative effects toward Escherichia coli and Staphylococcus aureus. The authors shed light on the advantageous effect of synthesis of AgNPs, which is eco-friendly and cost-effective [121].

4 ­DIAGNOSTIC APPLICATIONS OF BIOSYNTHESIZED SILVER NANOPARTICLES To understand the driving force behind the paradigm of biology and medicine at both the cellular and molecular levels with higher accuracy, an advanced analysis system is required. With the advancement of the nanotechnology, which has huge potential to address the streaming challenge, the solution is drawn [122]. Today, researchers are encouraged to upgrade the quality of their research in an attempt to have more application in biology and medicine, particularly in diagnosis [123]. Bioimaging and biosensing are the two important subsets of these diagnostic applications. Different nanoparticles including gold, silver, and quantum dots are now extensively used in disease diagnosis and sensing applications among other uses [124–126]. Additionally, with the advent of such nanoparticles, molecular diagnostic processes have benefited greatly. The nanoparticles provide greater sensitivity, specificity, cost-­effectiveness, and rapid solutions to problems [122]. Biosynthesized silver nanoparticles are being developed for use in various applications such as imaging and sensing.

4.1 ­ BIOIMAGING APPLICATIONS Advanced bioimaging technology involves visualization of cellular compartments and observation of functional alterations in the cell, which helps in the accurate diagnosis of diseases. In this context, nanotechnology plays an essential role in imaging biological systems with more accuracy. For the first time, our group demonstrated the bioimaging applications of biosynthesized silver nanoparticles prepared using Olax scandens leaf extract (b-AgNPs) [47]. The b-AgNPs exhibit red color fluorescence in B16F10 cells (Fig. 10) that can be used for bioimaging applications. Interestingly, these silver nanoparticles internalize into cancer cells and exhibit red color fluorescence; normal cells do not exhibit this fluorescence color. The cancer cell-specific nature of these biosynthesized silver nanoparticles is yet to be evaluated. The bioimaging properties of b-AgNPs suggests the future direction for investigating plant-based fluorescent molecules for biomedical applications [127].

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FIG. 10 Fluorescence and the corresponding phase images of untreated B16 cells and cells treated with Olax, b-AgNPs c-AgNPs, observed by an Olympus Fluorescence Microscope. Fluoresence images of B16 cells treated with (A) untreated or control, (B) Olax (100 μg/ mL) leaf extract, (C) b-AgNPs (at 30 μM), and (D) c-AgNPs (at 30 μM). Images of A′, B′, C′, and D′ correspond to phase images. All the treated B16 cells were extensively washed with DPBS (6 times) before taking the fluorescence images. It is to be noted that there is no significant cell death observed at 30 μM. Reproduced from Mukherjee S, Chowdhury D, Kotcherlakota R, Patra S, B V, Bhadra MP, et al. Potential theranostics application of biosynthesized silver nanoparticles (4-in-1 system). Theranostics 2014;4:316–35 (Open Acess Journal).

4 ­Diagnostic applications of biosynthesized silver nanoparticles

4.2 ­BIOSENSING APPLICATIONS Today, the world of sensing silver nanoparticles has generated tremendous applications because of their excellent optical and chemical properties [128, 129]. SPR (surface plasmon resonance), which is extremely sensitive toward the surrounding medium, is one of the reasons for these particles’ excellent sensing ability. Using a green-­chemistry approach, silver nanoparticles can be designed as biosensors in a cost-effective and simple manner [130]. The recent advancements of silver ­nanoparticle-based biosensing applications are discussed in the following text. Pandey et  al. synthesized silver nanoparticle composites from the aqueous solution of polysaccharide of guar gum (Cyamopsis tetragonoloba) plants that acted as a reducing agent [131]. The uniform-sized nanoparticles (<10 nm) were characterized through several techniques such as XRD, SEM, and TEM. The prepared nanocomposite (GG/AgNPs NC) showed excellent optical sensing property toward ammonia with very little response time (2–3 s) and detection limit (1 ppm) at room temperature. The authors explained that these ammonia sensors working at room temperature could be used for low detection of ammonia. They further added that this biosensor could detect the ammonia level in biological fluids (plasma, saliva, cerebrospinal liquid, sweat), which suggests a future direction for these biosensors [131]. Farhadi et  al. developed biosynthesized silver nanoparticles (AgNPs) from the soaproot plant that acted as a stabilizing agent. The synthesized AgNPs could act as a biosensor for sensing the mercury (II) ion in aqueous solution. The prepared nanoparticles were characterized through techniques like UV-vis, SEM, and XRD. The authors mentioned that the detection of Hg2+ could be visualized by the color change of the nanoparticles from yellow to colorless, which is actually associated with the blue shift and broadening of the surface plasmon resonance (SPR) band. The group proposed that the observed mechanism might be due to the binding of Hg2+ ions with Ag0 of freshly prepared AgNPs, which subsequently replaced the stabilizer compounds from its surface. The sensitivity and selectivity of AgNPs toward Hg2+ were determined by their LOD (2.2 × 10−6 mol L−1) value. Overall, the authors emphasized the future utility of highly stable, biosynthesized AgNPs as a biosensor for the selective detection of Hg2+ from various aqueous environmental samples [132]. Ravi et  al. developed a green-synthetic approach for the synthesis of silver and gold nanoparticles from the lemon, Citrus limon (CI-1), and sweet orange, Citrus limetta (Cl-2) fruit extract, which ultimately acted as reducing agents. The group mentioned that AgNPs and AuNPs were formed from the Cl-1 extract in the presence and absence of sunlight, respectively, whereas the formation of both the NPs from Cl-2 extract was carried out in the absence of sunlight. The prepared Cl-1-AgNPs exhibited good stability, which made it possible for sensing potentially hazardous Hg2+ ions in water at a wide range of pH (3.2–8.5). The group observed that there was a peak broadening with a blue shift with the increasing pH, and complete decoloration of the yellow-colored AgNPs was detected at higher pH (>8.5), which eventually indicated the selective sensing of Hg2+ ions at that pH. Finally, the authors highlighted the selective sensing ability of eco-friendly, cost-effective, green-synthesized Cl-1-AgNPs toward Hg2+ ions at a micromolar

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concentration [133]. Tagad et  al. prepared AgNPs by a green-synthesis approach from polysaccharide of locust bean gum (LGB) extract using hydrothermal method (at 55–60°C) [134]. They stated that the size of the prepared AgNPs varied from 18 to 51 nm, which was controlled by the concentration of AgNO3 and LGB extract. With regard to the oxidation property of hydrogen peroxide (H2O2), the group developed an optical fiber sensor for monitoring the low concentration of H2O2 (0.01 mM) using the LGB-stabilized AgNPs. The authors found out that the output voltage occurred due to backscattered light from AgNPs compacted to the sensor and decreased linearly with time in the presence of H2O2. Additionally, the changes of refractive index and degradation of AgNPs in the presence of H2O2 confirmed the sensitivity of the optical device. In conclusion, the authors predicted the future utility of this eco-friendly, simple, stable, cost-reductive, portable green-synthesized biosensor for detection of H2O2 in several research or industrial applications [134]. Luo et al. reported a bio-green method for the synthesis of AgNPs from a biopolymer xylan, which acted as a reducing as well as stabilizing agent [135]. The prepared AgNPs were uniformly distributed (size 20–35 nm), stable, and formed under microwave irradiation (800 W, temperature 60–70°C) via Tollen’s reaction. The nanoparticles were characterized through different techniques like UV-vis, XRD, DLS, TEM, and XPS. The authors explained the reaction mechanism by comparing the structural difference of xylan before and after the reaction process. The researchers collected the supernatant after high-speed centrifugation, which was tested by NMR, FTIR, HPAEC, and GPC. The authors also mentioned that the synthesized xylan-AgNPs composites exhibited specific sensitivity toward Hg2+ with a low detection limit of 4.6 nM, lower than the limit of 30 nM (maximum permitted level of Hg2+ in drinking water) recommended by WHO. The decrease in the SPR band at 410 nm in UV-vis spectra, the change in yellow color, and the aggregation in the AgNPs (observed by TEM analysis) after adding Hg2+ confirmed the selective detection compared to other metal ions. The group predicted that the plausible mechanism might be the greater affinity of binding of Hg2+ ions with hydroxyl/carboxyl group of xylan, the building block of AgNPs. Overall, this study delivered a new perspective based on environmentally friendly green synthesis of silver nanoparticles as biosensors for low-level precise detection of harmful metals such as Hg [135].

5 ­LIMITATIONS OF BIOSYNTHESIZED NANOPARTICLES As we know, the birth of nanoparticles in the material world has created a lot of buzz for researchers and scientists. Biological approaches for the synthesis of nanoparticles avoid toxicological effects and develop an eco-friendly process. Although there are several advantages to biosynthesized nanoparticles, there are also disadvantages. For example, extensive use of polyvinyl alcohol (PVA) as a drug delivery system can generate a toxicity issue [136]. In the synthesis of biosynthesized nanoparticles, instead of the desired active molecules, unintended plant compounds could also attach to their surfaces. Also, there is a major threat regarding autonomic imbalance cre-

7 ­ Conclusions and future prospects

ated by the nanoparticles’ effect on the heart and vascular function. Additionally, the inhalation of nanoparticles might cause lung failure and alveolar dysfunction. Above all else, due to limited targeting ability, discontinuation of therapy with nanoparticles is also not possible. Nanoparticles display disadvantages such as low drug-loading ability, unpredictable dynamics, unexpected gelatin tendency, and sometimes, an unexpected burst of drug release [137].

6 ­TOXICITY OF BIOSYNTHESIZED SILVER NANOPARTICLES Toxicological evaluation is the major task for newly developed materials to translate into medicinal applications. Several factors need to be considered to evaluate the toxicity of nanomaterials like blood and serum biomarkers, histopathological analysis, immune response, genotoxicity, mutagenicity, and effect on organ function. Considering this major concern for nanoparticles, investigators addressed the toxicity effect in different animal models and revealed their safety levels. Lathamuthiah et al. synthesized silver nanoparticles using Brassica oleracea plant extract and evaluated their toxicity in a zebra fish embryo model. Interestingly, these nanoparticles induced apoptosis in HepG-2 (human epithelial carcinoma cells) and were less toxic to zebra fish embryos [138]. On the other hand, Shanker et al. investigated the subacute toxicity studies of herbal-mediated silver nanoparticles (HMSNP) in female albino mice. The mice were given 100–2000 mg/kg of HMSNPs, and the toxicity was evaluated after 15 days through histopathology study of all vital organs. The results suggested a nontoxic effect of HMSNPs with no mortality [139]. Considering these results, biosynthesized silver nanoparticles could be used for various biological applications due to their nontoxic nature.

7 ­CONCLUSIONS AND FUTURE PROSPECTS Over the last few decades, researchers have explored the various biological properties of silver nanoparticles for medicinal applications including their anticancer, antimicrobial, antidiabetic, and wound healing abilities, and their suitability for surface coating of materials. It is well established from the literature that biologically produced silver nanoparticles also exhibit biomedical activities with more potency. Therefore, research should focus more on development of methods for large-scale production of biogenic silver nanoparticles. The biological source used for the synthesis of silver nanoparticles may play a major role in scale-up as well as continuous production. Plant sources are believed to be more suitable for large-scale synthesis of silver nanoparticles than bacteria as they avoid the need for maintenance of continuous cultures [140]. Toxicity is a major issue for nanomaterials that should be properly addressed before human application. The toxicity of nanomaterials is generally considered by studying the effect on metabolic rate and structural changes in body organs leading to various side effects. Nanoparticle interaction with biological molecules (like nucleic

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acids, proteins, and lipids) is responsible for their toxic effects. Moreover, route of administration, pharmacokinetic properties, and host immune responses need to be considered. The point is that many of the studies ended up with an evaluation of a few toxicity parameters or only in-vitro toxicity data that make it inconsistent to make decisions based upon on the nanomaterial’s safety level. Hence, precise determination of the toxicity of the nanomaterials is necessary before human use. The long-term fate of nanoparticles is another issue linked to their bioavailability in and excretion from the body. Biodegradable nanoparticles are more advantageous because they can be easily metabolized in the body after their therapeutic effect. FDA considers those nanoparticles with therapeutic effects that then clear from the body within a particular time of exposure [141]. Hence, in-vivo clearance studies should be conducted for their therapeutic importance in understanding the body’s excretion pathways. Currently, only a few studies are available that address the toxicity of biosynthesized silver nanoparticles. Therefore, further detailed toxicity studies are required to assess the safety levels of biosynthesized silver nanoparticles. Considering their potential, we believe that, after addressing all prior challenges, biosynthesized silver nanoparticles will enter translational research for the benefit of human life.

­ACKNOWLEDGMENTS CRP is thankful to CSIR and DST, New Delhi, for financial support for this research from the 12th Five Year Plan Project (CSC0302) and Nano Mission-DST (SR/NM/ NS-1252/2013; GAP 0570), respectively. SM and SD are thankful to CSIR, UGC, New Delhi for Senior Research Fellowships. IICT manuscript number is IICT/ Pubs./2018/135.

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