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Review article, multifunctional gold nanoparticles: a novel nanomaterial for various medical applications and biological activities.

• State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China

Nanotechnology has become a trending area in science and has made great advances with the development of functional, engineered nanoparticles. Various metal nanoparticles have been widely exploited for a wide range of medical applications. Among them, gold nanoparticles (AuNPs) are widely reported to guide an impressive resurgence and are highly remarkable. AuNPs, with their multiple, unique functional properties, and easy of synthesis, have attracted extensive attention. Their intrinsic features (optics, electronics, and physicochemical characteristics) can be altered by changing the characterization of the nanoparticles, such as shape, size and aspect ratio. They can be applied to a wide range of medical applications, including drug and gene delivery, photothermal therapy (PTT), photodynamic therapy (PDT) and radiation therapy (RT), diagnosis, X-ray imaging, computed tomography (CT) and other biological activities. However, to the best of our knowledge, there is no comprehensive review that summarized the applications of AuNPs in the medical field. Therefore, in this article we systematically review the methods of synthesis, the modification and characterization techniques of AuNPs, medical applications, and some biological activities of AuNPs, to provide a reference for future studies.

Introduction

Nanomaterials are a novel type of material which has emerged in recent years. The term refers to a material in which at least one dimension, of three-dimensional space, is at the nanometer scale (0.1–100 nm), or is composed of the basic unit, which is approximately equivalent to the size of 10–100 atoms, is closely arranged together ( Khan et al., 2017 ; Tayo, 2017 ). Nanoparticles are an example of nanomaterials, which now have the longest development time and are the most mature technology. Nanoparticles and nanotechnology are widely used and play an important role in a range of fields, such as medicine, biology, physics, chemistry and sensing, owing to their unique properties ( Ramalingam, 2019 ). In comparison with other metal nanoparticles, noble metal (Cu, Hg, Ag, Pt, and Au) nanoparticles have increasingly attracted the attention of researchers ( Ramalingam et al., 2014 ). Among these, gold nanoparticles (AuNPs) are known to be the most stable, and have now been prepared with various shapes and structures, including nanospheres, nanorods, nanocubes, nanobranches, nanobipyramids, nanoflowers, nanoshells, nanowires, and nanocages, by various synthetic techniques ( Figure 1 ) ( O’Neal et al., 2004 ; Chen et al., 2008 ; Li et al., 2015 ; Xiao et al., 2019 ). Moreover, they possess tunable and unique optical properties. Therefore, AuNPs have attracted extensive scientific and technological attention in recent decades. The optical properties of AuNPs are dependent on surface plasmon resonance (SPR), which is the fluctuation and interaction of electrons between negative and positive charges at the surface ( Ramalingam, 2019 ). SPR can also be described in terms of surface plasmon polariton (SPP), which originates from propagating waves along a planar gold surface ( Gurav et al., 2019 ). Due to their unique optical and electrical properties, and economic importance, AuNPs have abundant applications in various interdisciplinary branches of science, including medicine, material science, biology, chemistry and physics ( Khan et al., 2019 ).

Figure 1. The main morphologies of AuNPs.

Especially, AuNPs are widely employed across the medical field owing to their excellent biocompatibility, which respectively results from their high chemical and physical stability, easy to functionalize with biologically active organic molecules or atoms ( Pissuwan et al., 2019 ). AuNPs can directly conjugate and interact with diverse molecules containing proteins, drugs, antibodies, enzymes, nucleic acids (DNA or RNA), and fluorescent dyes on their surface, for diverse medical applications and biological activities ( Figure 2 ) ( Slocik et al., 2005 ; Ramalingam, 2019 ). Although AuNPs are so widespread and increasingly used in the medical field, there is no comprehensive review of their applications in medicine. Therefore, in this review, we have summarized the approaches that are available for synthesizing common AuNPs, as well as the techniques that are used to characterize them, based on their unique and diverse properties. We have also paid particular attention to the discussion of established medical applications of AuNPs.

Figure 2. Various connecting molecules of AuNPs.

Synthesis and Modification of Multifunctional AuNPs

Almost all the medical applications and biological activities of AuNPs was characterized based on the unique SPR, since the SPR can enhance the surface activity of AuNPs. Due to the excitation of SPR, the absorption spectrum connected with AuNPs shows a resonance band in the visible region, whose amplitude, spectral location and width can be modified by the diverse particle size and shape in the medium. Also, the SPR is strongly dependent on both size and shape ( Ramalingam, 2019 ). Therefore, the preparation of size-controlled and shape-controlled AuNPs is essential for the medical applications and biological activities. The first report on AuNPs was published in 1857 by Faraday with light scattering potential of AuNPs confirmed by the change of red color and colloidal nature of nanomaterials ( Faraday, 1857 ). Although AuNPs have a long history, the synthesis of small and stable structure of AuNPs is difficult, key challenge in nanotechnology. To our knowledge, there are two distinct approaches of synthesizing AuNPs, which are top–down and bottom–up respectively ( Figure 3 ). The materials of AuNPs prepared by different methods are various, which are bulk material, small gold seeds or gold target, HAuCl 4 ⋅4H 2 O and various biological extracts respectively. Furthermore, AuNPs can bind various active molecules, and have broad prospects in the application of diverse fields. Thus, the modification of AuNPs will also be introduced.

Figure 3. The top–down and bottom–up approaches for AuNPs synthesis.

Top–Down Approach

Generally, the top–down approach is a subtractive process, starting with the slicing of bulk materials and ending with self-assembled nanoscale objects ( Khanna et al., 2019 ). Micropatterning and photolithography are the most common approaches ( Chen et al., 2009 ; Walters and Parkin, 2009 ). Yun et al. (2006) demonstrated micropatterning of a single layer of nanoparticles and micelles through conventional and soft lithographical methods. Although the approach is fast, it has the limitation of synthesizing nanoparticles of uniform size. Thus, Chen et al. (2009) developed a novel patterning technique for AuNPs by removing salt-loaded micelles from substrate areas with a polymer stamp. They called the technique μ-contact (microcontact) deprinting, providing a fast and cheap way to produce nanoparticles on a wide range of substrates. In addition, there are several physical methods, such as pyrolysis, lithography, thermolysis and radiation induced methods in this category. Pyrolysis is another important technique frequently used, generally for the production of noble metal nanoparticles. As shown in Figure 4 , pyrolysis has four major steps, from generation of drops from a precursor solution to solid particle formation ( Figure 4 ) ( Li et al., 2004 ). Pyrolysis has several disadvantages, such as the formation of porous films, low purity in some cases and limited products ( Garza et al., 2010 ). In conclusion, the top–down approach has major limitations in the control of surface and structure of the AuNPs, which has a significant effect on their physical and chemical properties ( Amblard et al., 2002 ; Sant et al., 2012 ). Size distribution is uncontrolled and enormous energy is required to maintain conditions of high-pressure and high-temperature during these synthetic procedures. Thus, it is very uneconomical and difficult to meet product requirements.

Figure 4. The four major steps of pyrolysis.

Bottom–Up Approach

As a popular nanomaterial, AuNPs are expected to present with applications in many areas. However, their yield is currently too low in existing methods of synthesis. Developing more convenient and adjustable methods to improve their preparation efficiency, in order to achieve production on a technical scale, has become the focus of research. The bottom–up approach has been an emerging strategy in recent years. There are three types of bottom–up synthesis approaches: (1) physical approaches, such as laser ablation, sputter deposition, ion implantation, γ-irradiation, optical lithography, microwave (MW) irradiation, ultrasound (US) irradiation, and ultraviolet (UV) irradiation ( Table 1 ); (2) the chemical reduction of metal ions in solutions by introducing chemical agents and stabilizing agents, such as sodium hydroxide (NaOH), sodium borohydride (NaBH 4 ), cetyl-trimethylammonium bromide (CTAB), lithium aluminum hydride (LiAlH 4 ), sodium dodecyl sulfate (SDS), ethylene glycol (EG), and sodium citrate ( Figures 5 , 6 ); (3) biological approaches, using intracellular or extracellular extracts of prokaryotic cells (bacteria and actinomycetes) or eukaryotic cells (algae, fungi, and yeast), and extracts from various plants (leaves, stem, flower, fruits, peel, bark, and root) ( Table 2 ). These syntheses will be discussed in detail in the following parts.

Table 1. Physical synthesis of AuNPs with different morphology and size.

Figure 5. The chemical synthesis of AuNPs using different reaction conditions.

Figure 6. The factors affecting the size and shape of AuNPs.

Table 2. Organisms mediated synthesis of AuNPs with different morphology and size.

Physical Approach

Most of the physical methods used to prepare nanoparticles involve controlling experimental parameters in the presence of a reducing agent, to modulate the structures and properties of AuNPs without contamination ( Table 1 ). Laser ablation and ion implantation are the most common and important physical methods of synthesis. Laser ablation provides an approach which effectively alters the surface area, geometric shape, properties, fragmentation, and assembly of AuNPs in aqueous solution, a biocompatible medium ( Correard et al., 2014 ; González-Rubio et al., 2016 ). For example, Vinod et al. (2017) synthesized pure AuNPs through laser ablation of a gold target in water, and these nanoparticles are inherently non-toxic. And these particles are photothermally active when excited with 532 nm laser irradiation. However, the yield of this method is low, and the method is inconvenient. Therefore, the development of convenient, high-efficiency methods is necessary, in order to scale up production. Recently, Riedel et al. (2020) synthesized spherical, silica-coated AuNPs, with an average diameter of 9 nm and a coating thickness of 2 nm, by improved pulsed laser ablation in liquid (PLAL), and this method offers great progress to the large-scale production of nanoparticles. Another promising method for synthesis of AuNPs is ion implantation, which has been extensively used to prepare AuNPs with precise physical, chemical, and biological properties. Nie et al. (2018) reported the synthesis of embedded AuNPs in Nd:YAG single crystals, using ion implantation, and subsequent thermal annealing. Both linear and non-linear absorption of the Nd:YAG crystals have been significantly enhanced.

Chemical Approach

The easiest and most commonly used approach to synthesis is the chemical reduction of metal ions in solutions ( Figure 5 ). A typical synthesis of AuNPs is dependent on the reduction of Au(III) (from hydrogen tetrachloroaurate hydrate, HAuCl 4 ) to Au(0) atoms, formed as clusters and accumulated into large, polycrystalline particles via aggregation in the presence of reducing or stabilizing agent. Citrate-stabilized AuNPs were initially synthesized by Turkevich et al. (1951) , which was also the first chemical synthesis of AuNPs. This synthesis was based on the single-phase aqueous reduction of HAuCl 4 by sodium citrate. This synthesis was further refined by Frens (1973) by varying the ratio of sodium citrate and gold salt in order to control the size of AuNPs, from 5 to 150 nm. However, the diameter (<30 nm) of AuNPs was too poor. Leff et al. (1995) synthesized surfactant-mediated AuNPs over a range of diameters from 1.5 to 20 nm, by varying the gold-to-thiol ratio ( Leff et al., 1995 ). In 2007, adopting the classical reaction system, Ji et al. (2007) also synthesized AuNPs by changing the pH of solution, which can affect the composition of gold solute complexes, in order to alter the particle size. Then, Jimenez et al. (2010) synthesized small AuNPs with sodium citrate and heavy water (D 2 O). This was a faster reduction method, and by increasingly replacing water with deuterium oxide, smaller diameters were obtained. Today, the aqueous method remains the most commonly used. However, the shape of AuNPs is irregular, and the size and size distribution obtained are quite poor. Thus, Natan and Brown (1998) reported the seeded growth of AuNPs (up to 100 nm in diameter) by using hydroxylamine as a mild reducing agent. And Brown et al. (1999) prepared AuNPs with highly uniform shape and size by introducing the boiling solution of sodium citrate. The mean diameters of the AuNPs produced were between 20 and 100 nm, and they exhibit improved monodispersity. A similar procedure, utilizing the reductant NH 2 OH at room temperature, produces two populations of particles. The larger population is even more spherical than citrate-reduced particles of similar size, while the smaller population is very distinctly rod shaped. This work was improved by Jana et al. (2001) and Rodriguez-Fernandez et al. (2006) . They synthesized monodispersed AuNPs with narrow size distributions, using ascorbic acid (AA) and CTAB, which are used as a reducing agent and cationic surfactant respectively. Jana et al. (2001) prepared the AuNPs with diameters of 5–40 nm by varying the ratio of seed to gold salt, whereas Rodriguez-Fernandez et al. (2006) prepared the AuNPs with diameters from 12 to 180 nm by incorporating small gold clusters on the surface of seed particles ( Jana et al., 2001 ; Rodriguez-Fernandez et al., 2006 ). Although CTAB-based method can control the morphology of AuNPs, the thiolated cationic surfactant molecules that bind to the gold surface are difficult to remove and restrict further functionalization. The reason is that the strongly bound capping layer provided by the CTAB is difficult to exchange with the thiolated cationic surfactant molecules ( Leonov et al., 2008 ). Thus, Bastus et al. (2011) reported a kinetically controlled seeded growth method for the synthesis of monodispersed citrate-stabilized AuNPs, with a uniform quasi-spherical shape of up to ∼200 nm, via the reduction of HAuCl 4 by sodium citrate. They also evaluated the effect of temperature and pH on their final shape. According to the mentioned above, it is known that the temperature, pH, the solvent, and the reducing/stabilizing agent of the reaction system play a crucial role in controlling the size and shape of AuNPs ( Figure 6 ). This has also encouraged researchers to look for novel strategies to prepare AuNPs with controllable properties. Recent seed-mediated synthesis methods are considered very efficient, with respect to precise control of the size and shape of AuNPs.

Biological Approach

Although the synthesis of AuNPs by physical and chemical methods gives a high yield and is relatively cheap, there are a few disadvantages which have also been reported, such as the use of carcinogenic solvents, the contamination of precursors, and high toxicity ( Ramalingam, 2019 ). To overcome these difficulties, researchers have investigated the biological production of AuNPs, and have explored the potential of micro-organisms, due to the quest for economically as well as environmentally benign methods ( Table 2 ) ( Jain N. et al., 2011 ; Ramalingam et al., 2019 ). Biological systems and agents are excellent examples of hierarchical organization of atoms or molecules and this has caused researchers to use a wide range of biological agents as potential cell factories for the production of nanomaterials ( Gardea-Torresdey et al., 1999 ; Singaravelu et al., 2007 ; Kasthuri et al., 2008 ; Smitha et al., 2009 ). Using biological agents to reduce the metal ions requires benign conditions of external temperature and pressure, and little organic solvent ( Khan et al., 2019 ). For example, Dubey et al. (2010) reported a rapid, green synthesis for AuNPs, using the lower amounts extract of Rosa rugosa leaf ( Kumar et al., 2010 ). They also evaluated the effect of the quantity of leaf extract, the concentration of gold solution, the stability of AuNPs and different pH with zeta potentiometer. Although environmentally friendly and easy to regulate the shape and size of the nanoparticles, bacterial-mediated synthesis also has disadvantages, such as difficulty in handling and low yield ( Azharuddin et al., 2019 ).

Modification

The size and morphology controlled AuNPs can be prepared based on different approaches above mentioned. AuNPs exhibit excellent physiochemical properties like unique SPR property, wide surface chemistry, high binding affinity, good biocompatibility, enhanced solubility, tunable functionalities for targeted delivery ( Dreaden et al., 2012 ). Therefore, they have the ability to bind thiol and amine groups, which allows their modification for medical applications and biological activities ( Shukla et al., 2005 ). On the one hand, AuNPs can directly attach ligands such as drug ( Table 3 ), protein, DNA/RNA, enzyme, and so on ( Figure 2 ). For instance, Podsiadlo et al. (2008) synthesized AuNPs bearing 6-Mercaptopurine (6-MP) and its riboside derivatives (6-Mercaptopurine-9-β- D -Ribofuranoside, 6-MPR). 6-MP and 6-MPR are loaded on the surfaces of AuNPs through sulfur-gold (Au–S) bonds known for their strength. They found substantial enhancement of the antiproliferative effect against K-562 leukemia cells compared to the free form of same drug. On the other hand, AuNPs are also used to conjugate with various drug with polymer functionalized for medical applications and biological activities. Recently, the design and preparation of polymer-functionalized AuNPs have attracted increasing interest. The AuNPs functionalized with polymer have more biocompatibility, stability, controlled release of drug, and enhanced therapeutic applications ( Ramalingam, 2019 ). Some examples of polymer functionalized AuNPs for drug delivery are as shown in Table 3 . For example, Venkatesan et al. (2013) developed AuNRs–doxorubicin conjugates (DOX@PSS-AuNRs) by an electrostatic interaction between the amine group (−NH 2 ) of DOX and the negatively charged PSS-AuNRs surface. DOX@PSS-AuNRs conjugates exhibited improved drug loading efficiency, higher biological stability and higher therapeutic efficiency than free DOX. Therefore, the unique physical and chemical properties of AuNPs functionalized with/without polymer can enhance the efficiency of drug deliver and therapeutic efficiency, and increase the multifunctional application.

Table 3. Functionalized AuNPs without/with polymer for drug delivery with different morphology and size.

Characterization of Multifunctional AuNPs

Various analytical techniques have been developed, in recent years, to characterize noble metal nanoparticles, according to their unique thermal, electrical, chemical, and optical properties, and to confirm their size (average particle diameter), shape, distribution, surface morphology, surface charge, and surface area ( Roduner, 2006 ; Ray et al., 2015 ; Khanna et al., 2019 ). The characterization of AuNPs starts with a visual color change which can be observed with the naked eye, based on the principle of their unique and tunable SPR band ( Ramalingam, 2019 ). The characterization of AuNPs has been shown schematically in Figure 7 .

Figure 7. Characterization of AuNPs.

There are some indirect methods (spectroscopic technique) used to analyze the composition, structure, and crystal phase of AuNPs. Their striking optical properties are due to their SPR, which is monitored by UV-visible spectroscopy (UV-vis) ( Sharma et al., 2016 ). The absorption spectra of AuNPs fall in the range of 500–550 nm ( Poinern, 2014 ). It has been suggested a broadening of the SPR band width, which illustrates a redshift, can be used as an index of their state of aggregation, dispersity, size, and shape ( Govindaraju et al., 2008 ; Shukla and Iravani, 2017 ). The size of AuNPs and their size distribution in situ , in the same range of hydrodynamic diameter, can be observed and measured by dynamic light scattering (DLS) ( Wu et al., 2018 ). The purity and crystalline nature of AuNPs can be confirmed through X-ray diffraction (XRD), which gives a rough idea of the particle size, determined by the Debye-Scherer equation ( Ullah et al., 2017 ). The chemical composition of AuNPs can be confirmed by energy-dispersive X-ray spectroscopy (EDX) ( Shah et al., 2015 ). Small-angle X-ray scattering (SAXS) analysis can be used to provide a measure of the interparticle distance of AuNPs, of application to tumor imaging and tissue engineering ( Allec et al., 2015 ). Fourier transform infrared spectroscopy (FT-IR) can investigate the surface chemistry to determine the functional atoms or groups bound to the surface of AuNPs ( Dahoumane et al., 2016 ). The morphology of AuNPs can now be better characterized, due to recent developments in advanced microscopic techniques. These include scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HR-TEM), and atomic force microscopy (AFM), which are commonly employed to determine and characterize their size, shape, and surface morphology ( Azharuddin et al., 2019 ; Khanna et al., 2019 ). SEM provides nanoscale information about particles and determines their surface morphology and dispersion, while TEM is used to provide information about the number of material layers and broad evidence of uptake and localization, composition, polymer tethering, and physical properties ( Marquis et al., 2009 ; Khanna et al., 2019 ). Also, TEM is commonly used as a quantitative method to measure size, volume, and shape, and it produces mainly two-dimensional (2D) image of three-dimensional (3D) nanoparticles ( Quester et al., 2013 ). HR-TEM is used to determine the exact shape, size, and crystalline structure ( Khanna et al., 2019 ). AFM, which is similar to the scanning probe microscopy, provides information about surface topography of AuNPs ( Lu et al., 2004 ). AFM has the advantage of obtaining 3D images in a liquid environment ( Lu et al., 2004 ; Khan et al., 2017 ). Some examples of the characterization of AuNPs, its morphology and size are as shown in Table 4 .

Table 4. Characterization of AuNPs and its morphology and size.

Medical Applications of Multifunctional AuNPs

In the above parts, the synthesis, modification and characterization of AuNPs based on optical and physicochemical properties have been introduced. Although nearly all studies are in the experimental stages, it is clear that AuNPs have potential applications in different fields. Based on their characteristics, applications have been explored, particularly in medical field, including deliver carriers (drug, gene and protein deliver), therapeutics (PTT, PDT and RT), diagnostics, imaging, and other biological activities ( Figure 8 and Table 5 ). In the following sections, these applications will be discussed in detail.

Figure 8. A schematic representation of medical applications for AuNPs.

Table 5. The application or activity of AuNPs with different morphology and size.

Delivery Carriers

In recent years, the idea of using AuNPs as delivery carriers has attracted the wide attention of researchers. As shown in Figure 9 , AuNPs can be used for the delivery of drug, gene, and protein.

Figure 9. The application of delivery carriers for AuNPs.

Chemotherapy is the most common method of cancer therapy but its potential is limited in many cases. Traditional drug delivery (oral or intravenous administration) for chemotherapeutic drugs, results in the dissemination of the drug throughout the whole body, with only a fraction of the dose reaching the tumor site ( Singh et al., 2018 ). Targeting of specific cells, organs, and tissues, in a controlled manner, has become a key issue and challenge. Drug delivery systems (DDSs) is a promising approach to general anticancer therapy, which may provide efficient targeted transport and overcome the limitation of biochemical barriers in the body, e.g., the brain blood barrier ( Martinho et al., 2011 ). Moreover, DDSs can enable controlled function in delivering drugs for early detection of the diseases and damaged sites ( Baek et al., 2016 ). There are many useful forms for drug delivery, including liposomes, liquid crystals, dendrimers, polymers, hydrogels, and nanoparticles ( Yokoyama, 2014 ; Rigon et al., 2015 ). Among these, only a small number of polymers and liposomes have been clinically approved ( Piktel et al., 2016 ). Thus, many researchers have started to focus on the popular AuNPs. AuNPs have been examined for potential anticancer drug delivery ( Duncan et al., 2010 ). In addition, they also can be easily modified to transfer various drugs, which may be bound to AuNPs through physical encapsulation or by chemical (covalent or non-covalent) bonding. Conjugation of AuNPs with other drugs is also possible, but it should be remembered that functionalization can change the toxicity of AuNPs, and their ability to successfully load or attach the desired drugs. The use of modified AuNPs has reduced systemic drug toxicity and helped to decrease the possibility of the cancer developing drug resistance ( Yokoyama, 2014 ). For example, Wójcik et al. (2015) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, confirmed that glutathione-stabilized AuNPs (GSH-AuNPs) modified with non-covalent conjugation of the DOX were more active against feline fibrosarcoma cell lines than the activity exhibited by unmodified AuNPs.

Gene therapy is the use of exogenous DNA or RNA to treat or prevent diseases. Viral vectors are commonly used but cannot be functionalized and can activate host immune systems ( Riley and Vermerris, 2017 ). Their ‘design’ is inflexible, they target specific sites in a biological system with high cytotoxicity and reduce the efficiency of gene therapy ( Riley and Vermerris, 2017 ). The use of non-viral vectors system (such as metallic nanoparticles) can solve this problem. Recent studies have shown that AuNPs can protect nucleic acids through preventing their degradation by nucleases ( Klebowski et al., 2018 ). The unique properties of AuNPs, conjugated to oligonucleotides, can make them potential gene carriers, via covalent and non-covalent bonding. Covalent AuNPs can activate immune-related genes in peripheral blood mononuclear cells, but not in an immortalized and lineage-restricted cell line ( Ding et al., 2014 ). This shows promise application in its application for gene delivery systems. For example, Shahbazi et al. (2019) synthesized AuNPs core using the citrate reduction method, and developed a CRISPR nanoformulation, using colloidal AuNPs (AuNPs/CRISPR), with guide RNA and nuclease on the surface of AuNPs, with or without a single-strand DNA (ss DNA) template to support homology-directed repair. The outcome was an efficient gene editing. They also demonstrated the non-toxicity delivery of entire CRISPR sequences into human blood stem and progenitor cells.

Recently, researchers have also found some evidence that AuNPs can be used as protein carriers. For instance, Joshi et al. (2006) obtained insulin directly bound to bare AuNPs (Au-insulin nanoparticles) via a covalent linkage, which have been confirmed more active than insulin bound via hydrogen bonds with amino acid-modified AuNPs (Au-Asp-insulin nanoparticles) in the transmucosal delivery of drugs for the treatment of diabetes. In this case, the efficiency of insulin delivery can be enhanced by coating the AuNPs with a non-toxic biopolymer, which can strongly adsorb insulin to its surface.

Therapeutics

In the following section, we will discuss photothermal therapy (PTT), photodynamic therapy (PDT), and radiation therapy (RT) applications of AuNPs, which continue to be under development ( Figure 10 ).

Figure 10. The application of PTT, PDT and RT for AuNPs.

PTT, also known as thermal ablation or optical hyperthermia, is a non-invasive and is widely applied for cancer therapy due to its benefits of real-time observation of tumor sites and photoinduced destruction of tumor cells or tissues ( Singh et al., 2020 ). PTT uses materials with a high photothermal conversion efficiency, injected into the body, which gather near the tumor tissues by targeting recognition technology ( Murphy et al., 2010 ; Mubarakali et al., 2011 ). Under the irradiation of external light sources, usually visible or near-infrared (NIR) light, photothermal materials (such as metal nanoparticles) can convert light energy into heat energy (photothermal conversion), result in the destruction of the tumor tissue, and kill the cancer cells ( Murphy et al., 2010 ; Mubarakali et al., 2011 ). AuNPs as a photothermal material, with maximum absorption in the visible or NIR region, have a high photothermal conversion efficiency due to their SPR effect. In addition, the SPR peak of AuNPs can be adjusted to the NIR region by controlling their geometrical and physical parameters, such as size and shape, which contribute to the depth of effective penetration of PTT ( Boyer et al., 2002 ; Orendorff et al., 2006 ; Bibikova et al., 2017 ). Therefore, many researchers have been focusing on the different size and shape of AuNPs for application in PTT (both in vitro and in vivo ) due to their absorption peaks being in the visible or NIR region and their ability to load and deliver various anticancer drugs ( Sharifi et al., 2019 ; Sztandera et al., 2019 ). AuNPs used in PTT are generally nanorods or nanoshells but, when introduced into a biological environment, the cellular uptake can be limited ( Kim and Lee, 2018 ). Tian et al. (2017) synthesized gold nanostars (AuNSs) with pH (low) insertion peptides (pHLIPs) (AuNSs-pHLIP). They have low toxicity, are plasmon tunable in the NIR region, and exhibited excellent biocompatibility and effective PTT ( Tian et al., 2017 ).

PDT is another form of light therapy, developed in recent decades, and used to destroy cancer cells and pathogenic bacteria ( Abrahamse and Hamblin, 2016 ). PDT involves visible light, photosensitizer (PS), and molecular oxygen (O 2 ) from the tissues. PDT is completely dependent on the availability of O 2 in tissues. The process of PDT is that the PS absorbed by the tissue, is excited by laser light of a specific wavelength. Irradiating the tumor site can activate the PS that selectively accumulate in the tumor tissue, triggering a photochemical reaction to destroy the tumor. The excited PS will transfer energy to the surrounding O 2 to generate reactive oxygen species (ROS) and increase ROS level in the target sites. ROS can react with adjacent biological macromolecules to produce significant cytotoxicity, cell damage, even death or apoptosis ( Imanparast et al., 2018 ; Falahati et al., 2019 ; Singh et al., 2020 ). As a PS, AuNPs can absorb the NIR light, accumulate in the tumor area, raise the temperature, and generate high levels of ROS, which can ultimately damage the tumor growth and promote cancer cell death ( Jing et al., 2014 ). In addition, AuNPs have been considered for PS carriers due to their simple thiolation chemistry for the functionalization of desired molecules, enhancing its capability for loading PS drugs. For example, Yang et al. synthesized spherical AuNPs using UV-assisted reduction with sodium and chloroauric acid, and hollow gold nanorings with a sacrificial galvanic replacement method ( Yang et al., 2018 ). They utilized AuNPs and gold nanorings as drug delivery carriers, with a PS enhancer, to compare and investigate the shape-dependent SPR response in PDT. They found that gold nanorings exhibited efficient PS activation and SPR in the NIR region. Therefore, these may be promising nanoparticles to address the current depth limitation of PDT, for deep tumor therapy.

Besides PTT and PDT, radiation therapy (RT) is one of the least invasive and commonly used methods in the treatment of various cancers ( Sztandera et al., 2019 ). RT involves the delivery of high intensity ionizing radiations (such as γ-rays and X-rays) to tumor tissues, while simultaneously protecting the surrounding healthy cells, tissues, and organs, resulting in the death of tumor cells ( Retif et al., 2015 ; Klebowski et al., 2018 ). γ-rays and X-rays are usually used to ionize cellular components (such as organelle) and water. Water is the main component of the cell, as well as the main target of the ionizing radiations, resulting in the lysis of the water molecules. This lysis is named radiolysis, which causes the formation of charged species and free radicals. The interaction of free radicals and membrane structure can also cause structural damage, leading to the apoptosis of cell ( Kwatra et al., 2013 ). Recently, there have been many reports of radiosensitization using AuNPs in RT due to their high atomic number of gold ( Jain S. et al., 2011 ; McMahon et al., 2011 ). The most probable mechanism of radiosensitization from AuNPs is that Auger electron production from the surface of the AuNPs can increase the production of ROS, reduce the total dose of radiation, and increase the dose administrated locally to the tumor sites, eventually resulting in cell death. Moreover, side effects can also be reduced ( Jeynes et al., 2014 ; Retif et al., 2015 ).

Diagnostics

Diagnostics are very essential to medical science and clinical practice. Some diagnostic methods (such as immunoassay diagnosis) have been applied to clinical diagnosis but have limitations in precision molecular diagnostics because of their inaccuracy and low sensitivity ( Ou et al., 2019 ). With the development of nanotechnology, the sensitivity, specificity, and multiplexing of diagnostic tests have been improved. AuNPs exhibit substantial and excellent optical properties, mainly including localized surface plasmon resonance (LSPR) and surface-enhanced Raman scattering (SERS), which play an important role in their application to diagnostics ( Ou et al., 2019 ; Venditti, 2019 ). LSPR-based application of AuNPs is due to spectral modulation ( Figure 11 ) ( Ou et al., 2019 ). When the light is incident on the surface of AuNPs, if the incident photon frequency matches the overall vibration frequency of the electrons transmitted by the AuNPs, the AuNPs will strongly absorb the photon energy, and generate LSPR phenomenon, which is useful for diagnostics ( Link and El-Sayed, 2003 ; Liu et al., 2011 ; Baek et al., 2016 ; Cordeiro et al., 2016 ). The LSPR peak of AuNPs is usually in the visible-NIR region, often at around 500 nm or from 800 and 1200 nm ( Huang et al., 2009 ; Aldewachi et al., 2017 ). SERS is another very attractive spectroscopic technique in diagnostics, being non-invasive and having high sensitivity features ( Boisselier and Astruc, 2009 ; Zhou et al., 2017 ). Fleischmann et al. (1974) reported the enhancement of a Raman scattering signal, which was the first observation of SERS. The enhancement of SERS can be explained by two mechanisms. One is the chemical enhancement due to charge transfer between gold atoms and molecules ( Kawata et al., 2017 ). Another is the electromagnetic enhancement because of LSPR on the surface of metallic gold ( Kawata et al., 2017 ). Spherical AuNPs are commonly used as the substrate for SERS, although non-spherical AuNPs have also been produced and explored for these applications ( Tao et al., 2011 ; Yang et al., 2012 ). Nowadays, the phenomenon of LSPR and SERS in AuNPs has been widely used for the development of molecular diagnostics. For instance, El-Husseini et al. (2016) synthesized 15 nm unmodified citrate-coated AuNPs by the Frens method, for use in the diagnostic polymerase chain reaction (PCR) technique for detection of the equine herpes virus 1 (EHV-1). Their results showed that AuNPs-assisted PCR was more sensitive than the conventional PCR technique and, therefore, could be used as a more efficient molecular diagnostic tool for EHV-1.

Figure 11. The application of AuNPs on the LSPR.

X-ray computed tomography (CT) is one of the most important and mature tissue imaging techniques widely used in various research and clinical environments with broad availability and fairly low cost ( Kim et al., 2007 ). Specifically, CT is a non-invasive clinical diagnostic tool that can perform 3D visual reconstruction and tissue segmentation ( Lusic and Grinstaff, 2013 ). The images of CT are composed of X-ray images, which are taken at different angles by rotating around an object to form a cross-sectional 3D image called a CT scan ( Lusic and Grinstaff, 2013 ; Fuller and Köper, 2019 ). According to the content of the images, the contrast agent can attenuate the X-ray to improve the image quality to highlight the specific area, such as the structure of blood vessels or organs ( Lusic and Grinstaff, 2013 ). The basis of CT imaging is the fact that healthy and diseased tissues or cells have different densities, which can generate in a contrast between normal and abnormal cells by using contrasting agents (such as iodinated molecules) ( Figure 12 ) ( Cormode et al., 2014 ). Iodinated molecules are usually used as a contrasting agent, due to their unique X-ray absorption coefficient ( Klebowski et al., 2018 ). However, their usage has its own limitations, such as short imaging times, rapid renal clearance, reduced sensitivity and specificity, toxicity, and vascular permeation ( Chien et al., 2012 ; Mackey et al., 2014 ). Therefore, it is very essential to explore and develop novel materials as contrasting agents for X-ray imaging. In recent years, AuNPs are attracting attention in imaging as an X-ray contrast agent because they can strongly absorb ionizing radiation to enhance the coefficient of X-ray absorption and convert the light energy to heat energy through the SPR effect ( Rahman et al., 2014 ). Moreover, AuNPs have some advantages compared to iodinated molecules such as ease of synthetic manipulation, unique optical and electrical properties, non-toxicity, higher electron density, higher atomic number of gold, and higher X-ray absorption coefficient ( Mackey et al., 2014 ; Singh et al., 2017 ). The key factors for potential application of AuNPs in enhanced X-ray CT imaging are their migration and accumulation at target sites and longer vascular retention time, and these allow non-invasive tracking and visualizing of the therapeutic cells ( Yin et al., 2017 ; Meir and Popovtzer, 2018 ). For example, Liu et al. (2018) synthesized 30–40 nm sized gold nanocages (AuNCs) as part of an activatable probe, to investigate the potential of imaging. The AuNCs were PEGylated via conjugation with SH-PEG-NH 2. It is the first report to estimate protease activity in vivo using an imaging technique and activatable probe.

Figure 12. A simple scheme for X-ray imaging.

Besides the various applications described above, some other applications involving antimicrobial (antibacterial and antifungal) activity, antioxidant activity, and anticancer activity need to be mentioned.

The increasing incidence of bacterial infection with drug resistance is a major issue for human health ( Dutta et al., 2017 ). AuNPs are easily taken up by immune cells, due to their excellent cell affinity, which leads to precise delivery at the infected area, facilitating inhibition and damage to microbial pathogens ( Saha et al., 2007 ). AuNPs show excellent antibacterial activity against E. coli by absorbing light and converting it into heat ( Singh et al., 2009 ). The growing drug resistance of fungal strains also demands the development of new drugs for better treatment of fungal diseases. Among the various nanoparticles, AuNPs are sensitive to candida cells, which can inhibit the growth and kill the fungal pathogen C. albicans ( Wani and Ahmad, 2013 ; Yu et al., 2016 ). They increase the ROS and damage the cell membrane by their unique properties, which include converting light to heat when irradiated and strong anionic binding with fungal plasma membrane ( Wani and Ahmad, 2013 ; Yu et al., 2016 ). Cancer is caused by many factors and is considered one of the main causes for death worldwide. In tumor cells, AuNPs have a tendency to enter subcellular organelles and increase the cellular uptake, which enhances anticancer activity ( Kajani et al., 2016 ). AuNPs can increase the ROS level, to destroy cancer cells. However, the biocompatibility and selectivity of AuNPs, in targeting tumors, remains an important challenge. Therefore, new developing methods are required to overcome the question. Excessive ROS can lead to enzyme deactivation and nucleic acid damage, which can itself lead to diseases diabetes, aging, and cancer ( Li et al., 2009 ). Ramalingam (2019) synthesized AuNPs using NaBH 4 and HAuCl 4 as a reducing agent and precursor, respectively. Furthermore, they investigated and confirmed the anticancer activity of their AuNPs in human lung cancer cells, and antimicrobial activity against human clinical pathogens, such as P. aeruginosa , S. aureus , E. coli , V. cholera , Salmonella sp., K. pneumonia . Their results suggested that AuNPs could potentially act as anticancer and antimicrobial agents. Moreover, AuNPs have also been confirmed as a potential antioxidant agent. They can inhibit the formation of ROS, thus increasing the antioxidant activity of defensive enzymes. The synergism and antagonism of AuNPs, in their antioxidant activity, require further investigation ( Ramalingam, 2019 ). For instance, Tahir et al. (2015) produced AuNPs (2–10 nm) using the extract of Nerium oleander leaf, in a one-step, green synthetic method, and these AuNPs showed good antioxidant activity. Furthermore, the results showed that the extract of Nerium oleander leaf was very active for the reduction of AuNPs, and could be used as a reducing agent.

In summary, since Faraday first reported AuNPs in 1857 ( Faraday, 1857 ), there have been many reports focusing on their synthesis, as well as comparisons with other metallic nanoparticles or noble metallic nanoparticles. In this review, we have described the synthesis and modification of AuNPs, the techniques of characterization, and their diverse medical applications and biological activities. Since the yield is low, using a top–down approach, a series of synthetic approaches to the production of AuNPs have been proposed. Additionally, the unique properties of AuNPs suggest its broad applications, including drug and gene delivery, PTT, photodynamic therapy (PDT), diagnosis, and imaging. Moreover, further applications, arising from their antimicrobial (antibacterial and antifungal), antioxidant, and anticancer activities, have also been discussed. As the properties of AuNPs become better understood, a considerable number of principal experiments and studies are needed to focus on function, along with the design of different therapies, generally involving PTT and PDT. Although the antimicrobial, anticancer, and antioxidant activities of AuNPs have been confirmed, they remain to be used in clinical treatment. As a drug and gene carrier, AuNPs may also have broad applications, in the future. Although AuNPs possess many useful properties, some studies have demonstrated their toxic effects, based on their physicochemical properties. Sabella et al. (2014) showed that the toxicity of AuNPs was related to their cellular internalization pathways. The safety of AuNPs remains a very urgent and controversial issue, as more important concerns are raised, and this needs to be properly addressed. In recent studies, researchers have reduced the toxicity of AuNPs by introducing functional groups to their surface, improved existing methods of synthesis, and have developed new and better methods. In conclusion, the unique properties of AuNPs should be identified, such as their optical properties with SPR bands, and as carriers with anticancer activity, to broaden their applications in various fields.

Author Contributions

XH wrote the manuscript. YZ collected the literature and generated the figures and tables. TD edited and checked the manuscript format. JL and HZ reviewed the manuscript. All the authors contributed to the article and approved the submitted version.

This study was supported by the National Natural Science Foundations of China (Nos. 81922020 and 81970950), the Postdoctoral Research and Development Funding of Sichuan University (2020SCU12016), and the Research Funding for Talents Developing, West China Hospital of Stomatology Sichuan University (Nos. RCDWJS2020-4 and RCDWJS2020-14).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords : AuNPs, synthesis, modification, characterization, medical applications, biological activities

Citation: Hu X, Zhang Y, Ding T, Liu J and Zhao H (2020) Multifunctional Gold Nanoparticles: A Novel Nanomaterial for Various Medical Applications and Biological Activities. Front. Bioeng. Biotechnol. 8:990. doi: 10.3389/fbioe.2020.00990

Received: 28 April 2020; Accepted: 29 July 2020; Published: 13 August 2020.

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Copyright © 2020 Hu, Zhang, Ding, Liu and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jiang Liu, [email protected]

† These authors have contributed equally to this work

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Advanced Biomaterials and Systems Releasing Bioactive Agents for Precise Tissue Regeneration

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Multifunctional Gold Nanoparticles for Improved Diagnostic and Therapeutic Applications: A Review

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The medical properties of metals have been explored for centuries in traditional medicine for the treatment of infections and diseases and still practiced to date. Platinum-based drugs are the first class of metal-based drugs to be clinically used as anticancer agents following the approval of cisplatin by the United States Food and Drug Administration (FDA) over 40 years ago. Since then, more metals with health benefits have been approved for clinical trials. Interestingly, when these metals are reduced to metallic nanoparticles, they displayed unique and novel properties that were superior to their bulk counterparts. Gold nanoparticles (AuNPs) are among the FDA-approved metallic nanoparticles and have shown great promise in a variety of roles in medicine. They were used as drug delivery, photothermal (PT), contrast, therapeutic, radiosensitizing, and gene transfection agents. Their biomedical applications are reviewed herein, covering their potential use in disease diagnosis and therapy. Some of the AuNP-based systems that are approved for clinical trials are also discussed, as well as the potential health threats of AuNPs and some strategies that can be used to improve their biocompatibility. The reviewed studies offer proof of principle that AuNP-based systems could potentially be used alone or in combination with the conventional systems to improve their efficacy.

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Role of Gold Nanoparticles for Targeted Drug Delivery

Prospects in the use of gold nanoparticles as cancer theranostics and targeted drug delivery agents

Durdana Yasin, Neha Sami, … Tasneem Fatma

Biomedical Applications of Gold Nanoparticles

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Introduction

Medicine is among the many fields that have benefitted from nanotechnology. Nanotechnology emerged with a lot of opportunities to improve and develop novel diagnostic and therapeutic agents through the use of nanomaterials [ 1 , 2 ]. AuNPs, in particular, exhibit unique physicochemical properties and good chemical stability. They are easy to functionalize with almost every type of electron-donating molecules, through various chemistries or based on their strong affinity for thiolated molecules [ 3 , 4 ]. Due to their tiny size, AuNPs have a larger surface area and high drug loading capacity. Multiple moieties can be incorporated in the AuNPs for biomedical applications; these include targeting molecules to increase specificity, contrast agents for bio-imaging and to monitor disease response to drugs in real time, and therapeutic agents for disease treatment [ 5 , 6 ]. Interestingly, even without any added biomolecules, AuNPs are capable of targeting, imaging and treatment of diseases. Based on their size-dependent properties, novel AuNP-based systems can be created for use in various biomedical applications [ 7 ].

AuNPs are made from a metal precursor that is thermostable and are therefore very stable and non-biodegradable. Bulk gold is used in medicine and had proven to be bio-inert and non-toxic [ 8 , 9 ]; hence, the gold core in the AuNPs will essentially display similar properties [ 3 , 10 ]. AuNPs and their applications have been extensively studied for over five decades and have shown great promise as theranostic agents in preclinical [ 5 , 11 , 12 , 13 ] and clinical studies [ 14 , 15 , 16 , 17 , 18 ]. Many more opportunities for novel AuNP-based systems exist as discussed in this review. AuNPs are already explored in clinical trials as drug carriers for the treatment of late stage cancers [ 16 , 17 ], and as PT agents in the treatment of prostate cancer [ 19 ] and acne [ 18 ]. Without undermining the health and regulatory issues that surround the use of AuNPs [ 20 ], a future for these systems in biomedicine is at hand. Multifunctional AuNP-based systems that are capable of combating drug resistance with localized and improved efficacy are possible [ 11 , 21 , 22 ]. The review highlights the biological properties of AuNPs in preclinical and clinical studies, by reflecting on their bio-applications as both diagnostic and therapeutic agents. Their potential health threats and strategies that were used to overcome their limitations are also described. Finally, the future perspectives of the AuNPs in medicine are highlighted.

Gold Nanoparticles

The popularity of AuNPs in medical applications has gained a lot of momentum due to their unique chemical and physical properties. AuNPs are solid colloidal particles that range in size from 1 to 100 nm [ 23 ]. The applications of AuNPs in biology are rooted in their physicochemical properties, not limited to their size, surface plasmon resonance (SPR), shape and surface chemistry [ 3 , 10 ]. These parameters influence their activity and make them perfect candidates for use in disease diagnostics and treatment, either as delivery, sensitizing, contrasts, or therapeutic agents. Their small size is associated with a larger surface area, which allow for surface modification and attachment of multiple payloads, such as targeting, imaging and therapeutic agents [ 4 , 24 , 25 , 26 ]. Their small size also makes it possible for the NPs and their cargo to cross through biological barriers that are otherwise hard to reach and penetrate [ 11 ].

AuNPs are increasingly being recognized as feasible diagnostic, therapeutic and theranostic (an agent that can simultaneously be used to diagnose and treat a disease) agents, which has potential to address the off-target effects associated with conventional therapies. However, AuNPs possess different properties and functions compared with their biocompatible bulk counterparts, which could be hazardous to human health [ 27 , 28 , 29 ]. The clinical use of bulk gold compounds for disease treatment is ancient practice and certified as safe [ 8 ]. In recent years, research has shown that AuNPs have similar or improved medical properties [ 29 ]. Due to their unique optical, chemical and physical properties, AuNPs often present novel properties compared to the bulk gold [ 30 , 31 ] and can serve as diagnostic and therapeutic agents [ 5 ].

Synthesis of AuNPs

AuNPs can be produced in several ways following either the top-down or the bottom-up approach. The top-down approach uses physical and chemical methods to produce desired sizes from the bulk material, while the bottom-up approach involves chemical methods to assemble the building blocks in the formation of nanosized systems [ 32 , 33 ]. The physical methods (such as milling, photochemical, radiation and lithography) use extensive energy and pressure to scale down bulk materials into 10 –9 billionth of a meter in size [ 10 , 32 , 34 ]. Nucleation processes are easily controlled when using the physical methods, reducing agents are not required, and with some of these methods the synthesis occurs simultaneously with the sterilization of the NPs. However, the physical technologies are often costly, not readily available and require specialized equipment. Moreover, capping and stabilizing agents may not survive the high energy processes involved in these processes [ 34 ].

The bottom-up approach is mostly preferred in the synthesis of AuNPs as it is rapid, is easy and does not require the use of sophisticated equipment [ 33 , 34 , 35 ]. It is based on the chemical method developed by Turkevich in 1951 (Fig.  1 A), which use citrate for reduction and stabilization of a gold precursor, resulting in the production of 15-nm spherical AuNPs [ 3 , 10 , 23 , 33 , 36 , 37 ]. The method was further modified by varying the ratio of citrate to gold precursor content and resulted in size diameter range of 15–150 nm AuNPs (Fig.  1 B) [ 10 , 24 ]. A number of reducing agents such as sodium borohydride, cetyltrimethylammonium bromide (CTAB) and ascorbic acid were also introduced. Some of the chemical reducing agents are unfortunately toxic [ 33 , 34 , 36 ] and usually passivated by adding stabilizing agents on their surface such as polyethylene glycol (PEG), gum arabic, polysaccharides and bio-active peptides [ 37 , 38 ].

AuNP formulation through one-phase system by citrate reduction ( A ) and two-phase system reduction followed by stabilization and functionalization via ligand exchange reaction, Brust–Schiffrin method ( B ). Reproduced with permission [ 36 ]. Copyright 2013, De Gruyter. TOAB tetrabutylammonium bromide, SH thiolated molecules

Greener approaches such as microwave-induced plasma-in-liquid process (MWPLP) and green nanotechnology have been explored in synthesis AuNPs to avoid the use of toxic chemical reducing agents. The MWPLP uses microwaves to generate nucleation of metallic NPs and does not require any reducing agents, and the energy required for the synthesis is very low [ 34 ]. Green nanotechnology, on the other hand, uses natural compounds originating from plants and microorganisms as a source of reducing agents in the synthesis of biogenic AuNPs [ 12 , 33 , 39 , 40 , 41 ]. Green nanotechnology is considered as eco and environmentally friendly and thus more suitable for biomedical applications. Plant-mediated synthesis is more economical than using microorganisms. Moreover, the synthesis can be performed in just one step, and the NPs are easier to purify. In addition, plants are renewable; various parts of the plants such as leaves, stems, barks, roots, flowers and fruits can be harvested without killing the plant and used for synthesis. Extracts prepared from the plant material contain phytochemicals, proteins and enzymes that can function as the reducing, stabilizing and capping agents [ 10 , 12 , 24 , 34 , 35 , 40 , 42 ]. Epigallocatechin from green teas [ 42 ] and mangiferin (MGF) from mangoes [ 12 , 43 ] are among plant-derived compounds that have been extensively used to synthesize AuNPs [ 34 ]. More information on these methods is extensively reviewed in the following references [ 10 , 24 , 34 , 35 ].

Biological Application of AuNPs

The role and significance of AuNPs in medical science are undoubtedly becoming more visible, which is backed by the increasing number of studies demonstrating their multifaceted application in a wide range of biomedical fields. The biocompatibility of AuNPs is attributed to the long history of gold in the treatment of human diseases, which goes back to 2500–2600 BC. Chinese and Indian people used gold for the treatment of male impotence, epilepsy, syphilis, rheumatic diseases and tuberculosis. China discovered the longevity effect of red colloidal gold, which is still practiced in India as part of Ayurvedic medicine for rejuvenation and revitalization. Cinnabar-gold (also known as Makaradhwaja) is used for improved fertility in India. In the Western countries, gold has been used to treat nervous disorder and epilepsy. No toxicity was reported for its use in both in vitro and in vivo studies [ 8 , 44 , 45 ]. Since then, oral and injectable gold compounds continued to be used as treatments for arthritis [ 9 , 46 ] and have also been shown to have anticancer effects [ 8 ]. Similar and in some instances improved effects were also reported for AuNPs, which are emerging as promising agents for disease diagnosis [ 47 , 48 , 49 ] and therapy [ 3 , 29 , 50 , 51 ].

AuNPs have a larger surface area that can be exploited for biomedical applications, by attaching various biomolecules to suit a desired function. These can include targeting moieties to help recognize disease-specific biomarkers, contrasts agents for bio-imaging and therapeutic agents for treatment of diseases [ 24 , 25 ]. The advantage of using AuNPs over other nanomaterials is that they can be easily functionalized using various chemistries as demonstrated in Fig.  2 [ 4 , 26 ]. AuNPs have high affinity for thiolated molecules, and thiol-gold binding is the most commonly used method to adsorb molecules onto the NP surface [ 4 ]. Affinity-based chemistries such as biotin-streptavidin binding and carbodiimide coupling are also used. AuNPs are used in three main areas of biomedicine: delivery of pharmaceuticals, diagnostic and therapeutic purposes [ 24 , 35 ], and have demonstrated a huge potential in these areas as discussed below.

Synthesis and functionalization of AuNPs. Biomolecules with functional groups are first adsorbed on the NP surface through gold-thiol affinity. Then, other functional groups such as amine group can be used to bind molecules with a carboxyl groups to attach targeting or drug moieties. Adapted from [ 32 ]

AuNPs as Drug Delivery Agents

The most common application of AuNPs is as delivery vehicles for drugs [ 11 , 18 , 52 ], vaccines [ 53 ] and gene therapy [ 24 , 32 ]. AuNPs possess properties that can resolve most of the issues associated with conventional therapies such as drug resistance, low drug distribution, biodegradation and early drug clearance [ 11 ]. AuNPs can significantly reduce drug dosage, treatment frequency and capable of transporting hydrophobic and insoluble drugs. They are considered to be bio-inert and can mask their cargo from attack by immune cells, protect the drugs from proteolytic degradation as they travel through the circulatory system, and thus increase the drug circulation time. These factors can readily increase the efficacy of the drugs by concentrating and retaining them in the diseased tissues with little or no effect to the normal tissues [ 25 ].

The use of AuNPs in cancer treatment has been extensively studied [ 17 , 37 , 54 ], and over the years it has been extended to other diseases such as obesity [ 50 , 55 , 56 ] and acne [ 18 ]. Nano-based systems are smaller than most cellular components and can passively transverse through cellular barriers by taking advantage of the enhanced permeability and retention (EPR) effect on the vasculature of the diseased tissues [ 25 ]. The EPR in a pathological state is characterized by excessive angiogenesis and increased secretion of permeability mediators, which can enhance AuNP uptake by the diseased tissues. These characteristics are only associated with pathological states and not normal tissues, which provide an opportunity for selective targeting of the AuNP conjugates [ 25 ]. AuNPs are attractive as drug carriers as they can carry multiple molecules simultaneously, further diversifying their properties. This is a desirable trait in medicine in which most of the AuNP bio-applications are rooted upon, as AuNPs can be tailored for a specific biomedical function. This can help control the way they interact with cellular organelles and therefore hold promise for future development of effective diagnostic and treatment modalities for various diseases [ 4 ].

AuNP-Based Diagnostic Systems

The emergence of nanotechnology has raised the stance in developing detection systems that are rapid, robust, sensitive and highly competitive compared to the conventional diagnostic tests [ 48 ]. Nanomaterials are usually integrated in existing biosensing platforms for the detection of gases, DNA and protein markers involved in the development of diseases [ 47 ]. Among the various nanomaterials (which include metallic, polymeric, magnetic and semiconductor NPs) used in diagnostics, AuNPs have been widely used in biosensors, electrochemical sensors and chromogenic assays to detect or sense the presence of disease biomarkers [ 49 ]. Their localized SPR (LSPR), fluorescence resonance energy transfer (FRET), surface-enhanced Raman scattering, conductivity, redox activity and quantized charging effect make them an ideal tool for imaging and detection of target molecules [ 10 , 24 ]. Their electronic and optical properties, and ability to scatter visible and near-infrared (NIR) light are compatible and measurable with various technologies such as microscopic techniques (electron, confocal and dark-field light scattering) [ 57 ], computed tomography (CT), PT heterodyne imaging technique, UV–Vis and Raman spectroscopy [ 24 , 35 ].

The development of AuNP-based diagnostic systems involves modification of the AuNP surface, for example, through the attachment of biomolecules that recognize disease biomarkers [ 3 , 24 , 58 ]. Lateral flow assays (LFAs) are probably the best-known example of nanotechnology-based diagnostic tools. LFAs typically make use of AuNPs of about 30–40 nm because smaller particles have a very small extinction cross sections, whereas larger particles are usually unstable for use in these assays [ 59 ]. In addition, other molecules/enzymes that can trigger changes in SPR, conductivity and redox of AuNPs are included. These indicators give a detectable signal after binding of analytes to the AuNP conjugates [ 24 ], lack or presence of signal will then reflect the absence or presence of the target molecule or the disease. The signal generated by AuNPs is chemically stable, long-lasting and consistent when used in different test formats: test tube, strip, in vitro and in vivo [ 24 ]. Hence, their application has remarkably increased the speed and success of diagnostic assays.

Colorimetric AuNP-Based Assays

In colorimetric assays, AuNPs produce a visual signal (usually a color change) that can be detected with the naked eye without the use of advanced instruments. Generally, a colloidal solution of AuNPs has a ruby red to grape color that is highly dependent on the interparticle distance [ 60 , 61 ]. Binding of an analyte to the AuNPs modified with molecular bio-recognition elements (e.g., antibodies, peptides, aptamers, enzymes, etc.) induces a distinct shift in the LSPR, consequently resulting in the change of color from ruby red to blue [ 60 , 62 , 63 ]. The intensity of color is directly proportional to the concentration of an analyte and used to confirm the presence and state of the disease. The AuNP-based colorimetric diagnostics has been used successfully in the detection of influenza A virus [ 64 ], Zika virus [ 65 ], T7 Bacteriophage [ 66 ], Mycobacterium tuberculosis [ 67 ], and recently, for the detection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) [ 60 , 68 ].

An example of a colorimetric AuNP-based assay was demonstrated for the detection of SARS-CoV-2 [ 60 ], a virus that causes a highly infectious Corona virus disease 2019 (COVID-19) [ 60 , 68 ]. With this assay, the presence of the virus was reported by a simple color change; no instrumentation was required to do the diagnosis. The current clinical diagnostic tests of this virus either use the reverse transcriptase real-time polymerase chain reaction (RT-PCR) assay, which takes 4–6 h, while the rapid point-of-care (PoC) systems detect antibodies that might take several days to appear in the blood. In comparison, the colorimetric AuNP-based assay was more robust and faster as demonstrated in Fig.  3 . Incubating AuNPs-tagged with antisense oligonucleotides (ASOs) in the presence of SARS-CoV-2 RNA samples resulted in the formation of blue precipitate within ~ 10 min. In a SARS-CoV-2-positive test, binding of the ASOs to the N-gene in the nucleocapsid phosphoprotein of the virus induced a blue color that was visually detected. The test was very sensitive and had a limit of detection of 0.18 ng/μL for the SARS-CoV-2 RNA [ 60 ].

AuNP-based colorimetric diagnostic system. Selective naked eye detection of SARS-CoV-2 RNA by the ASO-capped AuNPs. Reproduced with permission [ 60 ]. Copyright 2020, ACS Nano

AuNP-based LFAs follow the same principle as the one shown in Fig.  3 ; however, instead of a color change in a solution, a visible line is formed on a test strip when an analyte is present. In the presence of an analyte, AuNPs were captured on the test line and formed a distinct red line, which was visualized by the naked eye. The intensity of the line is determined by the number of adsorbed AuNPs [ 69 ]. An example of a simple and rapid AuNP-based LFA is shown in Fig.  4 , for the detection of Pneumocystis jirovecii ( P. jirovecii ) IgM antibodies in human sera. The 40 nm AuNPs were conjugated with the recombinant synthetic antigens (RSA) of P. jirovecii , either the major surface glycoprotein or kexin-like serine protease, which were used as an indicator for the presence or absence of P. jirovecii . In a positive test, the P. jirovecii IgM was captured by the AuNP-RSA conjugate at the conjugate pad. The AuNP-RSA/IgM complex then flows to the analytical membrane where it binds the anti-human IgM (test line) and the excess move to the anti-RSA antibodies (control line), resulting in two red lines. The negative test will only have a red color on the control line [ 70 ]. An independent study used the AuNP-based LFA to selectively detect the SARS-CoV-2 IgM as confirmed by the appearance of the red lines in both test and control lines [ 68 ]. The color was visually detected by naked eyes within 15 min in the two systems, and only 10–20 μL serum samples were needed per test [ 68 , 70 ].

AuNP-based LFAs for detection of IgM P. jirovecii antibodies. The presence (positive test) or absence (negative control) of the P. jirovecii antibodies could be differentiated by the AuNP reddish color in both test and control lines, or only in the control line, respectively. Reproduced with permission [ 70 ]. Copyright 2019, Frontiers in Microbiology

One of the first examples of the use of AuNPs as a signaling probe on a LFA was for the detection of Ramos cells; the TE02 aptamer was used as a capture probe and the TD05 aptamer as a detection probe. The aptamer-AuNP biosensor can visually detect a minimum of 4 000 Ramos cells without any instrumentation and 800 Ramos cells with a portable strip reader within 15 min. Using this sandwich detection biosensor, the assay successfully detected Ramos cells spiked in human blood [ 71 ] and was used as a proof of concept for developing a rapid, sensitive and low-cost systems for qualitative and quantitative detection of circulating cancer cells. Since then, various AuNP-based LFAs have been designed for the diagnosis of numerous infectious diseases, including diseases caused by Pneumocystis pneumonia [ 70 ], Ebola virus [ 72 ], HIV, Hepatitis C virus, and Mycobacterium tuberculosis [ 73 ] and more recently SARS-CoV-2 virus [ 68 ].

AuNP-Based Imaging Systems

AuNPs have been intensively investigated for applications in bio-imaging because of their ability to absorb and scatter light matching their resonance wavelengths, up to 10 5 times more than the conventional fluorophores [ 74 ]. AuNPs have a higher atomic number and electron density (79 and 19.32 g/cm 3 ) as compared to the conventional iodine-based agents (53 and 4.9 g/cm 3 ), thus proving to be better contrast agents [ 24 ]. The AuNPs amass on the diseased cells or tissues and induce a strong X-ray attenuation making the targeted site highly distinct and easily detectable. AuNPs are attached to chemical moieties and molecular bio-recognition agents that can selectively target specific antigens to induce distinct and target-specific contrast for CT imaging [ 75 ].

In vitro targeted molecular CT imaging system was achieved by using AuNPs functionalized with a RNA aptamer that binds to the prostate-specific membrane antigen (PSMA). The AuNP–PSMA aptamer conjugate showed more than fourfold CT intensity for the PSMA-expressing prostate (LNCaP) cells compared to the PC-3 prostate cells, which lacks the target receptor [ 76 ]. Similarly, AuNP-diatrizoic acid-AS1411 aptamer conjugate was localized in CL1-5 (human lung adenocarcinoma) cells and CL1-5 tumor-bearing mice. The AS1411 aptamer targets nucleolin (NCL) receptor that is expressed by the CL1-5 cells on the cell surface, while diatrizoic acid is an iodine-based contrast agent. The AuNP–diatrizoic acid–AS1411 aptamer conjugate had a linear attenuation curve with a slope of 0.027 mM Au Hounsfield unit (HU −1 ) indicating accumulation of the AuNPs at the tumor site [ 77 ]. The AuNPs exhibited a longer vascular retention time, which prolonged their circulation time in the blood [ 77 , 78 , 79 ] and improved the CT signal of diatrizoic acid [ 77 ].

Figure  5 shows an in vivo CT vascular imaging of coronary arteries using AuNPs that were conjugated to collagen-binding adhesion protein 35 (CNA35) for targeting collagen I in myocardial infarction in rodents. The AuNP signal was still detected in the blood 6 h after intravenous (i.v) administration, which was significantly higher than the half-life (5–10 min) of iodine-based agents [ 79 ]. These effects were replicated by using green-synthesized mannan-capped AuNPs, which showed receptor-mediated uptake and non-toxicity in mannose expressing (DC 2.4 and RAW 264.7) cells. The mannan-capped AuNPs selectively targeted the popliteal lymph nodes in vivo after injection into the hind leg of the mice [ 38 ]. The AuNP-based CT imaging can provide significant information for diagnosis of various diseases not limited to coronary artery and cancers [ 76 , 77 , 79 , 80 , 81 ]. The use of AuNPs as contrast agents has shown potential in other imaging systems such as photoacoustic, nuclear imaging, ultrasound and magnetic resonance imaging. These systems are extensively reviewed elsewhere [ 82 , 83 ].

In vivo CT imaging using AuNPs as CT contrast agents. Mannan-capped AuNPs and their CT imaging of the lymph node ( A ), and CNA35-conjugated AuNPs CT imaging of myocardial scar burden ( B ). Reproduced with permission [ 79 ]. Copyright 2018, Elsevier

AuNPs in Fluorescent-Based Detection Systems

AuNPs are used in fluorescent-based detection systems as either fluorescent agents or fluorescent quenchers. At sizes ≤ 5 nm, AuNPs display properties of quantum dots (QDs) and can be used in their place. The Au 55 (PPh 3 ) 12 Cl 6 nanoclusters introduced in 1981 are probably the most intensively studied owing to their quantum size behavior [ 7 ]. Since then, various quantum-sized AuNPs (AuNPsQ) such as Au 25 (SR) 18 , Au 38 (SR) 24 and Au 144 (SR) 60 [ 84 ] have been studied mostly in electrochemical sensing as they are excellent electronic conductors and redox mediators [ 85 ].

AuNPsQ film electrodes were used in the fabrication of an ultrasensitive electrochemical immunosensor for the detection of prostate-specific antigen (PSA). The immunosensor had a sensitivity of 31.5 μA mL/ng and a detection limit of 0.5 pg/mL for PSA in 10 μL of undiluted human serum. The immunoassay performed eightfold better than a previously reported carbon nanotube forest immunosensor containing multiple moieties, at the biomarker concentration that was lower than the levels associated with the presence of cancer. As such, it can be used to measure the test biomarker in both normal and diseased states. The performance of the immunosensor was comparable to the reference ELISA method [ 86 ]. AuNPsQ was also incorporated into porously structured CaCO 3 spheres to form a fluorescent CaCO 3 /AuNPsQ hybrid for the detection of neuron-specific enolase, a diagnostic and prognostic biomarker for traumatic brain injury and lung cancer. The sensor had a detection limit of 2.0 pg mL −1 [ 87 ]. Until now, several AuNP-based fluorescent detection systems have been reported for the detection of analytes associated with Hepatitis B [ 73 , 88 ], Influenza A [ 89 ], cancer [ 90 ] and heart injury [ 91 ].

AuNPs are also excellent FRET-based quenchers [ 92 ]. Their unique optical properties (stable signal intensity and photobleaching resistance), size and ability to be modified have made them attractive probes in fluorescence sensing platforms [ 93 , 94 ]. Larger AuNPs (≥ 10–100 nm) have low quantum yields that are not suitable for direct fluorescent sensing; however, their ability to quench fluorescent dyes under relatively high excitation energy state has made them effective photoluminescence quenchers [ 94 ]. In principle, fluorescence nanoprobes are composed of a donor fluorophore (dye or QDs) and an acceptor AuNPs, and when brought into close proximity, the fluorescence of the selected fluorophore is quenched by the AuNPs [ 94 , 95 ]. In the absence of a target as indicated by a lack of a fluorescent signal, the nucleic acid probe hybridizes and forms a looped structure that brings the fluorophore and a quencher at its opposite ends into close proximity; while binding of the analyte to the nucleic acid probe displaces the fluorophore from the AuNPs resulting in a fluorescent signal [ 24 , 94 , 96 ]. Taking advantage of the above-mentioned properties, AuNPs were incorporated in molecular beacons for in vitro (gold nanospheres, AuNSs) and in vivo (gold nanorods, AuNRs) detection of the matriptase expression on tumor cells. The two molecular beacons were composed of a matriptase cleavage site as a linker between the AuNPs and the fluorophores. The AuNS–molecular beacon was constructed with the fluorescein isothiocyanate (FITC), and the AuNR–molecular beacon had a NIR fluorescent dye (mercaptopropionic acid, MPA). In the absence of the target, the AuNSs and AuNRs, respectively, blocked the FITC and MPA fluorescence. Cleavage of either FITC or MPA from the AuNP–molecular beacons in the presence of matriptase exhibited a quantifiable fluorescence signal. The fluorescent signal of the MPA–AuNR–beacon in the nude mice bearing HT-29 tumors lasted for 14 h in the tumor site, while the signal gradually disappeared from the non-tumor site over time [ 97 ].

The AuNPs were reported to have comparable or higher fluorescence quenching efficiency than organic quenchers such as 4-((4′-(dimethyl-amino)phenyl)azo)benzoic acid (DABCYL) [ 94 , 98 ] and Black Hole Quencher-2 [ 99 ]. The fluorescence quenching efficiency of 1.4 nm AuNPs was compatible with the four commonly used organic fluorophores (FITC, rhodamine, texas red and Cy5). The fluorescence quenching efficiency of the AuNPs was similar to that of DABCYL, and unlike DABCYL, the AuNPs showed consistency in both low and high salt buffers [ 98 ]. In a competitive hybridization assay, 10 nm AuNPs showed superior (> 80%) fluorescence quenching efficiency for Cy3 dye than the commercial Black Hole Quencher-2 (~ 50%). The assay had a limit of detection of 3.8 pM and a detection range coverage from 3.8 pM to 10 nM for miRNA-205 in human serum, and it was able to discriminate between miRNAs with variations in their nucleotide sequence [ 99 ]. The competitive sensor arrays were not only sensitive [ 96 , 99 ] but were able to differentiate between normal and diseased cells, as well as benign and metastatic cancers [ 96 ].

AuNP-Based Bio-barcoding Assay

AuNP-based bio-barcoding assay (BCA) technology has become one of the highly specific and ultrasensitive methods for detection of target proteins and nucleic acids up to 5 orders of magnitude than the conventional assays [ 100 ]. The assay relies on magnetic microparticle probes, which are functionalized with antibodies that bind to a specific target, and AuNP probes encoded with DNA that recognizes the specific protein target and antibodies. Upon interaction with the target DNA, a sandwich complex between the magnetic microparticle and AuNPs probes is formed. The sandwich is then separated by the magnet followed by thermal dehybridization to release the free bar-code DNA, enabling detection and quantification of the target [ 101 , 102 ].

The AuNP-based BCA assay was able to detect HIV-1 p24 antigen at levels that was 100–150-fold higher than the conventional ELISA [ 103 ]. The detection limit of PSA using these systems was 330 fg/mL [ 104 ]. The versatility of AuNPs for the development of a BCA-based platform was further demonstrated by measuring the concentration of amyloid-beta-derived diffusible ligands (ADDLs), a potential Alzheimer's disease (AD) marker found in the cerebrospinal fluid (CSF). ADDL concentrations were consistently higher in the CSF taken from the subjects diagnosed with AD than in non-demented age-matched controls [ 105 ]. These results indicate that the universal labeling technology can be improved through the use of AuNPs to provide a rapid and sensitive testing platform for laboratory research and clinical diagnosis.

AuNP-Based Therapies

Metal-based drugs are not new to medicine; in fact, they are inspired by the existing metallic drugs used in clinical treatment of various diseases [ 9 , 106 , 107 , 108 , 109 ]. The widely studied and clinically used metal-based drugs were derived from platinum (e.g., cisplatin, carboplatin, tetraplatin for treatment of advanced cancers), bismuth (for the treatment of infectious and gastrointestinal diseases), gold (for the treatment of arthritis) and gallium (for the treatment of cancer-related hypercalcemia) [ 108 , 109 ]. The approval of cisplatin in 1978 by the FDA for the clinical treatment of cancer [ 107 ] further inspired research on other metals (such as palladium, ruthenium, rhodium) [ 32 , 106 , 110 ].

Owing to the bioactivities, which included anti-rheumatic, antibacterial and anticancer effects, and the biocompatibility of bulk gold [ 8 , 9 , 46 , 111 ], AuNPs are extensively investigated for the treatment of several diseases. AuNPs displayed unique and novel properties that are superior to its bulk counterpart. AuNPs are highly stable and have a distinct SPR, which guides their application in medicine [ 112 ], as drug delivery and therapeutic agents. AuNPs have a lot of advantages over the conventional therapy; they have a longer shelf-life and can circulate long enough in the system to reach their targets [ 25 ] with [ 11 , 49 , 113 ] or without targeting molecules [ 14 , 15 , 24 , 25 , 114 ]. AuNPs can provide localized and selective therapeutic effects; some of the areas in which AuNPs were used in therapy are described below.

Therapeutic Effects of Untargeted AuNPs

The as-synthesized (i.e., unmodified or uncapped) AuNPs have been shown to have diverse therapeutic effects against a number of infectious [ 115 , 116 ], metabolic and chronic diseases [ 3 , 29 , 50 , 51 ]. Their antioxidant, anticancer, anti-angiogenic [ 3 , 32 ], anti-inflammatory [ 3 , 51 ] and weight loss [ 29 , 50 , 112 ] effects are beneficial for diseases such as cancer, rheumatoid arthritis, macular degeneration and obesity [ 5 , 25 , 113 , 117 ]. The above-mentioned diseases are characterized by a leaky vasculature and highly vascularized blood vessels [ 5 , 113 ], which provides the NPs an easy passage into the diseased tissues and increase the susceptibility of cells to their effects. Through the EPR effect, uncapped AuNPs can passively accumulate in the vasculature of diseased cells or tissues. Hence, AuNPs have been specifically designed to have anti-angiogenic effects in diseases where angiogenesis (the growth and extension of blood vessels from pre-existing blood vessels) spins out of control like cancer, rheumatoid arthritis, macular degeneration and obesity [ 5 , 25 , 113 , 117 ]. Targeting and destroying the defective blood vessels prevent oxygen and nutrients from reaching the diseased cells, which results in their death. The pores in the blood vessels at the diseased site (especially in cancer and obesity) are 200–400 nm and can allow materials in this size range to pass from the vasculature into the diseased tissues and cells [ 14 , 15 , 25 , 114 ].

The cellular uptake, localization, biodistribution, circulation and pharmacokinetics of the uncapped AuNPs rely strongly on size and shape [ 49 ]. Although these effects are applicable to all AuNPs, the biological effects of citrate-capped AuNPs (cAuNPs) are extensively studied and reviewed. Spherical cAuNPs demonstrated selective in vitro anticancer activity that was size and concentration dependent on murine and human cell lines [ 3 , 51 ]. Different sizes (10, 20 and 30 nm) of cAuNPs showed differential effects in human cervical carcinoma (HeLa), murine fibroblasts (NIH3T3) and murine melanoma (B16F10) cells. The 20 and 30 nm cAuNPs showed a significant cell death in HeLa cells starting at the lowest concentration of 2.2 µg/mL, while the 10-nm NPs was toxic at concentrations ≥ 8.75 µg/mL. The activity of these NPs was negligible in the noncancerous NIH3T3 cells, especially the 10 and 20 nm. The 20 nm reduced viability by ≤ 5% at the highest concentration (35 µg/mL), and ~ 20% for the 10 and 30 nm. The IC 50 values for 10, 20 and 30 nm cAuNPs in the Hela cells were 35, 2.2 and 4.4 μg/mL, respectively, while the IC 50 values for noncancerous cells were higher than 35 µg/mL [ 3 ]. Using a concentration range of 0.002–2 nM, 13 nm cAuNPs induced apoptosis in rabbit articular chondrocytes and no effects were observed for 3 and 45 nm cAuNPs under the same conditions. The 13 nm cAuNPs induced mitochondrial damage and increased reactive oxygen species (ROS); these actions could not be blocked by pre-treatment with a ROS scavenger, the N-acetyl cysteine [ 51 ]. Size-dependent effects were also observed in vivo after injecting cAuNPs of various sizes (3, 5, 8, 12, 17, 37, 50 and 100 nm) into mice (8 mg/kg/week) for 4 weeks. The 8, 17, 12 and 37 nm were lethal to the mice and resulted in tissue damage and death after 14 days of treatment; the other sizes were not toxic and the mice survived the experimentation period. On the contrary, the same-size AuNPs at a concentrations up to 0.4 mM were not toxic to HeLa cells after 24 h exposure [ 118 ].

The cAuNPs can interact and accumulate nonspecifically within various tissues and organs in the body, especially in the reticuloendothelial system (RES) organs (blood, liver, spleen, lungs) [ 55 , 119 ]. This was evident in high-fat (HF) diet-induced obese Wistar rats [ 55 ] and Sprague–Dawley rats [ 119 ] following acute (1 dose for 24 h) [ 55 ] and chronic (1 dose; 0.9, 9 and 90 µg/week over 7 week period) [ 119 ] exposure to 14 nm cAuNPs, respectively. Majority of the i.v injected cAuNPs were detected in the liver, spleen, pancreas, lungs, kidneys [ 55 , 119 ] including the skeleton and carcass of the rats [ 119 ]. Chen et al. observed that after intraperitoneal (i.p) injection of a single dose (7.85 µg/g bodyweight) of 21 nm cAuNPs in lean C57BL/6 mice, they accumulated in the abdominal fat tissues and liver after 24–72 h [ 29 ], as well as the spleen, kidney, brain and heart in the HF-induced obese mice that were injected with the same dose daily for 9 weeks [ 50 ]. The cAuNPs reduced the abdominal WATs (retroperitoneal and mesenteric) mass and blood glucose levels 72 h post-injection [ 29 ]. In the diet-induced obese mice, the 21 nm cAuNPs demonstrated anti-inflammatory and anti-obesity effects [ 50 ]. They also improved glucose tolerance, enhanced the expression of inflammatory and metabolic markers in the retroperitoneal WATs and liver [ 50 ]. Both the 14 and 21 nm cAuNPs showed no sign of toxicity or changes in the markers associated with kidney and liver damage [ 29 , 55 , 119 ].

Similar findings were reported for plant-mediated AuNPs, without targeting molecules they can access, ablate tumors [ 40 , 120 ] and obese WATs [ 121 ] in rodents. Differential uptake, distribution and activity of biogenic AuNPs also vary depending on the size and shape of the NPs. While certain sizes can pass through the vascular network and be retained at the site of the disease; others can be easily filtered out of the system through the RES organs and the mononuclear phagocytic system as shown in Fig.  6 [ 15 , 114 ]. NPs can be removed by tissue-resident macrophages (TRMs) before they reach the disease cells. Those that escape the TRMs and do not reach the disease site, especially smaller NPs (≤ 5 nm), are excreted through glomerular filtration in the kidney [ 25 , 114 ]. Pre-treatment with clodronate liposomes depleted the TRMs in the liver and spleen before exposure to 50, 100 and 200 nm AuNPs. This reduced uptake of the AuNPs by the liver, increased their half-life in the blood as well as their accumulation at the tumor site [ 122 ]. However, TRMs are not the only obstacle that the AuNPs that rely on EPR effect for uptake must overcome. EPR effect alone can only ascertain ≤ 1% AuNP uptake [ 15 , 114 ], and depletion of the TRMs prior to treatment resulted in just ≤ 2% of NPs reaching the target [ 122 ]. The success of non-targeted AuNPs depends on their ability to reach and accumulate in the diseased tissues, of which passive targeting through the EPR effect might not be efficient. The NPs also need to circulate longer, escape early clearance, and most importantly show reduced bystander effects [ 25 , 123 ]. These qualities can increase bioavailability and ensure selectivity and efficacy of the AuNPs. These can further be improved by changing the surface chemistry of the AuNPs as discussed below [ 15 , 124 ].

RES-based clearance of systemic administered AuNPs depends on their size. Large AuNPs accumulate in the liver, while smaller AuNPs are likely to end up in the spleen or be excreted in the urine via glomerular filtration. The AuNPs that escape the TRMs could accumulate in the diseased tissues. Reproduced with permission [ 114 ]. Copyright 2019, Frontiers in Bioengineering and Biotechnology

Therapeutic Effects of Surface-Functionalized AuNPs

The common strategy in AuNP-based therapeutics involves modifying the AuNP surface with therapeutic agents [ 3 , 124 , 125 , 126 ]. The therapeutic agents can be drugs already used for the treatment of a particular disease or biomolecules with known inhibitory effects on cell signaling. In some instances, the therapeutic AuNPs have also been designed to have molecules that facilitate active targeting of the AuNPs toward specific cells and tissues. The molecules can easily adsorb on the AuNP surface by thiolation, chemical modification using chemistries such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), streptavidin/biotin binding [ 3 , 124 , 125 , 126 , 127 ] and ionic interactions based on opposite charges between the NP surface and the biomolecules [ 124 , 125 , 126 ]. Functionalization of the AuNP surface influences their physicochemical properties and can affect their safety, biocompatibility and mobility. To ensure that the cargo carried by the AuNPs is delivered to the intended site, consideration should thus be given to both the physical and chemical properties of the AuNPs [ 124 , 125 , 126 ]. It is especially the size, shape, charge and the capping agents of the AuNPs that play an important role in the functionality of the AuNP conjugates [ 124 ] and can completely alter the pharmacokinetics of the AuNP-based therapeutics.

Functionalization allows for the development of customized nanosystems to reduce undesirable bystander effects often associated with traditional medicine. Functionalization of AuNPs can also prevent nonspecific adsorption of proteins onto the AuNP surface which can result in the formation a protein corona, resulting in the early clearance of the AuNPs through opsonization by the phagocytic cells [ 49 , 123 ]. The surface charge of NPs can have a major influence on the behavior of NPs within biological environments. AuNPs with a neutral surface charge are unreactive and have a higher rate of escaping opsonization than charged AuNPs. Hydrophilic NPs will also behave differently to those with hydrophobic surfaces [ 49 , 123 ]. PEG is one of the polymers most often used to mask AuNPs from phagocytic cells and has been shown to stabilize and enhance the biocompatibility of the AuNPs in numerous in vivo studies [ 49 , 55 , 123 ]. Pegylation improved the biocompatibility of 8.2 nm AuNPs by preventing neutrally and negatively charged AuNPs to bind to cell membranes or localize to any cellular components in African green monkey kidney (COS-1) cells [ 49 ]. And when the pegylated AuNPs were functionalized with a polyarginine cell penetrating moiety, the AuNPs were visualized on the cell membrane and inside the COS-1 cells [ 49 ]. Cell-penetrating peptides such as nuclear localization signal from SV40 virus, Tat from HIV and polyarginine peptides have been explored in translocation of AuNPs inside all cell type, normal or diseased. However, high specificity is required for clinical applications and can be achieved by taking advantage of the physiological differences between malignant and normal cells. This has been achieved by functionalizing the AuNPs with targeting molecules that recognize cell-specific receptors that are exclusively or overexpressed on the surface of target cells. This way, the AuNPs can be directed and delivered only to cells that express the target receptor. Therefore, conjugation of targeting moieties to the AuNPs (active targeting) will provide more selectivity, reduced bystander toxicity and enhanced efficacy since the AuNPs will be confined only to malignant tissues that express the target receptors [ 49 , 55 , 57 , 113 , 126 , 127 ].

A good example to demonstrate the versatility of AuNPs is shown in Fig.  7 , where four different molecules were conjugated onto the AuNPs to target two independent markers and mechanisms [ 11 ]. The multifunctional AuNPs were used for the treatment of leukemia (K562DR) cells that are resistant to doxorubicin (Dox). The 40 nm AuNPs were modified with two targeting moieties (folate and AS1411 aptamer) and two therapeutic agents (Dox and anti-miRNA molecules/anti-221). Folate molecule and AS1411 aptamer, respectively, recognize the folate and NCL receptors that are overexpressed on the cell surface and through receptor-mediated endocytosis will traffic the AuNP-conjugate into the cells. The AS1411 aptamer had dual functions, by also targeting the NCL receptor that is expressed inside the cells. After the AuNP-conjugate has been shuttled into the cells, the cargo (AS1411 aptamer, anti-221 and Dox) is off-loaded which independently act on three mechanisms that will synergistically bring about the demise of the cells. AS1411 aptamer together with anti-221 prevented leukemogenesis by suppressing the endogenous NCL and miR-221 function in the NCL/miR-221 pathway, thereby sensitizing the cells to the effects of Dox [ 11 ].

Multifunctional AuNPs in the treatment of multidrug-resistant (MDR) leukemia cells by increasing the sensitivity of the cells to Dox. Reproduced with permission [ 11 ]. Copyright 2019. Springer Nature. Folate (FA) receptor

Interestingly, similar dual targeting and treatment effects were achieved with green synthesized AuNPs without any additional molecules. With natural products acting as reducing agents, the biogenic AuNPs might also be more biocompatible than the chemically synthesized NPs [ 12 , 40 , 41 , 43 , 120 ]. MGF-AuNPs selectively targeted the laminin receptors in prostate (PC-3) and triple-negative breast cancer (MDA-MB-231) cells, and their xenografts in severe combined immunodeficiency (SCID) mice bearing these tumors [ 12 , 40 , 120 ]. In the normal SCID mice, the majority (85% at 30 min increasing to 95% after 24 h) of the i.v-injected MGF-AuNPs accumulated in the liver. Less than 10% were detected in the blood (2.7%), spleen (5%), lungs (0.6%), stomach, intestines and kidneys. When intra-tumorally injected in SCID mice-bearing prostate tumors, only 11% of the MGF-AuNPs were detected in the liver 24 h post-injection, while ~ 80% was in the tumor. Negligible amounts were found in the stomach, carcass and the small intestines. Some of the AuNPs were excreted through the renal and hepatic pathways in the urine and feces after 24 h [ 40 , 120 ]. Nano Swarna Bhasma, a mixture consisting of AuNPs synthesized from mango peel extracts and phytochemicals from mango, turmeric, gooseberry and gum arabic, showed reduced toxicity toward normal endothelial cells after 48 h compared to the MDA-MB-231 cells [ 12 ].

Several studies have demonstrated that AuNPs have potential for clinical application. In combination with conventional drugs, it can be used to sensitize diseased cells to the drug effects [ 12 , 128 ] and also prevent or reduce drug-related bystander effects [ 12 ]. AuNPs improved the pharmacokinetics of chemotherapeutic drugs, such as Dox [ 43 , 129 ] and 5-fluorouracil (5-FU) [ 128 ]. Great improvements were mostly seen in the permeability and retention of drugs in the diseased cells, resulting in enhanced efficacy [ 130 ]. Dox-loaded AuNPs, which were non-toxic toward normal mouse fibroblast (L929) cells, also demonstrated selective toxicity toward fibrosarcoma tumors in mice [ 129 ]. 5-FU conjugated to the cAuNPs had better activity than 5-FU on its own in colorectal cancer cells [ 128 ]. AuNP co-treatment with chemotherapeutic drugs was highly efficient in improving the efficacy of chemotherapeutic drugs [ 12 , 43 , 128 , 129 , 131 ]. Orally ingested Nano Swarna Bhasma in combination with Dox and Cyclophosphamide reduced tumor volumes in SCID mice-bearing breast tumor cells and also showed acceptable safety profile and reduced bystander effects of the chemotherapeutic drugs in stage IIIA/B metastatic breast cancer patients [ 12 ]. Active targeting alone can ensure that the AuNPs are directly delivered into the desired targets, achieving a balance between efficacy and toxicity while minimizing damage to healthy tissues [ 14 , 15 , 49 ]. Controlled drug release is also among the many advantages offered by the AuNP-based systems and is crucial as it allows for localized and selective toxicity [ 49 ]. The AuNPs can be designed in such a way that their conjugates respond to internal (glutathione displacement, enzyme cleavable linkers, pH) or external (light, heat) stimuli to function [ 24 , 25 , 34 , 128 ].

AuNPs as Transfection Agents in Gene Therapy

The use of AuNPs in gene therapy has shown promising outcomes by facilitating the delivery of genetic material to cells to silence or enhance expression of specific genes [ 24 , 32 , 132 ]. Thus, AuNPs can be used as transfection reagents in gene therapy for the treatment of cancer and other genetic disorders. AuNP conjugates have demonstrated higher transfection efficiency than experimental viral and non-viral gene-delivery vectors including polycationic reagents that has been approved for clinical use [ 24 ].

AuNPs are highly conductive and well suited for use as microelectrodes during electroporation for intracellular delivery of biomolecules for disease treatment. AuNPs significantly enhanced the performance of electroporation systems and have been used successfully for the delivery of DNA into hard-to-transfect cells such as the K562 cells [ 133 ]. To prevent cell loss which is often associated with electroporation, targeting moieties can be conjugated to the AuNPs to facilitate cellular uptake of AuNP conjugates through receptor-mediated mechanisms [ 133 ]. The use of AuNPs to transfect cells with oligonucleotide molecules also has the added advantage of increasing the half-life of these biomolecules and their efficacy [ 24 , 32 ].

Untargeted AuNP conjugates are passively transported into cells and rely on the surface charge and AuNP shape for efficient transfection [ 24 , 36 , 134 , 135 ]. The charge of the biomolecules that are conjugated onto AuNP surface plays a crucial role in their transfection efficiency; for instance, AuNPs functionalized with cationic molecules produce higher transfection efficiency than AuNPs functionalized with anionic molecules. Positively charged amino acids (lysine) can be attached on the NP surface to increase the rate of transfection. AuNSs [ 24 ] and AuNRs [ 36 , 134 , 135 ] are commonly used for transfections, and relative to the conventional transfection reagents (X-tremeGENE and siPORT), they inhibited the expression of target gene by > 70% in vitro [ 134 ] and in vivo [ 135 ]. In these studies, transfection efficiency was quantified based on target expression using RT-PCR and immunostaining [ 134 , 135 ]. As transfection reagents, AuNPs provide long-lasting effects, localized gene delivery and higher efficacy [ 36 , 134 , 135 ]. Other types of nanomaterials (e.g., polymeric, liposomes, ceramic and carbon nanotubes) had received more attention for use in gene therapy than AuNPs. Six clinical trials using either polymeric or lipid-based nanomaterials for delivery of siRNA in solid tumors have been completed [ 36 , 134 , 136 ]. All of which suffer from low loading efficiency, low stability, and insufficient payload release [ 36 , 136 ]. On the other hand, transfection systems based on AuNPs make use of easy chemistry that ensures efficient loading capacity and formation of stable complexes [ 36 , 135 ]. Their safety can be controlled by manipulating their shape, size distribution and surface composition [ 36 ].

Antimicrobial Effects of AuNPs

MDR microbes are a major health concern and a leading cause of mortality, worldwide [ 21 , 137 , 138 , 139 , 140 , 141 ]. These microorganisms have become resistant to conventional antimicrobial agents, due to over-prescription and misuse of these drugs [ 142 ]. No new antibiotics have been produced in over 40 years, mainly because the big pharmaceutical companies have retreated from their antibiotic research programs due to the lack of incentives [ 143 ]. As such, new and effective antimicrobial agents are urgently required to combat what could be the next pandemic, the antimicrobial resistance, and avoid surge in drug-resistant infections.

AuNPs are among the new generation of antimicrobial agents under review. They have shown broad antimicrobial (bactericidal, fungicidal and virucidal) effects against a number of pathogenic and MDR microorganisms and thus have potential to overcome microbial drug resistance [ 21 , 142 , 144 ]. Their antimicrobial effects are dependent on their physicochemical properties, especially their size, surface composition, charge and shape [ 21 , 144 ]. Due to their small size, AuNPs can easily pass through the bacterial cell membrane, disrupt their physiological functions and induce cell death [ 35 ]. The exact antimicrobial mechanisms of AuNPs are not yet fully elucidated; despite this, some of the reported modes of actions that results from the interaction of various nanostructured materials (NSMs) with the bacterial cells are illustrated in Fig.  8 . The highlighted mechanisms are also implicated in antimicrobial activity of AuNPs, they include induction of microbial death through membrane damage, generation of ROS and oxidative stress, organelle dysfunction, and alteration of gene expression and cell signaling [ 141 ].

Antimicrobial mode of actions of the NSMs. Various NSMs can induce cell death by altering various biological functions, X represents alteration of cell signaling by de-phosphorylation of tyrosine residues in proteins as one of the mechanisms. Reproduced with permission [ 141 ]. Copyright 2018, Frontiers in Microbiology

AuNPs have multiple roles to play toward the development of antimicrobial agents, aside from being antimicrobial agents by themselves; they can serve as drug sensitizers and drug delivery vehicles [ 35 , 58 , 132 , 145 ]. These features are applicable to both the chemical and green synthesized AuNPs, which have been reported to have antimicrobial effects against a number of human [ 21 , 145 , 146 , 147 ] and waterborne [ 148 ] pathogenic strains. Generally, the test bacteria had shown low susceptibility toward the chemically synthesized AuNPs, i.e., the cAuNPs [ 21 , 146 , 147 ] and the NaBH 4 -reduced AuNPs [ 149 ]. This was due to the repulsive forces between the negative charges on the AuNP surfaces and bacterial cells, thus preventing the interaction between AuNPs and the bacteria [ 21 ]. The activity of chemically synthesized AuNPs is based on their size, shape, concentration and exposure time. As an example, one study reported that NaBH 4 -reduced AuNPs had no activity against Staphylococcus aureus ( S. aureus ) and Escherichia coli ( E. coli ) at 500 µg/mL for the duration of 6 h [ 149 ]. In contrast, another study showed a significant dose (1.35, 2.03 and 2.7 μg/mL) and size (6–34 nm vs 20–40 nm) dependent antibacterial effects of the NaBH 4 -reduced AuNPs on Klebsiella pneumonia , E. coli , S. aureus and Bacillus subtilis [ 145 ].

The AuNPs are either used alone or in combination with other antimicrobial agents to treat microbial infections [ 35 , 58 , 132 , 145 ]. When used in combination with other antimicrobial agents, the AuNP conjugates resulted in synergistic antimicrobial effects that surpassed the individual effects of the AuNPs and drugs [ 21 , 35 , 58 , 132 , 150 ]. These drugs were conjugated onto the AuNPs by either chemical methods [ 4 , 151 ] or the drugs were used as reducing and capping agents [ 21 , 149 ]. By so doing, the AuNPs improved drug delivery, uptake, sensitivity and efficacy. Some of the FDA-approved antibiotics and non-antibiotic drugs that were loaded onto the AuNPs are shown in Table 1 [ 4 , 21 , 149 , 152 ]. Ciprofloxacin [ 152 ], cefaclor [ 149 ], lincomycin [ 4 ], kanamycin [ 21 ], vancomycin, ampicillin [ 151 ] and rifampicin [ 32 ] are among the antibiotics loaded on the AuNPs and demonstrated the versatility of AuNPs. These strategies were successful with various sizes and shapes of AuNPs, including gold silica nanoshells [ 152 ], AuNP-assembled rosette nanotubes [ 151 ] and AuNPs encapsulated in multi-block copolymers [ 153 ]. For instance, cefaclor-reduced AuNSs inhibited the growth of S. aureus and E. coli within 2–6 h depending on the concentration (10–50 µg/mL), while complete bacterial growth inhibition by the drug alone was only observed at 50 µg/mL after 6 h. The minimum inhibitory concentration (MIC) of the treatments was 10 µg/mL and 50 µg/mL for cefaclor-AuNPs and cefaclor, respectively [ 149 ].

AuNPs have presented properties that make them ideal candidates as alternative antimicrobial agents; the most important being their broad antimicrobial activity [ 21 , 35 , 58 , 132 , 150 ]. Owing to their biocompatibility and easily modifiable surface, microorganisms are less prone to developing resistance toward AuNPs [ 21 ]. For example, the kanamycin (Kan)-resistant bacteria ( S . bovis , S . epidermidis , E . aerogenes , P . aeruginosa and Y . pestis ) showed increased susceptibility toward Kan-reduced AuNPs. The MIC values for Kan-AuNPs on the test bacteria were significantly reduced to < 10 µg/mL when compared to the MIC values for Kan alone at 50–512 µg/mL. This shows that AuNPs can restore the potency of antibiotics toward the drug-resistant strains by facilitating the uptake and delivery of the antimicrobial agents [ 21 ]. AuNPs can enhance drug-loading capacity and control the rate at which the drugs are released. AuNP hybrids with the multi-block copolymers increased the loading capacity of rifampicin and the drug’s half-life to 240 h. By sustaining the drug in the system for that long, ensured slow release of rifampicin from AuNPs at the target sites after oral administration of the AuNP conjugates to rats for 15 days. The drug on the surface was released within 24 h followed by the drug trapped in the polymer matrix after 100 h. And lastly, the drug entrapped between the AuNPs and the polymer matrix took over 240 h to be released in the interstitial space [ 153 ].

The AuNP hybrids also allow for the conjugation of multiple molecules with independent but synergistic functions. This was demonstrated by co-functionalization of the AuNPs with antimicrobial peptide (LL37) and the pcDNA that encode for pro-angiogenic factor (vascular endothelial growth factor, VEGF) and used in the treatment of MRSA-infected diabetic wounds in mice [ 132 ]. The AuNPs served dual functions, as a vehicle for the biomolecules, and also as transfection agent for the pcDNA. After topical application of the AuNP conjugates on the wound, the LL37 reduced MRSA colonies, while the pcDNA promoted wound healing by inducing angiogenesis through the expression of VEGF [ 132 ].

AuNPs have been shown to confer activity and repurpose some non-antibiotic drugs toward antimicrobial activity. The examples of repurposed drugs, which were used for the treatment of diseases other than bacterial infections, include 5FU [ 58 ], metformin [ 147 ] and 4,6-diamino-2-pyrimidinethiol (DAPT) [ 13 , 112 ]. AuNPs as drug carriers are able to transport the drugs into the cells and allow direct contact with cellular organelles that resulted in their death [ 58 , 147 ]. 5FU is an anti-leukemic drug, when attached to AuNPs was shown to kill some bacterial ( Micrococcus luteus , S. aureus , P. aeruginosa , E. coli ) and fungal ( Aspergillus fumigatus , Aspergillus niger ) strains [ 58 ]. While bacteria are resistant to DAPT, DAPT-AuNPs displayed differential antibacterial activity against the Gram-negative bacteria. Furthermore, conjugation of non-antibiotic drugs (e.g., guanidine, metformin, 1-(3-chlorophenyl)biguanide, chloroquine diphosphate, acetylcholine chloride, and melamine) as co-ligands with DAPT on AuNPs exerted non-selective antibacterial activity and a two–fourfold increased activity against Gram-negative bacteria [ 13 ]. When used in vivo, orally ingested DAPT-AuNPs showed better protection by increasing the intestinal microflora in E. coli -infected mice. After 4 weeks of treatment, the DAPT-AuNPs cleared the E. coli infection with no sign of mitochondrial damage, inflammation (increase in firmicutes ) or metabolic disorders (reduction in bacteroidetes ) in the mice [ 112 ].

The virucidal effects of the AuNP-based systems have been reported against several infectious diseases caused by influenza, measles [ 154 ], dengue [ 155 , 156 ] and human immunodeficiency [ 115 ] viruses. Their anti-viral activity was attributed to the ability of AuNPs to either deliver anti-viral agents, or the ability to transform inactive molecules into virucidal agents [ 154 , 156 ]. AuNPs synthesized using garlic water extracts inhibited measles viral growth in Vero cells infected with the measles virus. When the cells were exposed to both the virus and AuNPs at the same time, they blocked infection of Vero cells by the measles virus [ 154 ]. The AuNPs were nontoxic to the Vero cells up to a concentration of 100 µg/mL but inhibited viral uptake by 50% within 15–30 min at a concentration of 8.8 μg/mL [ 154 ]. Based on the Plaque Formation Unit assay, the viral load was reduced by 92% after 6 h exposure to 8.8 μg/mL of the AuNPs. The AuNPs interacted with the virus directly and blocked its transmission into the cells [ 154 ]. Modification of the AuNP surface with ligands that bind to the virus [ 156 ] or anti-viral agents [ 115 , 155 ] protected them from degradation, enhanced their uptake and delivery onto the cells. The charge of the AuNPs also played a role, with cationic AuNPs being more effective in the delivery and efficacy of the AuNPs than the anionic and neutrally charged NPs. Cationic AuNPs complexed with siRNA inhibited dengue virus-2 replication in dengue virus-2-infected Vero and HepG-2 cells and also the virus infection following pre-treatment of the virus with AuNPs [ 155 ]. Inactive molecules are transformed into highly potent anti-viral agents after conjugation to AuNPs. One such example is the transformation of SDC-1721 peptide, a derivative of TAK-779, which is an antagonist of CCR5 and CXCR3 receptors for HIV-1 strain. SDC-1721 has no activity against the HIV-1, but when conjugated to the AuNPs it inhibited HIV-1 infection of the human phytohemagglutinin-stimulated peripheral blood mononuclear cells. The inhibitory effects of SDC-1721-AuNPs were comparable to the TAK-779 [ 115 ].

AuNPs as PT Agents

Diseased cells are sensitive to temperatures above 40 °C; cancer cells in particular appear to be even more sensitive to these high temperatures. Studies have shown that high fevers in cancer patients either reduced the symptoms of cancer or completely eradicated the tumors as a result of erysipelas infections [ 33 , 157 , 158 ]. Historically, fevers induced by bacterial infections, hot desert sand bath, or hot baths were used to increase the body temperature in order to kill the cancer cells [ 157 ]. These findings gave birth to PT therapy (PTT), which is mostly used for the treatment of cancer. PTT makes use of organic photosensitizers (indocyanine green, phthalocyanine, heptamethine cyanine) that are irradiated by the external source to generate heat energy that will increase the temperature to 40–45 °C (hyperthermia) in the target cells. Hyperthermia then triggers a chain of events (such as cell lysis, denaturation of the genetic materials and proteins), resulting in the destruction of the diseased cells [ 57 , 158 , 159 , 160 ].

The organic dyes are used alone, or in combination with chemotherapy and radiotherapy for enhanced efficacy [ 157 , 160 ]. Ideally, the effects of the PT agents must be confined to target cells and display minimal bystander effects. However, the organic PT dyes have several limitations such as toxic bystander effects, susceptibility to photobleaching and biodegradation [ 159 ]. In recent years, AuNPs are being explored as alternative PT agents as they exhibit strong plasmonic PT properties, and depending on their shape, they can absorb visible or NIR light. Absorption of light in the NIR spectrum is an added advantage that can allow deep tissue PTT [ 158 , 161 , 162 ]. Unlike organic dyes, AuNPs operate in an optical window where the absorption of light by interfering biological PT agents such as hemoglobin, melanin, cytochromes and water is very low [ 158 , 161 , 162 ].

The practicality of AuNP-based PTT has been demonstrated through in vitro and in vivo studies [ 158 , 162 , 163 ]. When the AuNPs are exposed to light, they can convert the absorbed light energy into thermal energy within picoseconds [ 57 , 158 , 159 ], consequently activating cell death via necrosis or apoptosis in the target cells or tissues. AuNP-based hyperthermia in diseased cells has been reported to occur at half the amount of the energy required to kill normal cells, thus perceived to be safer and better PT agents than the conventional dyes [ 33 , 160 ]. AuNPs can be easily modified to have localized and enhanced PT activity by targeting and accumulating in only diseased cells through either active or passive targeting. And since the tumor environment is already hypoxic, acidic, nutrient starved and have leaky vasculature, the tumors will be most sensitive to the AuNP-based hyperthermia than the surrounding healthy cells and tissues [ 33 , 160 ].

AuNP-based PTT has been extensively studied [ 158 , 161 , 162 ] and established that AuNPs (e.g., AuNRs, nanocages and nanoshells) that absorb light in the NIR spectrum are best for in vivo and deep tissue PTT [ 161 ]. While the ones that absorb and emit light in the visible spectrum (AuNSs and hollow AuNPs) have been demonstrated to treat diseases that affect shallow tissues (up to a depth of 1 mm), which could be of benefit to superficial tumors [ 158 , 161 , 162 ], ocular surgery [ 164 , 165 ], focal therapy and vocal cord surgery [ 158 , 165 ]. Although the PTT effects of AuNSs are limited in vivo or for use in deep tissues, combination therapy or active targeting can be incorporated to facilitate target-specific effects [ 158 , 161 , 163 ]. The AuNPs in the combination therapy will serve dual functions as both drug sensitizer and a PT agent, and was shown to enhance anticancer effects of chemotherapeutic drugs [ 158 , 162 , 163 ]. AuNS-Dox combination demonstrated enhanced cancer cell death after laser exposure when compared to the individual effects of the AuNSs and Dox with and without laser treatment [ 158 ].

Active targeting on its own can also improve AuNP uptake, localization and target-specific PT effects, which can be viewed in real time by adding fluorophores. AuNSs (25 nm) loaded with transferrin targeting molecules and FITC were shown to accumulate and destroy human breast cancer cells at a higher rate than in non-cancer cells and had better efficacy than the untargeted AuNSs [ 57 ]. An independent study also demonstrated that DNA aptamers (As42)-loaded AuNSs (As42-AuNP) induced selective necrosis in Ehrlich carcinoma cells that express HSPA8 protein, a receptor for the aptamers. None of these effects were observed in blood and liver cells mixed with target cells, or cells treated with the AuNSs without laser treatment [ 163 ]. The PT effects of the As42-AuNP were replicated in mice transplanted with Ehrlich carcinoma cells in their right leg. As shown in Fig.  9 , tail-vein injections of As42-AuNPs followed by laser irradiation resulted in targeted PT destruction of the cancer cells. The As42-AuNPs reduced tumor size in a time-dependent manner; cell death was attributed to increased temperature up to 46 °C at the tumor site. The tumor in mice treated with As42-AuNPs without laser treatment and the AuNPs conjugated with nonspecific DNA oligonucleotide continued to grow but at the lower rate compared to mice injected with PBS. This suggests that the AuNPs were also localized in the tumor [ 163 ]. In cases where AuNSs are not efficient for deep tissue PTT, other shapes such as nanocages, nanoshells and AuNRs can be used [ 158 ]. Alternately, the visible light absorption of the AuNSs can be shifted to NIR by using processes such as two-photon excitation [ 57 ].

In vivo plasmonic PT therapy of cancer cells using targeted AuNSs. As42-AuNPs localized in HSPA8-expressing tumor cells after i.v injection. Exposure to laser treatment resulted in hyperthermia that caused cancer cell death. Reproduced with permission [ 163 ]. Copyright 2017, Elsevier

The PT effects of the AuNPs have also been reported for the reversal of obesity [ 52 , 56 ], using hollow AuNSs (HAuNSs) [ 52 ] and AuNRs [ 56 ] for the PT lipolysis of the subcutaneous white adipose tissue (sWAT) in obese animals. The HAuNSs were modified with hyaluronate and adipocyte targeting peptide (ATP) to produce HA–HAuNS–ATP conjugate [ 52 ]. Hyaluronate was used to ensure topical entry of the HA–HAuNS–ATP through the skin [ 52 , 166 ], while ATP will recognize and bind to prohibitin once the HAuNSs are internalized. Prohibitin is a receptor that is differentially expressed by the endothelial cells found in the WAT vasculature of obese subjects [ 5 , 52 , 55 ]. The HA–HAuNS–ATP was topically applied in the abdominal region of the obese mice, and through hyaluronate were transdermally shuttled through the epidermis into the dermis where the ATP located the sWATs (Fig.  10 ) . Illumination of the target site with the NIR laser selectively induced PT lipolysis of the sWAT in the obese mice and reduced their body weight [ 52 ]. The AuNRs were used in the photothermolysis-assisted liposuction of the sWATs in Yucatan mini pigs. The untargeted PEG-coated AuNRs (termed NanoLipo) were injected in the sWATs through an incision, followed by laser illumination to heat up the sWATs, which was then aspirated using liposuction. The amount of fat removed from NanoLipo-treated porcine was more than the one removed with conventional suction-assisted lipectomy (SAL). NanoLipo-assisted fat removal had several advantages over the conventional SAL; it took less time (4 min) for liposuction compared to 10 min for SAL, the swelling in the treated site healed faster, and the weight loss effects lasted over 3 months post-liposuction [ 56 ].

PT lipolysis of the sWATs using HA-HAuNS-ATP. The ATP was conjugated to the AuNSs for targeted delivery and destruction of the prohibitin-expressing sWATs after NIR laser exposure. Reproduced with permission [ 52 ]. Copyright 2017, American Chemical Society

AuNP-based PTT clearly offers a lot of advantages compared to the conventional agents. Their biocompatibility allows for broader applications both in vitro and in vivo. Moreover, they can be customized based on their shapes for shallow (AuNSs) [ 158 , 161 , 162 ] or deep tissue (AuNRs and stars) PTT [ 158 , 161 ]. At 1–100 nm diameter, AuNPs and its conjugates can circulate long enough to reach and accumulate in the target tissues, with or without targeting moieties [ 159 , 167 ]. Active targeting can be used to ensure localized PT effects through various routes of administration and might be effective for solid and systemic diseases. AuNP-based PTT can also be used to sensitize cancer cells when administered in combination with chemotherapy, gene therapy and immunotherapy [ 159 ]. Therefore, AuNP-based PTT has potential for treatment of chronic diseases [ 161 ].

Toxicity of AuNPs

AuNPs can play an important role in medicine, as demonstrated by the preclinical and clinical studies under review. Their full potential in clinical application as both diagnostic and therapeutic agents can only be realized if they do not pose any health and environmental hazards. While their use in vitro appears to be inconsequential, in vivo application can be hampered by their potential toxicity, which could be detrimental to human health. A major concern with their clinical use is that AuNPs are non-biodegradable and their fate in biological systems has not been fully studied [ 5 , 30 ]. Although AuNPs are considered to be bio-inert and compatible, their properties (size, shape, charge and composition) raise concerns as they can alter their pharmacokinetics when used in biological environment [ 27 , 34 , 118 ]. The toxicity of AuNPs of varying sizes and shapes has been demonstrated in animals [ 27 , 118 ]. These NPs can accumulate in the RES organs where they induce damage.

AuNPs are 1–100 nm in diameter which makes them smaller than most of the cellular components. At these sizes, AuNPs can passively transverse cellular barriers and blood vessels by taking advantage of the EPR effect in pathological cells. AuNPs with smaller diameters (1–2 nm) can easily penetrate cell membranes and biologically important cellular organelles such as mitochondria and nuclei [ 7 , 168 ]. Accumulation of AuNPs in these organelles induces irreversible damage that can cause cellular demise. On the contrary, AuNPs larger than 15 nm are restricted to the cytoplasmic spaces and unable to penetrate internal organelles [ 168 ]. These features are desirable for targeting pathological cells, however, AuNPs can also be taken up by healthy cells and alter their physiology [ 118 ]. Administration of AuNP-based therapeutics can be done via different routes (i.e., intranasal, oral, transdermal, i.p or i.v) and transported through blood vessels into different tissues and organs [ 34 , 118 ]. They are able to pass through the blood brain barrier and the placental barrier [ 34 ]. Toxicity is size dependent, with certain sizes of AuNPs being well tolerated, while others could be lethal to healthy tissues. Unfunctionalized AuNSs at 8, 17, 12, 37 nm caused physical changes (i.e., change the fur color, loss of bodyweight, camel-like back and crooked spine) within 14 days of treatment (2 doses of 8 mg/kg/week) in rats [ 118 ]. Most (> 50%) of the rats died within 21 days (i.e., after 3 doses), and abnormalities in the RES organs (liver, lungs and spleen) were observed. On the contrary, mice treated with 3, 5, 50 and 100 nm AuNPs were not affected by the NPs and no adverse effects or death occurred throughout the duration (50 days) of the study [ 118 ]. In diet-induced obese rats that received i.v injections of 14 nm cAuNPs, the NPs were detected in various tissues after 24 h and were mostly confined to the RES organs [ 55 ].

The shape, charge and surface chemistry of AuNPs can influence their toxicity. These factors can determine how AuNPs will interact with the biological systems, their cellular uptake and effects on the cells. AuNSs are readily taken up by cells and proven to be less toxic than other shapes such as rods and stars. AuNP surfaces are charged and will influence how they interact and behave within a biological environment [ 169 ]. Cationic AuNPs are likely to be more toxic compared to neutral and anionic AuNPs, as their charge allows these NPs to easily interact with negatively charged cell membranes and biomolecules such as DNA. Both the positively and negatively charged AuNPs have been associated with mitochondrial stress, which was not observed with the neutrally charged AuNPs [ 34 , 35 ].

The shell that forms on the surface of the AuNP core can also influence the functioning of the NPs. These are usually reducing and/ or stabilizing agents such as citrate and CTAB, and once subjected to a biological environment, these molecules can cause either the desorption or absorption of biomolecules found in the biological environment. This can result in the formation of a corona or cause the NPs to become unstable. Citrate- and CTAB-capped AuNPs are highly reactive, which can facilitate the attachment of biocompatible polymers such as PEG, polyvinyl-pyrrolidone, poly (acrylic acid), poly(allylamine hydrochloride), and polyvinyl-alcohol) or biomolecules such as albumin and glutathione to prevent the formation of AuNP-corona with serum proteins. These molecules serve as a stabilizing agent and form a protective layer that can mask the AuNPs from attacks by phagocytes [ 7 , 29 , 34 , 170 ] and prevent off-target toxicity [ 7 ]. As discussed in “ AuNP-Based Therapies ” section, AuNPs can be functionalized with targeting and therapeutic agents to define their targets and effects [ 34 ].

In addition to their physicochemical properties, the dosage, exposure time and environmental settings also influence the activity of AuNPs. Lower doses and short-term exposure times might render AuNP as nontoxic, while increasing these parameters will lead to cytotoxic effects [ 34 ]. Moreover, in vitro studies do not always simulate in vivo studies. At times, AuNPs that seem to be nontoxic in cell culture-based experiments end up being toxic in animal experiments. Many factors could be responsible for these discrepancies [ 118 ], and some steps have been identified that can guarantee the safety of AuNPs in biomedical applications. The biocompatibility and target specificity of AuNPs can be improved by modifying the surface of the NPs. Attaching targeting moieties on the AuNPs can channel and restrict their effects to specific targets or pathological cells [ 5 , 55 , 127 ]. Modification of AuNP surface with bio-active peptides provides a platform for developing multifunctional AuNPs with enhanced specificity, efficacy and potentially sustainable effects [ 11 , 127 ]. All of these effects will be instrumental in the design and development of AuNP-based systems for clinical applications.

Clinical Application of AuNPs

Nanotechnology has the potential to shape the future of healthcare systems and their outcomes. Its promise of creating highly sensitive and effective nanosystems for medicine has been realized with the introduction of organic nanoformulations for cancer treatment. These systems have already paved the way for nanomaterials into clinical applications: doxil and abraxane have been in the market for over two decades and demonstrated the potential of nanotechnology in medicine [ 1 , 2 ]. More recently, this technology has been used for the development of the SARS-CoV-2 lipid NP-based vaccine to fight against the COVID-19 pandemic [ 171 ]. Inorganic nanosystems such as AuNPs offer many advantages over their organic counterparts, yet few of these systems are used clinically (Table 2 ) [ 19 , 32 ].

While several AuNP-based drugs are some of the inorganic nanomaterial-based drugs that were tested in clinical trials, they are not progressing at the same rate as organic liposome-based nanodrugs. Aurimune (CYT-6091) and aurolase were the first of AuNP-based formulations to undergo human clinical trials for the treatment of solid tumors. CYT-6091 clinical trials started in 2005 for delivery of recombinant TNF-α as an anticancer therapy in late-stage pancreatic, breast, colon, melanoma, sarcoma and lung cancer patients. CYT-6091 consists of 27-nm cAuNPs loaded with TNF-α and thiolated PEG. The CYT-6091 nanodrug has achieved safety and targeted biologic response at the tumor site at a dose lower than that required for TNF-α alone [ 16 , 17 ]. CYT-6091 is approved and yet to start phase II clinical trials in combination with chemotherapy. Based on phase II clinical trial strategy, several variants of CYT-6091 have been developed and tested in preclinical studies. All the nanosystems contain TNF-α with either chemotherapy (paclitaxel, dox and gemcitabine), immunotherapy (Interferon gamma) or apoptosis inducing agents attached to the 27 nm cAuNPs [ 14 , 15 , 16 ]. The AuNP conjugates preferentially accumulated in the tumor sites after systemic administration through the EPR effect and vascular targeting effects of the TNF-α. The AuNPs were not detected in the healthy tissues, and the anti-tumor effects of TNF-α were restricted to the tumor environment [ 14 , 16 , 19 ].

The first clinical trial for the PT treatment with AuroLase® for refractory and/or recurrent head and neck cancers was completed. Information on the outcome of this trial is still pending. The second trial is set to evaluate the effects of AuroLase® on primary and/or metastatic lung tumors in patients where the airway is obstructed [ 19 ]. The number of human trials based on AuNP-based formulation is increasing, covering the treatment of a wide range of medical conditions including skin, oral, heart and neurological diseases. AuNP-formulation (150 nm silica-gold nanoshells coated with PEG), which is similar to AuroLase®, was approved for PT treatment of moderate-to-severe inflammatory acne vulgaris. The nanoshells were topically applied on the acne area and transdermally delivered into the follicles and sebaceous ducts through low-frequency ultrasound or massage. Nanoshells applied through massage were effective in penetrating the shallow skin infundibulum (90%) and the sebaceous gland (20%), while the low-frequency ultrasound can penetrate both shallow and deep skin tissues. NIR laser treatment resulted in focal thermolysis of the sebaceous glands in the affected area and disappearance of the acne [ 18 , 167 ]. The gold–silica nanoshells were well-tolerated, showed no systemic toxic effects with minor side effects (reddiness and swelling) at the treatment site [ 18 ]. AuNPs offer many health benefits based on their unique properties but at the same time have raised a lot of political and ethical issues, and resulted in termination of some clinical studies (NCT01436123).

Conclusion and Future Perspectives

Applications of AuNPs in biomedicine are endorsed by their unique physicochemical properties and have shown great promise as theranostic agents. The increasing interest in biomedical applications of AuNPs is further encouraged by the biocompatibility and medical history of bulk gold, which suggests that the gold core in AuNPs will essentially display similar or improved properties [ 3 ]. But at the same time their small size can infer unique properties that will completely change their pharmacokinetics [ 144 ]. The diverse biomedical applications of AuNPs in diagnostics and therapeutics herein discussed demonstrate their potential to serve as adjunct theranostic agents. They can be used as drug delivery, PTT, diagnostic and molecular imaging agents [ 12 , 33 , 128 ]. In time, and with better knowledge of mechanisms of action, more AuNP-based systems will obtain approval for clinical use. However, the excitement of these biomedical applications of AuNPs should unequivocally be balanced with testing and validation of their safety in living systems before any clinical applications.

In conclusion, more work needs to be done to taper the toxicity of AuNPs. This can be achieved by introducing biocompatible molecules on their surface [ 14 , 15 , 58 , 159 ], and developing new and better synthesis methods, such as the use of green chemistry to produce biogenic NPs. All these developments may further broaden the applications of AuNPs in nanomedicine. AuNPs are non-biodegradable, and off-target distribution could result in chronic and lethal effects. All these concerns must be addressed before clinical translation; the existing trials will soon provide some clarity on their impact in human health. Should their health benefits outweigh their potential risks as is the case with the existing clinical drugs, it is a matter of time before they are approved for clinical use.

Availability of Data and Materials

All the information in this paper was obtained from the studies that are already published and referenced accordingly.

Abbreviations

5-Fluorouracil

Alzheimer's disease

Amyloid-beta-derived diffusible ligands

Antisense oligonucleotides

• Gold nanoparticles

Quantum-sized AuNPs

Gold nanorods

Gold nanospheres

Bio-barcoding assay

Citrate-capped AuNPs

Corona virus disease 2019

Cerebrospinal fluid

Computed tomography

Cetyltrimethylammonium bromide

4-((4′-(Dimethyl-amino)-phenyl)-azo)benzoic acid

4,6-Diamino-2-pyrimidinethiol

Doxorubicin

1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide

Enhanced permeability and retention

Food and Drug Administration

Fluorescein isothiocyanate

Fluorescence resonance energy transfer

Hollow AuNSs

Hounsfield unit

Lateral flow assays

Localized surface plasmon resonance

Multidrug resistant

Mercaptopropionic acid

Microwave-induced plasma-in-liquid process

Near-infrared

Nanostructured materials

Pneumocystis jirovecii

Polyethylene glycol

Prostate-specific antigen

Prostate-specific membrane antigen

Photothermal

Photothermal therapy

Quantum dots

Reticuloendothelial system

Reactive oxygen species

Severe acute respiratory syndrome-coronavirus-2

Severe combined immunodeficiency

Surface plasmon resonance

Subcutaneous white adipose tissue

Tetrabutylammonium bromide

Tissue-resident macrophages

Vascular endothelial growth factor

White adipose tissue

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Acknowledgements

The study was financially supported by the DSI/Mintek NIC.

The study was funded by the DSI/Mintek NIC Biolabels Node.

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Nicole Remaliah Samantha Sibuyi, Koena Leah Moabelo, Adewale Oluwaseun Fadaka, Abram Madimabe Madiehe & Mervin Meyer

Nanobiotechnology Research Group, Department of Biotechnology, University of the Western Cape, Bellville, South Africa

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Department of Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, Bellville, South Africa

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Sibuyi, N.R.S., Moabelo, K.L., Fadaka, A.O. et al. Multifunctional Gold Nanoparticles for Improved Diagnostic and Therapeutic Applications: A Review. Nanoscale Res Lett 16 , 174 (2021). https://doi.org/10.1186/s11671-021-03632-w

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211At on Gold Nanoparticles for Targeting Radionuclide Therapy Application

(note: the full text of this document is currently only available in the pdf version ).

Jeffrey Tanudji , Hideaki Kasai , Michio Okada , Tetsuo Ogawa , Susan Menez Aspera and Hiroshi Nakanishi

First published on 3rd April 2024

Targeted alpha therapy (TAT) is a methodology that is being developed as a promising cancer treatment using the alpha-particle decay of radionuclides. This technique involves the use of heavy radioactive elements being placed near the cancer target area to create maximum damage to the cancer cells while minimizing the damage to healthy cells. Using gold nanoparticles (AuNPs) as carriers, a more efficient therapy methodology may be realized. AuNPs can be good candidates for transporting these radionuclides to the vicinity of the cancer cells since they are able to be labeled not just with the radionuclides, but also a host of other proteins and ligands to target these cells and serve as addi-onal treatment options. Research has shown that astatine and iodine are capable of adsorbing on the surface of gold, creating a covalent bond that is quite stable to be used in experiments.

Gold nanoparticles: A critical review of therapeutic applications and toxicological aspects

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• 1 a Laboratório de Toxicologia e Essencialidade de Metais, Faculdade de Ciências Farmacêuticas de Ribeirão Preto , Universidade de São Paulo , Ribeirão Preto , São Paulo , Brazil.
• PMID: 27282429
• DOI: 10.1080/10937404.2016.1168762

Gold (Au) compounds have been utilized as effective therapeutic agents for the treatment of some inflammatory diseases such as rheumatoid arthritis. However, Au compound use has become limited due to associated high incidence of side effects. Recent development of nanomaterials for therapeutic use with Au-containing drugs is improving the beneficial actions and reducing toxic properties of these agents. Lower toxicity in conjunction with anti-inflammatory and antiangiogenic effects was reported to occur with gold nanoparticles (AuNP) treatment. However, despite this therapeutic potential, safety of AuNP remains to be determined, since the balance between therapeutic properties and development of adverse effects is not well established. Several variables that drive this benefit-risk balance, including physicochemical characteristics of nanoparticles such as size, shape, surface area, and chemistry, are poorly described in the scientific literature. Moreover, therapeutic and toxicological data were obtained employing nonstandardized or poorly described protocols with different experimental settings (animal species/cell type, route and time of exposure). In contrast, effective and safe application of AuNP may be established only after elucidation of various physicochemical properties of each specific AuNP, and determination of respective kinetics and interaction of compound with target tissue. This critical review conveys the state of the art, the therapeutic use, and adverse effects mediated by AuNP, with primary emphasis on anti-inflammatory and antiangiogenic potential, highlighting the limitations/gaps in the scientific literature concerning important points: (i) selection of experimental designs (in vitro and in vivo models) and (ii) consideration of different physicochemical properties of AuNP that are often disregarded in many scientific publications. In addition, prospects and future needs for research in this area are provided.

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• Angiogenesis Inhibitors / adverse effects
• Angiogenesis Inhibitors / therapeutic use
• Anti-Inflammatory Agents / adverse effects
• Anti-Inflammatory Agents / therapeutic use
• Gold / adverse effects
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• Metal Nanoparticles / adverse effects*
• Metal Nanoparticles / therapeutic use*
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Improving infectious disease testing with gold nanoparticles

by Tohoku University

By harnessing the power of composite polymer particles adorned with gold nanoparticles, a group of researchers have delivered a more accurate means of testing for infectious diseases. Details of their research are published in the journal Langmuir .

The COVID-19 pandemic reinforced the need for fast and reliable infectious disease testing in large numbers. Most testing done today involves antigen-antibody reactions. Fluorescence, absorptions, or color particle probes are attached to antibodies. When the antibodies stick to the virus, these probes visualize the virus's presence. In particular, the use of color nanoparticles is renowned for its excellent visuality, along with its simplicity to implement, with little scientific equipment needed to perform lateral flow tests.

Gold color nanoparticles (AU-NP), with their high chemical stability and unique plasmon absorption, are widely employed as probes in immunoassay tests. They exhibit extreme versatility, with their colors fluctuating according to their size and shape. Additionally, their surface can be modified by using thiol compounds.

Conventional tests that use AU-NP often have to amplify AU-NP's optical density, so that scientists can easily measure the strength of the signal produced by the interaction between antibodies and the target substance.

Adding more gold nanoparticles is one means to do this. But because nanoparticles are tiny, it requires a large quantity of them to achieve a strong enough signal for accurate detection.

To overcome this, the researchers proposed a new method called self-organized precipitation (SORP). SORP works by dissolving polymers into organic solvents before adding a liquid that doesn't dissolve the polymers well, like water. After the original organic solvent is removed by evaporation, polymers assemble together, forming tiny particles.

"Using gold nanoparticle decorated polymers (GDNP) assembled by SORP, we set out to see how effective they would be in detecting the influenza virus , and whether they offered improved sensitivity in detecting antigen-antibody reactions," states Hiroshi Yabu, co-author of the paper and professor at Tohoku University's Advanced Institute for Materials Research (AIMR). "And it did. Our method resulted in a higher optical density than original AU-NPs and GNDPs decorated with smaller AU-NPs."

Yabu and his colleagues' findings reinforce that GNDP particles have broad utility, extending beyond laboratory settings to real-world diagnostic scenarios.

Journal information: Langmuir

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Biologically Derived Gold Nanoparticles and Their Applications

1 Department of Biotechnology, School of Engineering & Technology, Sharda University, Greater Noida, India

Chetan Pandit

2 Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, India

3 Department of Physics, Faculty of Sciences, University 20 Août 1955, BP26 21000, Skikda, Algeria

Mohammed S. Alqahtani

4 Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia

5 BioImaging Unit, Space Research Centre, University of Leicester, Michael Atiyah Building, Leicester LE1 7RH, UK

Muhammad Bilal

6 School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huai'an 223003, China

Saiful Islam

7 Civil Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia

Md. Jamal Hossain

8 Department of Pharmacy, State University of Bangladesh, 77 Satmasjid Road, Dhaka, Bangladesh

Mohammed Jameel

9 Department of Civil Engineering, College of Engineering, King Khalid University, Abha, Saudi Arabia

Associated Data

All data used to support the findings of this study are included within the article.

Nanotechnology is a rapidly evolving discipline as it has a wide variety of applications in several fields. They have been synthesized in a variety of ways. Traditional processes such as chemical and physical synthesis have limits, whether in the form of chemical contamination during synthesis operations or in subsequent applications and usage of more energy. Over the last decade, research has focused on establishing easy, nontoxic, clean, cost-effective, and environmentally friendly techniques for nanoparticle production. To achieve this goal, biological synthesis was created to close this gap. Biosynthesis of nanoparticles is a one-step process, and it is ecofriendly in nature. The metabolic activities of biological agents convert dissolved metal ions into nanometals. For biosynthesis of metal nanoparticles, various biological agents like plants, fungus, and bacteria are utilized. In this review paper, the aim is to provide a summary of contemporary research on the biosynthesis of gold nanoparticles and their applications in various domains have been discussed.

1. Introduction

Nanotechnology is an evolving area due to its wider range of applications in a variety of disciplines [ 1 , 2 ]. Optics, electronics, catalysis, biomedicine, magnetics, mechanics, and energy research are some of the fields where nanotechnology is applied [ 3 ]. Nanobiotechnology is a collaborative area that entails technology research and development in a variety of domains such as nanotechnology, biotechnology, chemistry, material science, and physics [ 4 ]. It is about the biofabrication of nano-objects or bifunctional macromolecules that may be utilized to produce or modify nano-objects [ 5 ]. Nanoparticles are metallic units that come in a variety of forms, including spherical, triangular, and rod shaped [ 6 ]. Nanoparticles have distinct features (chemical, physical, optical, and so on) as compared to bulk material [ 7 ]. Currently, research on nanoparticles production is one of the hot topics.

One of most well-defined noble metals is gold. It is utilized in automobiles as a heat insulator and as a reflective coating on some high-end CDs [ 8 ]. Gold nanoparticles (GNPs) are being researched for usage in ultrasensitive chemicals, optoelectronic devices, or biological sensors, or as catalysts [ 9 ]. Among all types of nanomaterials, metallic nanoparticles are the most promising because of their excellent antibacterial characteristics due to their huge surface area to volume ratio. Researchers are interested in the antibacterial effect of metallic nanoparticles because of the rising microbial resistance to antibiotics or the creation of resistant strains. Silver, platinum, gold, titanium, iron, palladium, aluminum, and copper [ 10 ] are some of the metallic nanoparticles that have received a lot of attention recently owing to their critical value. Gold has been used in medicine in various forms throughout the history of civilization. Rheumatic illnesses, such as discoid lupus erythematosus and restorative dentistry, and different skin inflammation conditions, such as urticaria, pemphigus, and psoriasis, have been treated with gold and gold compounds [ 11 ].

Biological agents such as plant tissues, bacteria, fungi, actinomycetes, and other molecules have been used for synthesis of gold nanoparticles. The extracellular synthesis of gold nanoparticles has attracted a lot of interest because it avoids many stages of the synthesis process. In general, there are two techniques for nanoparticle synthesis, that is, a ‘top-bottom' and a ‘bottom-top' strategy. Nanoparticles could be synthesized by chemical (chemical reduction) or biological (uses of plant, microbes, etc.) processes through self-assembly of atom new nuclei that develop into nanoscale particles in the bottom-top approach [ 12 ]; however, in the top-bottom method, appropriate bulk materials are reduced into small particles using different lithographic processes. Physical and chemical processes for nanoparticle synthesis are not environmentally friendly due to the usage of toxic substances that pose a variety of biological dangers and are costly [ 13 ]. This review provides a summary of contemporary research on biosynthesis of gold nanoparticles and their applications in various domains.

2. General Chemistries of Gold

There are six possible oxidation states for gold, ranging between −1 and +5, due to its comparatively high electronegativity. Auric (Au (I)) or auric (Au (III)) are two of the main oxidation states for gold complexes [ 14 ]. To dissolve gold in aqueous solution, the oxidation and complexation processes work together. Au (I) or Au (III) could form a stable complex in the presence of complex ligands, or, in solution, these could be reduced to metals of gold. Stabilities of gold's complex is governed not just by complex ligand's property, but also by the donor atom of ligands which is directly attached to gold atoms [ 15 ]. The first rule, according to research, is that stability of gold's complex reduces as the electronegativity of the donor atom rises. In solution, the stability of the gold halide complex, for example, follows the I- > Br- > Cl- > F patterns [ 16 ]. The second rule is that Au (III) is preferred to Au (I) in harsh ligands, whereas Au (I) is preferred to Au (III) in gentle ligands (III). Preferred coordination numbers of Au (I) are 2, which results in a linear complex, whereas Au (III) has a preferred coordination number of 4, which results in a square planar complex. Two precursor uses in the production of GNPs are the gold (III) chloride complexes or the gold thiosulfate (I). In most GNP biosynthesis techniques, the gold (III) chloride complexes are extensively employed as precursors.

3. Green Synthesis of Gold Nanoparticles

One of the basic and technical concerns is the production of nanoscale gold within the regulated phase or shapes. Michael Faraday described production of gold colloids, now known as GNPs, nearly 150 years ago using phosphorous to decrease AuCl4 ions. A variety of biological, physical, or chemical methods have been explored in the past years in order to create GNPs for usage in electrical, biotechnological, industrial, pharmaceutical, agricultural, or medical sectors [ 17 ]. These methods are used to manufacture gold nanostructures with well-defined compositions, such as colloids, clusters, wires, powders, tubes, rods, and thin films [ 18 ]. Physical and chemical approaches to make GNPs have been used in the past, as shown in Figure 1 . These approaches have yielded GNPs within size ranging from 1 to 100 nm or varieties of morphology. These synthesis processes have certain limitations despite their considerable research, such as the use of harsh chemicals, rigorous synthesis conditions, energy or capital demands [ 19 ], or lower productivities [ 20 ]. Currently, mix-shaped nanoparticles (NPs), produced by synthetic methods, need high-cost, low-yield purification processes such as differential centrifugation [ 6 ]. Furthermore, these processes create more sludge and pose environmental risks due to harmful solvents or additives. As a result, there is a growing need to create clean, nontoxic, ecologically friendly, and long-term synthesis methods. A key issue is the development of high-yield, low-cost NPs production technologies. Because of their wide range of applications, researchers in nanoparticles synthesis had turned to a biological system.

Synthetic methods for the synthesis of gold nanoparticles.

Biosynthesis has been shown to be a viable method for producing tiny particles on a wide scale [ 21 ] ( Figure 2 ). It is worth noting that biologically produced NPs have higher stability [ 23 ] and better morphological control. Biological systems that create NPs include bacteria, fungus, actinomycetes, and plants [ 24 , 25 ]. Microbes create NPs intracellularly and/or extracellularly due to their inherent potential [ 26 ]. However, due to the further processing procedures, such as ultrasonication or treatments with appropriate detergents, extracting NP generated via intracellular biosynthesis is often challenging [ 27 ]. As a result, bacteria that produce NP extracellularly must be thoroughly screened [ 28 ]. Microorganisms as potential biofactories for GNP production is a promising new field of study. Additionally, it can easily be scaled up for larger-scale production and is economical, time-saving, and ecologically friendly [ 29 ]. Next sections go through the various microbial synthesis techniques for GNPs in further depth.

Mechanism of GNPs biosynthesis [ 22 ].

3.1. Bacteria

Prokaryotes have gained a lot of interest in the field of GNP synthesis among microorganisms. For the first time, bacterial generation of GNP in Bacillus subtilis 168 was described, indicating the presence of 10–35 nm octahedral NPs in the cell wall [ 30 ]. Rhodopseudomonas capsulata generated spherical GNPGNP within diameters of 10–20 nm at a lower concentration [ 31 ] or nanowires within networks at high concentrations [ 32 ]. In a study, GNP synthesis has been reported in six cyanobacteria which include Plectonema sp. , Calothrix sp. , Anabaena sp., and Leptolyngbya sp. GNP [ 33 ]. Govindaraju et al. [ 34 ] reported synthesis of GNPs from single celled protein, that is, Spirulina platensis GNP. Table 1 summarizes the synthesis of bacterial GNP. Ahmad et al. [ 44 ] demonstrate microbial generation of monodispersed GNPs from an extremophilic Thermomonas sp. A study reported that after 48 hours of incubation with aqueous chloroauric acid (HAuCl 4 ) solution at pH ranges of 4.0–7.0, bacterium Rhodopseudomonas capsulata produces spherical GNPs in 15–25 nm ranges [ 31 ]. Furthermore, pH of the solution is an important factor that influences types of biogenic AuNPs or location of gold deposition in the cell. Due to metal ion reduction by enzyme present in cell walls or on the cytoplasmic membrane but not in the cytosols, alkalotolerant Rhodococcus sp. formed more intracellular monodispersed GNPs on the cytoplasmic membrane than on the cell walls. Pseudomonas aeruginosa cell supernatant was used for the reduction of gold ions and extracellular production of GNPs [ 36 ]. Heterotrophic sulphate-reducing bacteria were employed in the bacterial cell membrane to decrease gold (I) thiosulfate complexes Au (S 2 O 3 ) 2 to elementals golds of 10 nm sizes, resulting in H2S as a metabolic end product [ 48 ]. E. coli DH5 biologically reduces chloroauric acid to Au0, leading to the synthesis of nanoparticles on the cell surface, which were mostly spherical but also included some triangles or quasihexagons. This cell-bounded nanoparticles might be useful in hemoglobin or protein electrochemistry [ 49 ]. Rhodobacter capsulatus , a photosynthetic bacterium with a larger biosorption capacities for HAuCl 4 , have also been found to bioreduce trivalent aurum. Carotenoid or NADPH-dependent enzyme incorporated in plasma membranes or released extracellularly had been identified to have a role in biosorption or bioreduction of Au 3+ to Au 0 both inside and outside cells [ 50 ].

Bacteria synthesize gold nanoparticles.

Fungi are among the most effective microbial agents for the production of metal nanoparticles. Fusarium oxysporum, Trichothecium sp. , Colletotrichum sp. , Trichoderma asperellum, Phanerochaete chrysosporium, T. viride, Fusarium semitectum, Coriolus versicolor, Aspergillus fumigates, or Phoma glomerata are examples of fungi. Fungi are believed to be more advantageous for GNP synthesis than other bacteria because fungal-mycelial meshes, unlike bacteria, could withstand flow pressure, agitations, or other bioreactor conditions. They are easy to culture and manage. They produce more reductive protein extracellular secretions and are more easily processed downstream [ 51 ]. Fungus Trichothecium sp. was reported to produce GNPs both extracellularly and intracellularly [ 52 ]. Under stationary conditions, gold ion interacting within Trichothecium sp. fungal biomass results in rapid extracellular formations of GNPs with spherical rod-like and triangular shapes, whereas in case of shaking condition it resulted in intracellular formation of the GNPs. A study reported that whenever gold ions are exposed to extremophilic actinomycete Thermomonospora sp., it reduces metal ions extracellularly [ 53 ]. Table 2 provides an overview of fungal derived GNP production.

Fungi synthesize gold nanoparticles.

One of the most significant methods for biosynthesis of nanoparticles was the use of plant extracts ( Figure 3 ). In a study, Azadirachta indica leaf extract showed bioreduction of Au 3+ or Ag + ion [ 69 ]. Aloe vera leaf extract was used to make gold nanotriangle and spherical silver nanoparticles [ 70 ]. Some of the ecological benefits of processing plants or their extracts in producing GNPs include uses of nontoxic biocomponents to cap or reduce GNP, limiting waste generation, eliminating the need for further purification methods or ease of availability. Flavonoids, phytosterols, quinones, and other plant biocomponents contribute to the formation of GNPs because they include functional groups that aid in the reduction and stability of GNPs. To create specified shapes and sizes of GNPs, technique requires the combination of gold salt with plant extracts for a certain period of time under various reaction variables such as pH, incubation duration, and temperature.

Green synthesis of GNPs from a plant [ 68 ].

Song et al. [ 71 ] reported GNPs synthesis from leaf extract of two plants, that is, Magnolia kobus and Diospyros kaki . GNPs were synthesied by using a plant extract mixed with an aqueous HAuCl4 solution. At a reaction temperature of 95°C, more than 90% of the GNPs were recovered in just a few minutes. Emblica officinalis fruit extract was also used as a reducing agent in extracellular synthesis of extremely stables Ag nanoparticles [ 72 ]. In a study, Cinnamomum camphora leaf extract was used to make gold nanoparticles [ 73 ]. Further information on the plants that have been used for synthesis of GNPs has been provided in Table 3 .

Plants synthesize gold nanoparticles.

Algae is one of the potential biological agents which can be utilized for the synthesis of different types of nanoparticles. There is a current interest in the study of algal mediated synthesis of metal nanoparticles, with a focus on the evaluation of the effect of reaction conditions, such as pH, temperature, and stirring rate, upon the final nanoparticles with respect to size, morphology, stability, and so forth [ 102 ]. A study employed algal system to explore procedure of gold's reduction by Chlorella vulgaris biomass from gold (III) chloride solution [ 103 ]. XAS data show that Au (III) was significantly reduced to Au (I), also Au (I) is coordinated along sulfur atom from free-sulfhydryl residue or lighter-atoms elements, most likely nitrogen. Another study reported that elemental gold was largely precipitated on cell wall of Sargassum natans biomass [ 104 ]. According to a study, hydroxyl groups of saccharide or carboxylates anions of amino acid residues from peptidoglycans layers on cell walls seemed to be the gold binding site [ 105 ]. A marine alga Sargassum wightii was also used for production of GNPs [ 106 ]. After 12 hours of reaction, stable GNPs in the size range of 8–12 nm was produced through reducing aq. AuCl4- ions within extracts of marine alga, with 95% of golds recovered. Some other algae which are used for the synthesis of gold nanoparticles include Acanthophora spicifera , Kappaphycus alvarezii, Chlorella pyrenoidosa , Sargassum myriocystum , Stoechospermum marginatum , Sargassum wightii , and Laminaria japonica [ 107 ]. Arockiya Aarthi Rajathi et al. [ 108 ] reported synthesis of gold nanoparticles using Stoechospermum marginatum and the synthesized nanoparticles were 18.7–93.7 nm in size. Another study reported synthesis of gold nanoparticles using Tetraselmis kochinensis with 5–35 nm in size [ 109 ]. Abdel-Raouf et al. [ 110 ] reported synthesis of gold nanoparticles using Galaxaura elongata with the size range of 3.85–77.13 nm. Sargassum cymosum synthesized gold nanoparticles were reported by Costa et al. [ 111 ] with the size range of 7–20 nm.

3.5. Biomolecules

Biomolecules are molecules that are produced by living organisms to help the body's biological processes. Some of the biomolecules include amino acids, nucleic acids, carbohydrates, and lipids. Carbonyl and hydroxyl groups of biomolecules convert Au 3+ ion to Au 0 atom. After that, Au 0 is capped, yielding stable GNPs. The biosafety of the reactants employed in the manufacture of GNP's may be addressed using this technique. Table 4 depicts the various biomolecule-mediated GNP production methods. List of different biomolecules which were utilized for gold nanoparticles synthesis has been reported in Table 4 .

List of biomolecules involved in the production of GNPs.

4. Advantages of Biologically Synthesized Gold Nanoparticles

Biogenic gold nanoparticles are free from hazardous by-products which are generally found in case of chemical synthesis, that resulted in minimising usage in different applications [ 128 ]. To be used in biomedical applications, gold nanoparticles must be biocompatible. Biological production of gold nanoparticles had various advantages, including its simplicity, one-step nature, environmental friendliness, cost effectiveness, and biocompatibility [ 129 ]. Furthermore, no external stabilising agents are required since biogenic components of plants and microorganisms serve as stabilising or capping agents. Biosynthesis of gold nanoparticles requires less time than chemical one. Another advantage of biological synthesis is that it could decrease numbers of chemical synthesis steps required, such as adding functional groups to surfaces of gold nanoparticles to make them physiologically active [ 129 ].

5. Applications of GNPs

The productions of inorganic or metal-based nanomaterials had encouraged establishment of newer industry which brings together experts from several sectors to hunt for new type of nanoparticles having distinct property. Developing or designing creative or cost-effective processes for scaling up the nanomaterial manufacturing has not only given an intriguing topic of research but will also address future human needs such as health, safety, and environmental concerns. Nanomaterials are rapidly being used in industry, also these would soon replace hazardous or toxic chemical usage. The utilization of nanoparticles or nanocomposites is relatively safer option, opening up new areas for antibacterial research. Different ancient cultures (India, China, or Egypt) employed gold to heal diseases like smallpox, syphilis, skin ulcers, or measles [ 130 ].

5.1. Medical Application

Gold nanoparticles are versatile materials with several uses in a wide range of industries. Gold particles were coated with DNA and inserted into plant embryos or plant cells by researchers. This ensures that some genetic material enters and transforms the cells. This technique improves plant plastids. Because GNPs may be detected using a number of methods, including optical absorptions fluorescent or electrical conductivities, they had been mainly used in biosensor labelling and bioimaging applications [ 131 ]. GNPs were focused and amplified in regions of interests, giving contrasts for observations or visualisations. Light energy causes free electrons in GNPs to form collective oscillations k / a , a surface plasmon, which has the property of considerably absorbing and scattering visible light. The excited electron plasma thermally relaxes by the transfer of energies to gold lattices, causing GNPs to heat up as a result of light absorption. The interaction of GNPs with light can assist in optical microscopy, fluorescent microscopy, photothermal imaging, or photoacoustic imaging. In addition, transmission-electrons microscopy [ 132 ] may be used to investigate interactions of GNPs with electrons wave or X-ray. Gold nanoparticles have long been used to carry therapeutic compounds into cells [ 133 ]. Before being administered to cells by gene guns or particle ingestion, the chemicals are adsorbed on the surface of GNPs.

5.1.1. Anticancer Activity

GNPs are used to treat cancer because of their biocompatibility. GNPs might be utilized to treat epithelial ovarian cancer. They have the capacity to suppress the evolution of ovarian cancer and metastasis [ 134 ]. Growth factors VEGF (vascular-endothelial growth factors) are involved in the development of ovarian cancer and tumour growth. GNPs have also been demonstrated to inhibit activity of VEGF, which promotes cell proliferation, in multiple myeloma (MM), a plasma cell cancer. As a result of VEGF inhibition, cell-cycle inhibitor proteins such as p21 or p27, that limit proliferations, are upregulated [ 135 ]. Chronic lymphocytic leukaemia (CLL) is a kind of leukaemia characterised by an excess of lymphocytes that originate in bone marrow but could spread to different organs. GNPs have been found to inhibit the action of factor produced by CLL cells or to promote apoptosis [ 136 ] because they have the potential to impair the function of heparin-based growth factors.

5.1.2. Tumour Detection

Newly developed functionalized GNPs (dendrimers) have been developed to target and destroy tumours and combat cancer [ 137 ]. GNPs are intended not only to recognise, target, and destroy tumours, but also to transport an additional chemical that can delay or kill cancerous cells. Dendrimers function as arm for GNPs, allowing other molecules to be attached to the arms. Laser and infrared light heat gold's particle, prompting dendrimer in releasing chemicals that kill tumours. The Mie equations suggest that the surface plasmon resonance scattering of GNPs will increase as the nanoparticle size grows. By conjugating GNP to anti-EGFR antibodies, using stronger scattering images of GNP coupled to antibodies which just adhere to cancerous cells and not to noncancerous cells, researchers were able to distinguish between cancerous and noncancerous cell [ 138 ]. A basic optical microscope is used to view the scattering. They obtain 500% greatest bindings ratios to sick cells compared to nonmalignant cells, allowing cancerous cells to be spotted using a dark field microscope to examine scattered light. Because of their higher X-ray's absorption coefficient, simplicity of synthetics modification, nontoxicity, surfaces functionalities for colloidal stabilities, targets distribution, GNPs had received most attention as an X-ray's contrasting agent. Low-molecular-weight vascular contrasting age agents, like iodinates compounds, are common. These iodinated aromatics have a high-water solubility, indicating minimal toxicity. However, the period of blood circulation is brief, and waste is quickly removed by the kidneys. As a result, a limited imaging windows might necessitate numerous injections, increasing risks of thyroid-gland dysfunctions.

5.1.3. Antibacterial Activity

Gold nanoparticles are able to inhibit bacterial growth by conferring themselves onto the bacterial cell surface due to their surface changes. Alteration of surface releases reactive oxygen species which causes protein denaturation, DNA destruction, and mitochondrial disfunction and finally leads to cell death [ 139 ]. A study reported synthesis of gold nanoparticles using Mentha piperita and evaluated its antibacterial effect against E. coli and S. aureus and found that gold nanoparticles showed antibacterial activity against E. coli only [ 140 ]. Another study reported synthesis of gold nanoparticles using Commelina nudiflora and found that it was effective against Salmonella typhi and Enterococcus faecalis [ 141 ]. Abdel-Raouf et al. [ 110 ] reported synthesis of gold nanoparticles using Galaxaura elongate and evaluated its antibacterial activity against Escherichia coli , Klebsiella pneumoniae , Staphylococcus aureus , and Pseudomonas aeruginosa and MRSA.

5.2. Environmental Application

5.2.1. removal of pollutants.

GNP-based technologies are being developed now for pollution control and water purification in the environment. Bimetallic gold-palladium nanoparticles have been found to be a potent catalyst for degrading trichloroethene (TCE), which is one of the primary contaminants in groundwater, into a nontoxic form [ 142 ]. GNPs in water purifications system have been shown to effectively gather and eliminate halocarbon-based pollutants from drinking water [ 143 ] and improve mercury oxidation from coal-fired power plants [ 144 ].

5.2.2. Ornamental Applications

GNPs were developed to selectively oxidize biomass-derived chemicals such as furfurals or hydroxymethyl furfurals to produce methyl-esters, carbon monoxide (CO), or trimethylamine. These chemicals are used in polymers and industrial solvents, as well as in flavour and fragrance applications [ 145 ]. A range of gases, including carbon monoxide (CO) and nitrogen oxides, have been detected using Au nanoparticle-based gas sensors (NOx) [ 146 ].

5.2.3. Removal of Inorganic Compounds

Green GNPs are widely recognised for their catalytic activity, particularly their catalytic reduction abilities. Although gold is not commonly used as a catalyst, gold nanoparticles have been reported to decrease ferrocyanide (III), nitroarenes, cyanosilylation of aldehydes, and deoxygenation of epoxides into alkenes. For example, p-nitrophenols, which are common by-products of the production of herbicides, pesticides, and synthetic dyes and are known to be environmentally poisonous and inhibitory in nature, have been successfully reduced to p-amino phenols by green synthesized GNPs, which would otherwise be incapable of being converted to its neutral and nontoxic form even by the strongest reducing agent [ 147 – 149 ].

6. Future Perspective

Nanotechnology is a rapidly expanding area with several applications in various fields. Gold nanoparticles are synthesized using a variety of processes because of their vast range of uses. Traditional chemical procedures have limitations, either in the form of chemical contamination during the synthesis process or in future applications. Chemical reduction of gold uses a variety of chemicals (reducing agents) that are usually hazardous and difficult to dispose of owing to environmental concerns. Synthesis is also carried out at higher temperatures in a variety of different situations, which generate a lot of heat and are highly expensive. Biological synthesis of gold nanoparticles has sparked considerable attention because it is a quick, ecofriendly, nonpathogenic, and cost-effective method that can be completed in a single step at room temperature and pressure. Compared to standard physical and chemical techniques, biological synthesis is an environmentally friendly approach that uses a diverse variety of resources such as plants, bacteria, actinomycetes, yeast, and fungi. The biosynthesis of gold nanoparticles is still in its early stages of investigation. There are a few issues that must be addressed. Several studies are still required to better understand the impacts of time, temperature, light, and other elements on the formation of gold nanoparticles, as well as the control of the nanoparticle size and shape. Furthermore, researchers face challenges due to a lack of knowledge of the chemical components and mechanisms involved in the reduction and stability of biosynthesized gold nanoparticles. As a consequence, more studies are recommended on the mechanism of gold nanoparticle synthesis and its influence on the shape and size of gold nanoparticles for various applications.

7. Conclusion

Biological approach for nanoparticle synthesis is an important alternative in the development of clean, nontoxic, cost-effective, and environmentally friendly technologies for the synthesis of GNPs, with substantial advantages over previous approaches. Many biological agents have the capacity to synthesise GNPs both inside and outside the cell. Research into the production of GNPs is still in its early stages. For widespread usage of GNPs in commercial applications, more research is required on biosynthesis processes and with well-defined size and shape. The capacity to vary the features of GNPs simply by changing their size or shape is intriguing, and it will be employed in unique applications in the future. GNPs are employed in a wide range of applications, including electronics and catalysis, as well as biology, medicine, and medical diagnostics and therapy. However, further research into the mechanics and kinetics of GNP production is required, since this might lead to process optimization, eventually leading to GNP synthesis with strict control over size, shape, and large-scale manufacturing.

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University (KKU) for funding this work through the Research Group Program Under the Grant Number R.G.P.2/248/43.

Data Availability

Conflicts of interest.

The authors declare no conflicts of interest.

Gold Nanoparticles Used to Improve Infectious Disease Testing

The COVID-19 pandemic reinforced the need for fast and reliable infectious disease testing in large numbers. Most testing done today involves antigen-antibody reactions. Fluorescence, absorptions, or color particle probes are attached to antibodies. When the antibodies stick to the virus, these probes visualize the virus’s presence.

Gold color nanoparticles (AU-NP), with their high chemical stability and unique plasmon absorption, are widely employed as probes in immunoassay tests. They exhibit extreme versatility, with their colors fluctuating according to their size and shape. Additionally, their surface can be modified by using thiol compounds.

Conventional tests that use AU-NP often have to amplify AU-NP’s optical density, so that scientists can easily measure the strength of the signal produced by the interaction between antibodies and the target substance.

Adding more gold nanoparticles is one means to do this. But because nanoparticles are tiny, it requires a large quantity of them to achieve a strong enough signal for accurate detection.

To overcome this, researchers proposed a new method called self-organized precipitation (SORP). SORP works by dissolving polymers into organic solvents before adding a liquid that doesn’t dissolve the polymers well, like water. After the original organic solvent is removed by evaporation, polymers assemble together, forming tiny particles.

“Using gold nanoparticle decorated polymers (GDNP) assembled by SORP, we set out to see how effective they would be in detecting the influenza virus, and whether they offered improved sensitivity in detecting antigen-antibody reactions,” states Hiroshi Yabu, co-author of the paper and professor at Tohoku University’s Advanced Institute for Materials Research (AIMR). “And it did. Our method resulted in a higher optical density than original AU-NPs and GNDPs decorated with smaller AU-NPs.”

Yabu and his colleagues’ findings reinforce that GNDP particles have broad utility, extending beyond laboratory settings to real-world diagnostic scenarios.

Gold Nanoparticle-Decorated Polymer Particles for High-Optical-Density Immunoassay Probes . Langmuir, 30 January 2024.

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