Eco-friendly synthesis and biomedical applications of gold nanoparticles: A review

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Eco-friendly synthesis and biomedical applications of gold nanoparticles: A review Kalishwaralal Kalimuthu , Byung Seok Cha , Seokjoon Kim , Ki Soo Park PII: DOI: Reference:

S0026-265X(19)31829-6 https://doi.org/10.1016/j.microc.2019.104296 MICROC 104296

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Microchemical Journal

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18 July 2019 27 September 2019 27 September 2019

Please cite this article as: Kalishwaralal Kalimuthu , Byung Seok Cha , Seokjoon Kim , Ki Soo Park , Eco-friendly synthesis and biomedical applications of gold nanoparticles: A review, Microchemical Journal (2019), doi: https://doi.org/10.1016/j.microc.2019.104296

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Highlights    

Overview of various, green synthesis methods for gold nanoparticles (GNPs). The indispensable role of GNPs in diseases diagnosis and bioimaging is described. Novel green synthesis strategies for GNPs are discussed. Discussion on the development of new clinical applications of GNPs.

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Eco-friendly synthesis and biomedical applications of gold nanoparticles: A review

Kalishwaralal Kalimuthu,# Byung Seok Cha,# Seokjoon Kim, and Ki Soo Park*

Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea

# These authors equally contributed to this work *Corresponding author: Prof. Ki Soo Park, Department of Biological Engineering, College of Engineering, Konkuk University, Seoul 05029, Republic of Korea E-mail: [email protected] or [email protected]

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Abstract Nanotechnology is revolutionizing various aspects of our lives, and gold nanoparticles (GNPs) are at the forefront of this “nanotechnology revolution.” GNPs exhibit a variety of unique beneficial properties, which when harnessed and manipulated effectively, would lead to the development of materials that can be used for various applications. The use of microbes has recently emerged as a novel approach for the synthesis of GNPs with pre-defined size, shape, and composition. This has brought a new era to the field of nanomedicine and has altered the foundations of disease diagnosis, treatment, and prevention. This review provides an overview of various, green GNP synthesis methods and the indispensable role of GNPs in disease diagnosis and bioimaging. In addition, the review discusses the future directions in GNP synthesis and the development of new clinical applications of GNPs.

Keywords: Gold nanoparticles (GNPs), microbial synthesis, disease diagnosis, bioimaging

Abbreviations: AD

Alzheimer’s disease

AMI

Acute myocardial infarction

cfu

Colony-forming unit

CRP

C-reactive protein

CTAB

Hexadecyltrimethylammonium bromide

cTnT

Cardiac troponin T 3

EGFR

Epithelial growth factor receptor

LSPR

Localized surface plasmon resonance

OAm

Oleyl amine

PEG

Polyethylene glycol

SEM

Scanning electron microscopy

SERS

Surface-enhanced Raman scattering

SPR

Surface plasmon resonance

TEM

Transmission electron microscopy

WHO

World Health Organization

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1. Introduction Gold was known only as a metal until the recent past. With the advent of nanotechnology, it was realized that the physicochemical properties of gold make it an ideal material for the fabrication of nanoparticles. The term “nanotechnology” was coined by the Japanese researcher Norio Taniguchi in 1974 [1] and it was later defined as the science and engineering involved in the design, synthesis, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale – ranging from one to hundred nanometers [2]. Nanotechnology has contributed to significant scientific and technological advances in biotechnology, diagnostics, and therapeutics [3]. In particular, nanotechnology is increasingly being used to develop new and improved drug delivery systems [4-8].

Metallic nanoparticles like gold nanoparticles (GNPs) can be synthesized by various physical, chemical, and biological methods and are an active area of academic and more significantly, “application research” [4]. Although there are several physical and chemical strategies for the synthesis of metallic nanoparticles [5, 9-11], biological synthesis of nanomaterials has garnered significant interest owing to the use of mild synthesis conditions such as lower temperature, pH, and pressure. Harnessing this eco-friendly technique to its fullest potential could present added advantages over chemical synthesis, including higher productivity and lower costs. In the past few decades, a new dimension in metal–microbial interaction has emerged, and the synthesis of GNPs using bacteria, fungi, phage, and other organisms has been reported [12-14].

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GNPs have attracted significant attention owing to their unique electronic, optical, thermal, chemical, and biological properties [6]. For example, GNPs possess size-dependent optical properties, whereby they exhibit different colors across a broad range of the optical spectrum spanning the visible and the near-infrared spectral regions [15]. Specifically, when GNPs form larger aggregates from smaller dispersed particles, their color changes from red to blue, which has been utilized in a variety of assays for the detection of biomolecules including DNA and proteins [16]. In addition, the unique shape of GNPs has been investigated to improve the plasmonic enhancement effect [17]. The most widely used GNPs are the star-shaped nanoparticles (nanostars) that have multiple branches with sharp tips. The nanostars exhibit strong localized surface plasmon resonance (LSPR) in the near-infrared region with intense electric fields at the tips and serve as excellent amplifiers owing to the presence of a large number of hot spots. Consequently, these unique structures result in the significant signal enhancement in Raman scattering for molecules positioned near metallic surfaces compared to nanospheres and nanorods [18, 19]. In particular, the strong optical absorption, scattering properties, and remarkably low toxicity of GNPs have made them a class of nanomaterials with potential novel biomedical applications [7, 20]. In this review, we focus on the green synthesis of GNPs using various biological methods. We also discuss the applications of GNPs in diagnostics, bioimaging, and medicine as well as the future directions in this field.

2. Synthesis of gold nanoparticles

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The size of nanoparticles usually ranges from 1 to 100 nm in each spatial dimension, and they are generally synthesized using two strategies – top-down and bottom-up [8, 13]. In the topdown approach, the bulk materials are progressively broken down to nanosized materials, whereas in the bottom-up approach, atoms or molecules are assembled to molecular structures in the nanometer range [1]. An array of physical, chemical, and biological methods has been used to synthesize GNPs, of which the biological synthesis of nanoparticles, is an emerging hot topic in nanobiotechnology that has received significant attention because of the growing need to develop environmentally benign technologies for nanomaterial synthesis [12, 13, 21].

Among the conventional methods, the reduction of gold(III) derivatives, using the citrate reducing agent introduced by Turkevitch in 1951 has been the most popular GNP synthesis strategy since a long time [9]. GNPs can also be synthesized by the reduction of gold(III) using various reducing agents such as gallic acid, hydrogen peroxide, and hydrazine [19,20]. In addition, the two-phase Brust-Schiffrin method is also used to synthesize GNPs, where an aqueous solution of gold(III) is transferred to an organic phase, mediated by a phase transfer agent, followed by reduction with borohydride [9-11, 22].

The seeding-growth procedure is another popular technique that has been in use for over a century. In this technique, gold seed particles are used to grow GNPs in the presence of a weak reducing agent. This step-by-step particle enlargement is more effective than a one-step seeding method as it avoids secondary nucleation [23]. The seeding-growth method has been used to fabricate gold nanorods [24]. Moreover, Kim and colleagues developed a simple 7

method for the size-selective synthesis of GNPs, where thiol-functionalized ionic liquids were used as a critical component [25]. Although the abovementioned methods are useful for the synthesis of GNPs, the organic solvents used in these techniques render them unsuitable for diagnostic applications to detect biomolecules such as nucleic acids, proteins, and saccharides [26]. Furthermore, the use of toxic chemicals and non-polar solvents in the synthesis of GNPs limits their application in the clinical fields [13, 20]. In particular, chemicals used for the synthesis of nanoparticles, including citric acid, sodium borohydride (NaBH4), polyethylene glycol (PEG), hexadecyltrimethylammonium bromide (CTAB), trioctyl-phosphine (TOPO), and oleyl amine (OAm) are considered toxic, harmful, irritating, flammable, or hazardous to the environment [27]. Therefore, the development of clean, biocompatible, non-toxic, and eco-friendly methods for the synthesis of nanoparticles is warranted [28].

Biological synthesis of GNPs using bacteria, fungi, yeasts, actinomycetes, and viruses have been reported as a green chemistry approach that interconnects nanotechnology and microbial biotechnology (Table 1). Biological GNP synthesis methods have the advantages of high reproducibility and biocompatibility and do not involve the use of toxic chemicals or organic solvents [14]. Moreover, microbes such as bacteria, fungi, and yeast are easy to handle and can be manipulated genetically. Owing to the rich biodiversity of microbes, their potential as biological factories for nanoparticle synthesis is yet to be fully explored. Therefore, the cellular, biochemical, and molecular mechanisms that mediate the synthesis of biological nanoparticles

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should be studied in detail to increase the rate of synthesis and improve the properties of nanoparticles [14, 29].

3. Green synthesis of gold nanoparticles While exploring the mechanisms underlying the synthesis of nanoparticles by microbes, which are regarded as potent eco-friendly green nano-factories, it was found that magnetotactic bacteria synthesize magnetite particles [30, 31], diatoms produce siliceous materials [32], and the S-layer bacteria synthesize gypsum and calcium layers [33]. In the last decade, the production of low-cost and energy-efficient metallic nanoparticles has been reported using bacteria, fungi, actinomycetes, algae, and plant extracts (Figure 1) [14, 29].

Microbes produce inorganic nanomaterials with exquisite morphologies, either intra- or extracellularly [12]. The accumulated nanoparticles, in intracellular production, are of specific dimensions and are polydisperse, depending on the localization of the reductive components of the cell. However, when the reductive enzymes on the cell wall or the secreted soluble enzymes are involved in the reduction process of metal ions, metal nanoparticles are synthesized extracellularly [12, 34]. Extracellular production of nanoparticles has wider applications in optoelectronics, bioimaging, and sensor technology compared to intracellular accumulation, as the intracellularly synthesized nanoparticles require additional processing steps such as ultrasound treatment or reaction with suitable detergents for nanoparticle release [13]. In

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addition, the nanoparticles produced outside the cells are devoid of unnecessary cellular components, and thus can be directly used for various biomedical applications.

3.1. Bacteria Various species of gram-positive and gram-negative bacteria have been reported to adsorb and take up heavy metal ions [1]. Ease of handling and genetic manipulation are the significant advantages of using bacterial systems for nanoparticle synthesis [7, 28, 35]. However, some of the challenges, including the lack of fine control over the shape and size of the particles and the industrial scaling-up of synthesis, need to be resolved. The underlying concepts and the mechanism of synthesis of GNPs at the molecular and genetic level are yet to be understood. Understanding the molecular mechanisms underlying nanoparticle synthesis in bacteria may eventually help in providing better control over size, shape, and crystallinity of the nanoparticles [36, 37].

Only a few groups of bacteria can selectively reduce metal ions [38]. Beveridge et al. (1985) demonstrated the synthesis of GNPs using Bacillus subtilis [39]. In the subsequent years, the intracellular synthesis of GNPs with different morphologies – cubic, hexagonal, and spherical – in the range of 5-200 nm was reported by using sulfate-reducing bacteria [13], Shewanella algae [40], Pediastrum boryanum [41], Escherichia coli DH5α [42], Rhodobacter capsulatus [43], Lactobacillus sp. [44], Brevibacterium casei [28], and Pseudomonas aeruginosa [45] (Table 1).

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Bacteria-mediated extracellular synthesis of GNPs has also been reported for many applications. Kalishwaralal et al. reported a green chemistry approach using Bacillus licheniformis in the synthesis of gold nanocubes at room temperature without using any harmful reducing agents. The average size of the nanocubes was found to be 10–100 nm [7]. This single-step, green approach is cost-effective, and the gold nanocubes could find applications in drug delivery, cancer diagnosis, and treatment [46]. In addition, Rhodopseudomonas capsulata, a prokaryotic bacterium, was found to reduce Au(III) to Au(0) at room temperature. The resulting particles at pH 7.0 were mainly spherical in size and ranged from 10–20 nm, but when the pH of the solution was changed to 4, GNPs with triangular nanoplates were dominantly obtained [47]. Husseiny et al. demonstrated that Pseudomonas aeruginosa synthesized GNPs extracellularly with a size distribution in the order of 40±10 nm, 25±15 nm, and 15±5 nm [45]. Furthermore, the dried powder of Bacillus megatherium D01 was used to reduce Au(III) into monodispersed GNPs, and dodecanethiol was used as a capping ligand to stabilize the particles. It was confirmed that the presence of thiol during biosynthesis led to the formation of small spherical GNPs, 1.9±0.8 nm in size [48]. Moreover, Wadhwani et al. utilized Acinetobacter sp. SW30 to investigate the effect of different cell densities and Au(III) concentrations on the formation of GNPs. Their results showed that monodispersed spherical GNPs, 19 nm in size, were obtained by incubating with a cell suspension of 2.1 × 109 cfu, while higher cell densities led to the fabrication of polyhedral GNPs, 39 nm in size. These findings highlight the ability to customize the size and dispersity of GNPs [49].

3.2. Fungi 11

The fungal GNP synthesis system has several advantages when compared to other microbial systems as the fungal mycelial mesh can withstand higher flow pressure and agitation in bioreactors or other chambers. Mukherjee et al. demonstrated the use of Verticillium sp. for fungi-mediated intracellular synthesis of GNPs [50]. In this method, GNPs with approximately 20 nm diameter were synthesized on the fungal surface and the cytoplasmic membrane of the fungal mycelium. These nanoparticles had well-defined dimensions and good dispersity [50]. TEM images of ultrathin sections of fungal mycelia demonstrated the presence of spherical, triangular, and hexagonal nanoparticles on the cell wall and particles with a quasi-hexagonal morphology on the cytoplasmic membrane. In addition, Verticillium luteoalbum incubated with Au(III) at pH 3.0 generated spherical particles of <10 nm diameter; however, spheres and rods were synthesized together with triangular and hexagonal particles at pH 5.0 [51, 52].

In most cases, fungi produce nanoparticles extracellularly because of their enormous secretory components, which also help the reduction and capping of nanoparticles [51]. Shankar et al. found that an endophytic fungus, Colletotrichum sp. isolated from the leaves of the geranium plant (Pelargonium graveolens) rapidly reduced Au(III) to GNPs [53]. Similarly, the fungus Trichothecium sp. cultured in static conditions reduced Au(III) to form GNPs [54]. TEM images showed triangular and hexagonal GNPs in addition to highly polydispersed spheres and rod-like structures, with an average size of 5-200 nm. It is assumed that some loosely bound enzymes or proteins released by Trichothecium sp. are involved in the synthesis of nanoparticles with different morphologies [54].

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3.3. Yeasts It was reported that Saccharomyces cerevisiae, commonly known as baker’s yeast, reduces Au(III) to form GNPs using the aldehyde group present in the reducing sugars of their cell wall [55]. Similarly, another yeast Pichia jadinii formed GNPs with spherical, triangular, and hexagonal morphologies (<100 nm) intracellularly, with the particles distributed mainly in the cytoplasm [51, 52]. In addition, the tropical marine yeast, Yarrowia lipolytica NCIM 3589, was reported to synthesize GNPs on their cell walls. Interestingly, the reduction of Au(III) occurred in a pH-dependent manner. When cells were incubated at pH 2.0, they produced hexagonal and triangular gold crystals; the nucleation on the cell surfaces and rapid reduction process resulted in a golden color. However, at pH 7.0 and pH 9.0, it produced pink and purple colored particles, respectively, with an average size of 15 nm [56].

3.4. Actinomycetes Even though they are classified as prokaryotes, actinomycetes share some important features of fungi and are popularly known as ray fungi. A novel extremophilic actinomycete, Thermomonospora sp. was reported to extracellularly synthesize monodispersed GNPs with an average size of 8 nm [54, 57]. Fourier transform infrared spectroscopic (FTIR) analysis confirmed the presence of amide (I) and (II) bands of protein as capping and stabilizing agents on the surface of nanoparticles. In contrast, an alkali-tolerant actinomycete, Rhodococcus sp. intracellularly accumulated 5–15 nm GNPs, which was attributed to the reductases present both on the cell wall and cytoplasmic membrane that reduces Au(III) to Au(0) [58]. Until now, actinomycetes have been generally regarded as the primary source for the synthesis of 13

secondary metabolites such as antibiotics, but screening for actinomycetes with nanoparticle generation capabilities will result in the identification of novel species for GNP synthesis.

3.5. Algae GNPs can also be synthesized by utilizing algae as a “biofactory.” Singaravelu adopted a systematic approach to study the synthesis of GNPs by Sargassum wightii [59]. To our knowledge, this is the first report in which a marine alga was used to synthesize highly stable GNPs extracellularly in a relatively short time compared to other biological methods. Interestingly, 95% of Au(III) ions were reduced within 12 h [59]. In addition, Tetraselmis kochinensis was found to intracellularly produce GNPs when exposed to Au(III) ions within 48 h. The purple color of the algal cells with absorption at around 540 nm confirmed the intracellular formation of GNPs on the cell wall with an average particle size of about 15 nm [60]. Recently, Borase et al. revealed that Nitzschia diatom belonging to a group of aquatic, unicellular, photosynthetic microalgae, fabricate GNPs showing a characteristic ruby red color with a sharp absorbance peak at 529 nm. Interestingly, an 8-h incubation of the diatom cell mass with Au(III) ions was sufficient for the fabrication of GNPs. These GNPs were irregular in shape, with an average size of 43 nm [61].

3.6. Plant extracts While microorganisms such as bacteria, fungi, yeasts, and actinomycetes continue to be studied for the synthesis of metallic nanoparticles, the use of whole plants for the biosynthesis of nanoparticles is an exciting domain that remains relatively unexplored and underexploited [62, 14

63]. A representative example is lemongrass (Cymbopogon flexuosus) plant extract, which was used for a single-step, room temperature reduction of Au(III) ions to synthesize triangular gold nanoprisms [64]. It is assumed that gold nanoprisms are formed because of the complexation of ketones or aldehydes present in lemongrass with the surface of nanoparticles [64]. In another study, Armendariz et al. reported that the size of GNPs produced by Avena sativa (Oat) biomass was highly dependent on pH values [63]. Interestingly, at pH 2, larger nanoparticles (25-85 nm) were formed in small quantities, but at pH 3 and 4, smaller nanoparticles were formed in larger quantities. The authors explained that at low pH (i.e., pH = 2), the aggregation of GNPs to form larger nanoparticles is favored over the nucleation to form new nanoparticles, whereas at pH 3 and 4, more functional groups are available on the biomass for gold binding and thus more Au(III) complexes are formed. In addition, extracts of Sphaeranthus indicus mixed with Au(III) ions successfully synthesized GNPs in a facile, cost-effective manner [65]. After a 30 min incubation, the light-yellow color transformed into wine red color, indicating the synthesis of GNPs. SEM and TEM images showed spherical GNPs, with an average size of 25 nm [65].

4. Applications of gold nanoparticles in diagnostics Nanotechnology, in particular, GNPs, has revolutionized the field of medical diagnostics (Figure 2) [66]. The earlier a disease is diagnosed, the more effective and cheaper its treatment will be [67]. Therefore, low-cost and high sensitivity diagnostic tests enabling rapid and accurate screening for various diseases with few early symptoms have received considerable attention [68, 69]. Nanodiagnostics, defined as the use of nanotechnology (materials, devices, or

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systems) for the diagnosis of diseases, is a growing field of interest as improved techniques with increased sensitivity are being developed to meet the demands of clinical diagnostics [69]. Even a single analyte molecule can now be identified using one-to-one interactions between the target analyte and the signal generating moieties, such as noble metal nanoparticles such as GNPs [70].

GNPs are the perfect raw materials for robust and rapid diagnostic testing. They are required in minute quantities making it a low-cost technique, while their stability, sensitivity, and reproducibility guarantee high-quality supplies [71]. C.A. Mirkin et al. (1996) reported that oligonucleotide-modified GNPs undergo sequence-specific particle assembly and disassembly in the presence of target DNA and with thermal denaturation, respectively, accompanied by changes in absorbance, facilitating the potential use of GNPs as bio-detection agents beyond conventional histochemical staining [72]. Specifically, when GNPs were used for the assay, the color of the solution changed from red to blue upon target-induced GNP-aggregation as a consequence of both interacting particle surface plasmons and aggregate scattering properties of GNPs [73]. This simple phenomenon pointed toward the use of GNPs as DNA detection agents in a type of “litmus test” for nucleic acid targets. The advantages of GNPs, such as the high surface area and unique optical properties, created worldwide interest in exploring their potential for diagnostic applications [74].

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Another interesting approach is the fluorescence detection method using GNPs as molecular quenchers for the detection of target nucleic acids [75]. The GNPs are modified with oligonucleotides functionalized on one end with a thiol and a molecular fluorophore on the other end [76]. The thiol end binds to the GNPs’ surface, and the fluorophore non-specifically binds to the gold surface, resulting in a loop structure in which the GNPs quench the emission from the fluorophore. However, the binding of target DNA complementary to the oligonucleotides breaks the loop structure, thereby distancing the fluorophore from the nanoparticle quencher with the concomitant increase in fluorescence signal [77]. In addition to the unique colorimetric response and fluorescence quenching properties of GNPs, they also serve as a visible alternative to fluorophores or semiconductor nanoparticles for biological labeling because they readily conjugate with biomolecules [78]. Most importantly, they are non-susceptible to photobleaching or chemical/thermal denaturation, a problem commonly associated with organic dyes.

Several GNP-based diagnostic reagents/kits are now commercially available. The First Response® pregnancy testing kit, marketed by Church & Dwight, utilizes GNPs modified with a specific DNA sequence that is responsive to the presence of pregnancy-indicating hormones [79]. The Merck® Single path assay also uses GNPs to detect the presence of Salmonella enteritidis and Typhimurium within 20 min, while the Duo path assay can be used to identify a range of pathogens including enterohaemorrhagic Escherichia coli and Campylobacter, thereby making it a reliable diagnostic method for food poisoning [80]. In addition, German-based

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Loewe (LOEWE®FAST) uses GNPs for the reliable and specific detection of plant pathogens, including virus, bacteria, and fungi [81].

4.1 Infectious disease According to the World Health Organization (WHO), HIV infection in humans is considered a pandemic disease. It is estimated that over 36.9 million people are living with HIV, with 940 billion AIDS-related deaths reported in 2017 alone [82]. Many of these deaths might have been preventable if access to appropriate diagnostics and therapies had been more widely available. Toward these goals, a sensitive colorimetric assay based on GNPs in combination with functional split aptamers was developed for the detection of HIV-1 Tat protein, a transactivator of HIV gene expression [83]. Moreover, multivalent GNPs, which were conjugated to a TAK-779 derivative, a known CCR5 antagonist that serves as the main entry co-receptor for the most commonly transmitted HIV-1 strain, was found to inhibit HIV fusion by inhibiting HIV-1 replication, demonstrating the feasibility for therapeutic applications [84].

An Illinois-based company, Nanosphere, has developed a fully integrated diagnostics platform called Verigene™, which utilizes GNPs for the specific detection of biomolecular targets. These gold-based probes are non-toxic, have a long shelf life and, most importantly, are extraordinarily sensitive. The system can be used to diagnose a broad range of conditions during HIV infection [85]. In addition, another company, Pointcare, has developed two products (AuRICA™ and PointCare NOW™) for the accurate measurement of CD4-positive white blood 18

cells. These cells are attacked and destroyed by HIV, so having an accurate measurement of their number is critical for understanding the extent of the viral infection, and for choosing treatment strategies. These products exclusively rely on unique properties of GNPs, including SPR in the visible wavelength range depending on their size/shape and the ease of conjugation to biomolecules such as antibodies [86, 87]. The label in these products is composed of antiCD4 antibodies conjugated with GNPs, enabling the estimation of extent of the viral infection and the adoption of effective treatment strategies [88]. The real strength of this diagnostic test lies in its simplicity and robustness [89].

Baptista et al. reported a colorimetric method using GNPs for the sensitive detection of Mycobacterium tuberculosis, the human tuberculosis etiologic agent, in clinical samples [90]. A specific oligonucleotide derived from the M. tuberculosis RNA polymerase -subunit gene was designed for the identification of mycobacteria. In the absence of the complementary DNA sequence, GNPs are aggregated at high salt concentration, turning the solution into purple. However, when the specific DNA sequence is present (i.e., DNA from M. tuberculosis), GNPaggregation does not occur, and the solution remains red [90, 91]. Recently, Gootenberg et al. reported a multiplex, colorimetric detection of specific RNA and DNAs in a lateral flow assay by employing CRISPR-Cas technology and GNPs [92].

4.2 Cancer Cancer is a group of diseases caused by abnormal cell growth and is the second most common cause of death in the United States [93]. The precise diagnosis of cancers at an early stage 19

contributes to a significant increase in survival rates [94]. GNPs coated with specific antibodies represent a promising probe for the specific detection of cancer cells [95]. The interaction between GNPs and proteins has been known for some time [96, 97]. GNPs are highly interactive with proteins through electrostatic, hydrophilic, and hydrophobic interactions, and the resulting nanoparticle-protein complexes are called protein corona [98, 99]. These interactions have been applied in the immunogold labeling technique where GNPs modified with antibodies are used to mark specific cells and act as a probe for TEM or SEM [100]. The immunogold labels in a TEM or SEM image appear as extremely dense round spots marking the antigen in ultrathin sections of tissues [101].

The intense light-scattering property of GNPs makes them promising probes for cancer detection. In principle, antibody-conjugated GNPs specifically label cancer cells by binding to the antigens overexpressed in cancer cells [102]. For instance, cervical epithelial cancer cells (SiHa cells) that overexpress the transmembrane glycoprotein and epithelial growth factor receptor (EGFR), were detected using immune-targeted GNPs. The scattering of GNPs was strong enough to allow the use of even a laser pointer, suitable for a resource-poor setting, instead of a scanning laser to detect the cancer cells [103]. Similarly, Qian et al. demonstrated the use of dark-field microscopy, a straightforward and cheap technique, for the selective detection of cancerous cells using GNPs conjugated with anti-EGFR antibodies [104].

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Recently, a colorimetric assay was reported for the direct detection of cancer cells using aptamer-conjugated GNPs. It was shown that the GNP-aptamers could be assembled on a cell membrane surface, providing direct visualization of cancer cells. The assay was also demonstrated on two different cell types whose specific aptamers were identified using the cell-SELEX method, indicating possible expansion for the detection of cancers or even other diseases. Cell-specific aptamers have been generated for leukemia, lymphoma, lung cancer, and liver cancer, suggesting that the assay could work for the detection of these diseases [105-107].

4.3 Cardiovascular diseases & Alzheimer’s disease Cardiovascular diseases (CVDs) account for 80% of deaths worldwide. WHO reported that CVDs caused 17.3 million deaths in 2013 [108]. One of the most specific biomarkers for acute myocardial infarction (AMI) is cardiac troponin T (cTnT). Pawula et al. developed GNPs conjugated to anti-cTnT antibodies and a surface plasmon resonance (SPR) immunosensor for the sensitive detection of cTnT by direct and sandwich assays. In addition, Rong et al. developed Raman reporter-embedded gold-core silver-shell nanoparticles conjugated with antiCRP (C-reactive protein) antibodies and proposed a surface-enhanced Raman scattering (SERS)based lateral flow assay for the accurate detection of CRP, one of the biomarkers for cardiovascular diseases [109].

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease. In 2017, approximately 50 million people were living with AD worldwide [110]. Since there are no treatments to cease or reverse its progression, the early diagnosis of AD is critical. Amyloid  oligopeptide (AO) levels in cerebrospinal fluid (CSF) are higher in AD patients than in healthy individuals, making AO a valuable biomarker for AD diagnosis [111]. AOs are predominantly derived from the sequential proteolytic cleavage of amyloid precursor protein (APP) by – and -secretase. These A peptides, in turn, aggregate into oligomers or fibrils and eventually form plaques, enhancing the neurotoxicity and the progression of AD [81, 112]. Extensive efforts have been made to detect AO levels to successfully diagnose AD at an early stage. For instance, one group reported a colorimetric strategy to detect AO for AD diagnosis using GNPs coated with N- and C-terminus-specific antibodies for AO. The presence of AO allowed the aggregation of GNPs, accompanied by an obvious color change from red to blue [113]. In addition, another group reported a label-free colorimetric assay using an AO aptamer. The AO aptamer bound to GNPs tended to aggregate in a solution with high salts and displayed a purple color, indicating a characteristic absorption of aggregated GNPs. However, upon interaction with AO, the aptamer formed a folded structure, which stabilizes the GNPs and prevents salt-induced aggregation more effectively than GNPs stabilized by the aptamer alone and thus exhibited a red color. The proposed aptasensor was successfully applied for the detection of AO in artificial cerebrospinal fluid [114].

5. Conclusion & future prospects 22

As a readily available and well-understood material, GNPs are now ready to be deployed in the battle against infectious disease, cancers, and other diseases and to contribute to the development of life-improving technologies [115]. GNPs are replacing organic dyes in applications where high photo-stability and multiplexing capabilities are required. Their high stability, sensitivity, and reproducibility make them ideal materials for early disease diagnosis and pathogen-related detection at the initial stages of an infection. A major trend in the further development of GNPs is to make them multifunctional and controllable by external signals or the local environment, thereby essentially converting them into the stimuli-responsive nanodevices [6]. For instance, GNPs conjugated with peptides whose amino acids possess aromatic groups can be controlled by external heating and cooling to reversibly induce the formation of nanoassemblies [116]. In addition to heat, external stimuli such as light, pH, and magnetic field can also be utilized to reversibly modulate GNPs, expanding their application scope for the development of drug delivery platforms and bioimaging and biosensor systems [117].

Another research interest is to identify optimal strategies for scaling-up the production of GNPs. Industrial-scale production of GNPs using physical and chemical methods demand high energy and are not cost-effective. Further, the use of harmful chemical reagents, including Oam and toluene as solvents and CTAB and NaBH4 as capping/reducing agents during the chemical synthesis of GNPs can lead to environmental pollution [27, 118]. At this instance, eco-friendly biological syntheses of GNPs act as the panacea. In particular, microbial synthesis can be utilized for the large-scale production of GNPs [37]. Although several studies have described the microbial generation of GNPs with promising results, the size and shape of GNPs are not 23

precisely controlled, and an in‐depth understanding of the mechanisms underlying the biological synthesis of nanoparticles is still lacking [8, 12]. Thus, further studies are required to fully understand the mechanisms, which would help the production of well-defined GNPs by the microbial system.

Undoubtedly, nanotechnology has been the focus of several research programs around the world over the past decade, and the number of studies on the development of nanoparticles is rapidly increasing. These interests will continue to generate basic and in-depth knowledge that will accentuate even newer technologies. We believe that the applications highlighted in this review will be considered the beginning of the nanotechnology revolution.

Funding This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2018R1D1A1B07050079 and 2017R1C1B5017724).

Conflict of interests There are no conflicts to declare.

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Table 1. List of biologically synthesized GNPs No.

Name

Size (nm)

References

35-65 nm 5-50 nm 50 nm 39 nm 5-30 nm 10-15 nm 10-50 nm 8.2 nm 10-100 nm 5-30 nm 7-56 nm 2-50 nm 12-14 nm 8-25 nm 40 nm 10-20 nm

[119] [120] [121] [122] [123] [124] [28] [125] [7] [126] [127] [128] [129] [42] [130] [47]

12±5 nm 24.4±11 nm 8.7-15.6 nm 2-70 nm 16-25 nm 60-80 nm 7-93 nm 20-150 nm 20-80 nm 10-60 nm 5-100 nm 32 (3-100) nm 5-50 nm 5-35 nm

[131] [132] [34] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143]

4-20 nm 5 nm 20-40 nm

[144] [145] [146] [147]

5 nm

[148]

Bacteria 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Klebsiella pneumoniae Geobacillus sp. strain ID17 Escherichia coli K12 Acinetobacter sp. SW 30 Bacillus stearothermophilus Bacillus Subtilis Brevibacterium casei Streptomyces clavuligerus Bacillus licheniformis Lactobacillus kimchicus DCY51 Lactobacillus casei Shewanella oneidensis Geobacillus stearothermophilus Escherichia coli DH5α Stenotrophomonas maltophilia Rhodopseudomonas capsulata

Fungi 1 2 3 4 5 6. 7 8 9 10 11 12 13 14

Alternaria alternate Aspergillus clavatus Aspergillus sydowii Helminthosporum solani Rhizopus oryzae Penicillium citrinum Alternaria sp. Volvariella volvacea Penicillium rugulosum Penicillium brevicompactum Penicillium Chrysogenum Neurospora crassa Epicoccum nigrum Cylindrocladium floridanum

Yeast 1 2 3 4

Instant high-sugar dry yeasts Yeast extract mannitol (YEM) Baker’s yeast (Saccharomyces cerevisiae) Hansenula polymorpha

Algae 1

Spirulina platensis

36

2 3 4 5 6 7

Turbinaria conoides and Sargassum tenerrimum Sargassum swartzii Stoechospermum marginatum Cystoseira baccata Tetraselmis kochinensis Kappaphycus alvarezii

27-35 nm 35 nm 18-39 nm 8 nm 5-35 nm 10-40 nm

[149] [150] [151] [152] [60] [153]

Medicago sativa Chilopsis linearis Pelargonium graveolens Cymbopogon flexuosus Avena sativa Cicer arietinum Tamarindus indica Triticum aestivum Sesbania Aloe vera Brassica juncea Emblica officinalis Cinnamommum camphora Azadirachta indica Panax ginseng Cacumen platyclad Rosa hybrida Euphorbia hirta L Trigonella foenum-graecum

4-10 nm 1.1 nm 21-70 nm 10-30 nm 6-20 nm 10-20 nm 55-80 nm 10-40 nm 20-50 nm 10 nm 6-71 nm 15-20 nm

[154] [155] [53] [156] [63] [157] [158] [159] [160] [161] [162] [163] [21] [62] [164] [165] [166] [167] [168]

Tobacco mosaic virus Bacteriophages

10-40 nm 20-100 nm

[169] [170]

Plant extracts 1 2 3 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Virus 1 2

37

Figure legends Figure 1. Biological synthesis of gold nanoparticles (GNPs) with different morphologies.

Figure 2. Biomedical applications of gold nanoparticles (GNPs).

38