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Investigation of nanoparticles is a priority direction of modern science. The application of nanoparticles is widely incorporated into many spheres of human activity. The ability of nanoparticles to penetrate deeply into tissues, cells, and nuclei can be used in medicine. The possibilities of molecular diagnosis and identification of biomarkers unique for every patient create preconditions for improving therapy by addressing the delivery of medicines. In recent years research in the field of formation and investigation of physicochemical properties of supramolecular aggregates based on functional metal nanoparticles has been actively pursued. Due to the wide availability of stabilizing ligands, it’s possible now to obtain various systems that differ in their properties and the final purposes of their use. In this chapter, the authors will present a brief review of classical and modern methods of the production of gold nanoparticles (GNPs) and their application in diagnostics and transport drug delivery as particles with strong antioxidant and antimicrobial properties.
Department of Chemistry, MV. Lomonosov Moscow State University, Moscow, Russia
Tatyana I. Shabatina*
Department of Chemistry, MV. Lomonosov Moscow State University, Moscow, Russia
Faculty of Fundamental Sciences, NE. Bauman Moscow Technical University, Moscow, Russia
*Address all correspondence to: tatyanashabatina@yandex.ru
1. Introduction
It is a well-known fact that interest in metallic gold appeared in the period of alchemy development. At the beginning of the twentieth century, scientists began to actively study methods of colloidal gold synthesis, their aggregation, stabilization as well as to study their optical properties. One of the first practical applications of colloidal gold in medicine was its use as a coagulating agent in pathologies of cerebrospinal fluid. As part of biological research, it was discovered that colloidal gold could be used as a conjugate with immunoglobulins and thus used as an immunochemical marker [1, 2, 3, 4, 5, 6].
Such research has broadened the interest of scientists in the study of these metallic particles. The rapid growth in the development of industries, such as nanotechnology, biotechnology, biomedicine, and theranostics has further provoked the interest of researchers in the study of GNPs whose physical and chemical properties can be controlled. They began to actively investigate, improve, and propose new methods of synthesis of GNPs, study the factors influencing the shape and size of nanoparticles, and study the influence of stabilizing ligands with different natures on the physicochemical properties of nanoparticles [7, 8, 9, 10].
It is worth noting that research aimed at studying the properties of GNPs is increasing. This is facilitated by the development of interest in “green chemistry” approaches––soft and innovative methods that allow the synthesis of different nanoparticles without the intervention of aggressive substances and solvents as well as interest in the creation of new drug nanoforms including for their potential use for targeted drug transport delivery.
Now numerous works are already known and presented in the literature that investigate and prove the antibacterial, and antioxidant properties of GNPs, as well as their application in therapy for the treatment of breast and gastric cancer. Thus, GNPs have taken a leading position in many biomedical studies. In this chapter, the authors will present the most interesting works and results of modern biomedical research on the application of GNPs and their production methods [7, 8, 9, 10, 11, 12].
The development of modern nanotechnology is impossible without the creation of new-generation materials with predetermined physical and chemical properties. With respect to metallic nanoparticles, the most important characteristics are their shape and size and, therefore, their optical properties. Therefore, one of the challenges facing scientists worldwide is the ability to control these parameters during the synthesis of metallic nanoparticles. These characteristics are influenced primarily by the molar ratios of the using reagents, the temperature, pH, and the nature of the reducing agent and stabilizer. Below we will consider the main methods of obtaining GNPs, their advantages, and disadvantages [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31].
The methods of producing nanoparticles can be divided into physical and chemical methods. In physical methods, nanoparticles are produced by grinding large metal particles using colloidal mills or ultrasonic dispersion. In chemical methods, nanoparticles are produced by chemical reduction of metal ions in solution. The most used reducing agents are sodium borohydride (NaBH4), hydrazine (N2H4), sodium citrate (Na3C6H5O7), glucose (C6H12O6), and ascorbic acid (C6H8O6) [7].
The synthetic possibilities are limitless. Therefore, in recent years scientists have been proposing new methods for the synthesis of GNPs or improving the known ones. Like other metallic nanoparticles, GNPs are highly aggregative unstable which creates the need for their stabilization. A convenient approach is to use the same substance both as a reducing agent and as a stabilizing ligand. Depending on the nature of stabilizing ligands, it is possible to obtain new and new functional nanomaterials, the relevance and importance of which in biomedicine is undeniable.
Taking into account, the trends of modern science the search and development of new methods of “green synthesis” of GNPs is an actual direction too. This approach eliminates the problems of chemical synthesis––working with organic solvents with pronounced toxicity and insufficient purity of the obtained samples. Figure 1 shows all possible synthetic abilities for obtaining GNPs. Further, we will dwell on each of them [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37].
Figure 1.
Synthetic methods for preparation of GNPs.
2.1 The Turkevich’s method
Tukevich’s method is one of the basic and classical methods for the chemical equation synthesis of GNPs. The method is based on the production of GNPs from gold hydrogen chloride acid (HAuCl4) under the action of sodium citrate (Na3C6H5O7) in aqueous solution. The scheme of synthesis is presented in Figure 2.
Figure 2.
Scheme of GNPs synthesis by Turkevich’s method.
In the literature [7, 8, 9], there is a huge amount of data devoted to the optimization and improvement of this method. Different factors have a strong influence on the shape and size of the formed GNPs. The main ones are as follows:
The order of reagent’s mixing.
Temperature.
The molar ratio of reagent’s concentrations.
pH-value.
For example, if HAuCl4 and Na3C6H5O7 are mixed simultaneously, a solution of coarse dispersed and poorly stable particles is obtained. In more recent studies, it was shown that changing the order of mixing reagents (first the reducing agent, then HAuCl4) leads to the formation of stable GNPs with small size––from 8 to 10 nm. In the classical synthesis technique, HAuCl4 is initially introduced into a solution of distilled water, then heated and the reducing agent is introduced into the saturated solution [7].
In the series of experiments, it was found that carrying out the synthesis at a higher temperature (100°C) leads to greater aggregation of GNPs compared to a lower temperature (70°C). The average size of GNPs decreased from 20 to 16.5 nm. In other studies, the effect of the amount of sodium citrate on the average size of GNPs was evaluated. A trend was found that decreasing the volume of 1% Na3C6H5O7 solution from 1.0 to 0.2 ml resulted in an increase in the average size of GNPs from 16 to 150 nm. Later, it was found that a strong influence on the shape of GNPs as well as their size is exerted by the pH of the medium which is controlled by the concentration ratio of HAuCl4-Na3C6H5O7. At pH < 5.0, the particles have an elliptical shape and a wide variation in average size (from 40 nm). At the shift to the region of neutral medium (pH > 6.0), the shape of GNPs changes to spherical, the size distribution has a narrower character, and the average size is in the range of 6–15 nm [7].
Summarizing, it is worth noting that the possibilities of Turkevich’s method are not limited. By changing the synthesis conditions, it is possible to control the shape and size of GNPs. In addition, this method allows to obtain moderately dispersed GNPs of spherical shape and small size (on average from 10 to 20 nm). That is why this method is still one of the most relevant and simple. Producing nanoparticles of small size down to nanosizes makes possible their further application in the field of transport drug delivery where the size effect is one of the most important.
2.2 The Brust-Shiffrin method
Brust-Schiffrin’s method is another method for the two-phase chemical reduction and production of GNPs. Its disadvantage compared to Turkevich’s method is the operation in non-aqueous media (organic solvents) as well as the use of an interfacial carrier which may eventually lead to contamination of the sample. However, this method involves not only the reduction of HAuCl4,forming GNPs, but also the simultaneous introduction of stabilizing ligands, which significantly reduces the aggregative instability of the nanoparticles due to the functionalization of their growing surface. As a rule, sodium borohydride (NaBH4) is used as a reducing agent, and tetra-n-octylammonium bromide (TOAB) as an interfacial carrier [14].
The choice of stabilizing ligand depends on further applications of functional GNPs. Most often S-containing ligands are used since gold shows a high affinity toward sulfur atoms which affects the binding strength of surface gold atoms to the ligand. The AuCl4− anion transferred from aqueous solution to toluene using TOAB then reduced by NaBH4 in the presence of a stabilizing ligand. The mechanism of interaction of surface Au-atoms with S-containing ligands is still discussed and has no unified validity. It is assumed that during such interaction the S‒H bond in the ligand molecule is broken and thus the alkyl-thiolate anion is bound to the active centers at the surface of metal NPs. The reaction can be schematically represented as an oxidative addition of thiol to the gold surface with reductive elimination of hydrogen:
R−SH+(Au0)n==>R/S−Au+(Au0)n−1+0.5H2E1
It was found that the Au-thiolate bond is quite strong and its energy is 40 kcal/mol. Studies show that such functional GNPs are highly stable, stabilization by the ligand leads to the formation of self-ordered monolayers, and the size distribution is narrow. Depending on the nature of the ligand both ultrasmall particles (1–3 nm) and larger particles (15–40 nm) can be obtained. The scheme of synthesis of GNPs by the Brust-Shiffrin method is presented in Figure 3.
Figure 3.
Scheme of synthesis of GNPs by the Brust-Shiffrin’s method.
2.3 Producing of GNPs using synthetic polymers
The main advantage of Turkevich’s and Brust-Schiffrin’s methods is the broad synthetic possibilities which are primarily related to the nature and structure of the stabilizing ligands. This opens up possibilities for further applications of such functionalized materials in many branches of science and nanotechnology [9, 10, 11, 12, 13, 14].
The synthesis of GNPs using synthetic polymers has not been conducted very often. The main reason is that in most cases the polymer is both a reducing agent and a stabilizer of surface gold atoms. This limits the potential applications of GNPs in biomedicine. The structural formulas of the main synthetic polymers for the recovery and stabilization of GNPs are in Figure 4.
Figure 4.
The structural formulas of the main synthetic polymers for the recovery and stabilization of gold nanoparticles.
One of the most common polymers is polyethylene glycol (PEG). In the studies, PEG has been shown to act both as a reducing agent and as a stabilizer. In this way, functionalized GNPs of spherical shape with an average size in the range of 15–20 nm are prepared. At the beginning of the developments, PEG was used for drug transport delivery. Even then the surface of liposomes acting as a “nanocontainer” was functionalized with PEG. Since then, scientists have evaluated its effect on the human body. The verdict is simple––it is toxic, and therefore, its use is currently limited [7].
Another available and used synthetic polymer is poly(ethylenimine) (PEI). The activity of this polymer as a reducing agent is higher as compared to others. However, in addition to its strong reducing activity, PEI is also a powerful stabilizer of GNPs. The PEI samples showed results in the formation of ultrafine particles down to 1 nm. However, if the concentration of HAuCl4 is increased with respect to PEI, an increase in the average size of GNPs up to 20 nm is observed.
Polyvinylpyrrolidone (PVP) is another synthetic polymer, which is used both as reducing agent and stabilizer simultaneously. A rapid method for the preparation of functional GNPs at room temperature with an average size of 11 nm has developed. The advantages of GNPs coated with synthetic polymers include their high stability and homogeneity. However, practical applications of such materials were limited.
2.4 Synthesis of gold nanoparticles using biopolymers
As with synthetic polymers, GNPs can be produced by using biopolymers [15, 16, 17, 18, 19, 20]. Often, they also possess two functions: a reducing agent and a stabilizer. Dextrin, chitosan, and their modified analogues, bovine serum albumin (BSA), pectin, immunoglobulins, enzymes, and amino acids are used as biopolymers for the synthesis of GNPs. However, in contrast to synthesis with synthetic polymers in this case a direct relationship of the obtained functionalized GNPs with the field of biomedicine is obvious. Basically, the surface of such materials is used as a carrier of drugs for transport delivery in the therapy and treatment of a wide range of diseases––from skin diseases to cancerous tumors.
It is known that gold complexes with chitosan and its analogues have proven antibacterial activity. Chitosan is a natural biopolymer with anticancer properties. For example, a material based on chitosan hydrogel-loaded GNPs and paclitaxel (chemotherapeutic agent) was obtained in this work. The size distribution of the GNPs was determined using a field emission scanning electron microscope. The average size lies in the range of 45–60 nm. X-ray diffraction was used to analyze the GNPs. The crystalline nature of the nanoparticles was evident with five peaks corresponding to the standard Bragg reflections. Results demonstrated that chitosan hydrogel-coated GNPs loaded by paclitaxel have a significant cytotoxic effect against colon cancer cells, even more so than paclitaxel alone. More recent studies show that “chitosan-GNPs-drug” complexes are used as nanocontainers for transdermal delivery. Chitosan-GNP complexes with insulin have also been described in the literature. They have found application in the transmucosal delivery of insulin in the treatment of diabetes.
GNPs obtained by synthesis with various functionalized dextrin derivatives are used as carriers for drug delivery of anticancer antibiotics to cancer cells. Dextrin samples have a large surface area and are often used as adsorbents. Adsorption is usually due to the “guest-host” effect. Such GNPs are stable with an average size range of 15-nm. Temperature, “HAuCl4-dextrin” molar ratio, and pH also influence the size of nanoparticles.
The recent work [7] describes the preparation of GNPs, in which glucose was used as a reducing agent and starch as a stabilizer. Clinical trials on rats have shown that such GNPs are nontoxic to living cell lines which makes their use for transport drug delivery possible. Also described in the literature are works on the use of gelatin and collagen as reducing agents and stabilizers of GNPs. Such particles exhibit low cytotoxicity, good biocompatibility, and effective penetration into the cell.
Thus, GNPs obtained by reduction and simultaneous stabilization with various biomolecules have specific biomedical applications. We will discuss the various complexes based on GNPs with drugs in more detail in Section 3.
2.5 “Green synthesis” for production of gold nanoparticles
The development of “green nanotechnology” has generated the interest of researchers in environment-friendly biosynthesis of nanoparticles and minimizes the use of various toxic surfactants, polymers, dendrimers, ionic liquids, and other organic compounds. Green synthesis is based on three main aspects.
Selection of an environment-friendly medium.
Environment-friendly reducing agent.
Nontoxic material for stabilization of nanoparticles.
Biosynthesized GNPs are applicable in industries including biomedicine due to their proven antimicrobial and antioxidant properties. Generally, GNPs-based materials are biocompatible and biodegradable [21, 22, 23, 24, 25].
To obtain GNPs using “green chemistry” methods various natural sources are used: microorganisms, plants, flowers, and fruit/vegetable extracts (Figure 5).
Figure 5.
Scheme of producing GNPs by green chemistry methods.
The use of various plant extracts is explained by the presence of natural biomolecules (proteins, carbohydrates, fatty acids, and vitamins) in their composition. Numerous studies show that secondary metabolites found in the composition of such natural extracts act both as substances responsible for the reduction of metal ions and the formation of nanoparticles and for their stabilization. Table 1 summarizes the works related to the use of various natural extracts for the synthesis of GNPs, their main characteristics and current research directions.
“Green” extract to produce GNPs
GNPs characteristics
Application
Coleus scutellarioides (L.) leaf extract
The result of UV–visible spectroscopy of GNPs samples showed a peak at 532 nm indicating the occurrence of surface plasmon resonance. The crystal structure of GNPs confirmed by X-ray diffraction analysis. GNPs are spherical in shape with an average particle size of 40 nm.
Studies on anticancer activity and antioxidant properties [26].
Extract Descurainia sophia
GNPs are polymorphic and aggregated, the size spread of was 10–38 nm.
The diffraction peaks of the samples are: 2θ = 7.6° (110), 19.7° (060), 20.6° (131), 26.5° (080), and 34.7° (441) can be indexed by standard SC data. Characteristic peaks in the region of angles 2θ = 38.0° (111), 44.3° (200) and 64.5° (220) are consistent with face-centered cubic gold planes.
Cytostatic activity in the treatment of gastric cancer [29].
Calendula officinalis flower extract
GNPs are highly dispersed, hemispherical in shape with an average size in the range of 20–25 nm.
Investigation of the therapeutic effect of samples on diabetes-induced cardiac dysfunction in rats [30].
Aqueous extract of Andrographis paniculata A. paniculata
GNPs are spherical in shape and uniformly distributed with an average particle size of 10–15 nm.
The possibilities of using the material for the colorimetric detection of heavy metals Pb2+, catalytic removal of organic dyes analyzed. The bioactivity study also confirmed the potential of the extract and GNPs as effective antibacterial and antioxidant agents [31].
Aqueous extract of sweet granadilla Passiflora ligularis Juss
GNPs are spherical in shape, not aggregated, particle size distributed in the range of 8.4–13.0 nm.
The sample demonstrates strong neuroprotective effects in the therapy of autism [32].
Neem flower extract Azadirachta indica
The formation of GNPs was confirmed by a characteristic absorption peak at 530 nm. The metallic form of the photosynthesized GNPs was confirmed by X-ray photoelectron spectra with a characteristic difference in the binding energies of the 4f-shells ΔE = 3.8 eV. Transmission electron microscopy and X-ray diffraction studies confirmed the crystalline nature of the formed particles.
Studies of antioxidant and antimicrobial properties of GNPs against both gram-positive and gram-negative bacteria [33].
Aqueous extracts of the leaves of Ziziphus spina-christi and Cordia myxa L.
The diffraction peaks indexed in the (1 1 1), (2 0 0), (2 2 0 0), and (3 1 1) planes confirm that the GNPs are face-centered cubic lattices as evidenced by the peaks at 2θ = 38.21°, 44.40°, 64.67°, and 77.58°, respectively. SEM images showed relatively spherical shape of the nanoparticles with a diameter spread in the range of (31.26–58.06) nm and (56.49–89.38) nm, respectively.
The GNPs have a spherical shape, a size of about 13 nm, a plasmonic absorption peak at 530 nm, and a surface charge of −30.6 mV.
The biosynthesized GNPs have significant anticancer efficacy against human breast cancer cells (MDA-MB-231) with an IC50 of 41.72 μg/ml [35].
Nothapodytes foetida leaf extract
GNPs exhibited a characteristic UV-absorption peak at 524 nm. The results of comprehensive studies showed that GNPs are highly stable (− 60.7 mV) crystalline, mostly spherical, with sizes ranging from 5 to 30 nm.
The radical scavenging ability of GNPs and their antibacterial activity were evaluated. It was shown that GNPs also reduced the viability of MG63 and A549 cells, exhibiting significant anticancer activity along with notable wound healing properties [36].
Aqueous extract of the sea coral Sarcophyton crassocaule
GNPs exhibited a characteristic UV absorption peak at 540 nm. Electron microscopic studies showed spherical and oval shaped GNPs in the size range of 5–50 nm.
Bactericidal efficacy studies against clinically relevant bacterial pathogens. The studies of antioxidant effects against DPPH [37].
Table 1.
Natural extracts for the synthesis of gold nanoparticles.
Studies confirm the relevance of using “green chemistry” methods for GNPs production. However, conducting “green synthesis” is complicated by the composition of the natural extracts used. Moreover, extracts of many plants, flowers, and fruits/vegetables are quite specific, exotic, and are unavailable in most countries of the world [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37].
Theranostics is one of the new approaches to the development of pharmaceutical compositions, which consists in the integrated solution of therapeutic and diagnostic problems by creating drugs that are both an early diagnostic tool and a therapeutic agent [38, 39, 40, 41, 42, 43, 44, 45, 46, 47].
GNPs are actively used in this area as they have different advantages (Figure 6).
Figure 6.
Advantages of using GNPs in diagnostics and theranostics.
All these factors favor their use in various fields, such as in vitro diagnostics, targeted drug delivery, photothermal drug delivery, and photothermal therapy. The high surface area-to-volume ratio of GNPs significantly facilitates the creation of complex nanoplatforms based on them which can be used in several therapeutic and diagnostic applications. The unique electrical and optical properties of GNPs known as localized surface plasmon resonance, are particularly relevant for diagnostics of various diseases. In diagnostics, GNPs can be used as tags to detect various biomolecules such as DNA, RNA, antibodies, and antigens. They can also be used to amplify signals in various diagnostic techniques, such as fluorescence microscopy, resonance plasmon spectroscopy, and electrochemical analysis. In therapeutics, GNPs can be used as agents to deliver drugs, genes, and vaccines to target cells or tissues. They can also be used for thermal destruction of tumors using laser irradiation which causes heating of the nanoparticles and surrounding tissues. In addition, GNPs can be used for photodynamic therapy in which they activate photosensitizers that generate reactive oxygen species that can kill cancer cells [39]. Modern and relevant practical applications of functionalized GNPs in biomedicine will be presented below. Figure 7 presents a scheme reflecting the main directions of GNPs use in biomedicine.
Figure 7.
The main directions of GNPs use in biomedicine.
In this section, we review the works describing the use of GNPs for transport drug delivery. The first serious developments in this field back in 1980 when it became necessary to create new innovative drugs for the treatment of cancer. At that time, nanoparticles were used to actively develop methods for the delivery of the main anticancer antibiotics––doxorubicin and epirubicin [7]. Nanoparticles penetrate the tumor due to the so-called “enhanced permeability and retention” effect. This effect is caused by excessive vessel overgrowth––angiogenesis––caused by the tumor’s need for oxygen and nutrition. In pathological angiogenesis, pores up to 200 nm in diameter appear in the vessel walls. Tumor growth also causes compression of lymphatic vessels and prevents the normal outflow of intercellular fluid. Nanoparticles enter the tumor through the pores and cannott leave the tumor due to impaired drainage. The pathway into cancer cells is determined by the material of the nanoparticle [42].
The transported drug substance can simultaneously be either a ligand or anchored on the surface of the stabilizing layer of GNPs. A visualization of the surface of GNPs for drug transport is shown in Figure 8 shows a visualization of the surface of GNPs for drug transport.
Figure 8.
The surface of GNPs for drug transport.
Usually, drug substances stabilized prepared GNPs or nanocomposites. However, a more environment-friendly route is one in which the drug substance acts both as a reducing agent and as a stabilizer of GNPs. One of the first successful works in this direction is the use of dopamine hydrochloride as a reducing agent from HAuCl4 and a stabilizer of surface gold atoms. Such a complex was used as a strong neurotransmitter in Parkinson’s disease [48].
One of the first works on photodynamic therapy of GNPs described below [39]. The investigators produced GNPs-containing drug the Aurimune of 27 nm during the 1980s and demonstrated the high antitumor activity. They used them as carriers for tumor necrosis factor (TNF) protein. This disrupts cancer cell nutrition and increases tumor permeability to antibiotics. However, an excess of TNF caused different side effects, such as hypotension, hepatotoxicity, and physical malaise. The introduction of GNPs into the drug significantly reduced the above side effects. Developing this scientific approach scientists proposed to modify the surface of Auramine with paclitaxel. The obtained second-generation drug is undergoing preclinical testing. A significant advantage of GNPs is that they can convert optical radiation into heat due to the effect of surface plasmon resonance. As is known a feature of the absorption spectra of small-sized metal nanoparticles is the occurrence of an intense plasmonic absorption band. Based on this functional property, two therapies have been developed––photothermal and photodynamic. The first is based on heating the cells that have absorbed the nanoparticle under the action of radiation. The second therapy consists of the introduction of photosensitizer molecules chemically bound to the nanoparticle. When activated by light, they react with oxygen inside the cell to form reactive oxygen species that trigger apoptosis. Both activities of nanoparticles are stimulated by electromagnetic radiation so a promising approach is to combine these methods into a single therapy [7, 39].
Later [40], another innovative drug based on GNPs Aurolase represents combined nanoparticles of silicon and gold covered with a polymer shell of PEG. The drug has passed clinical trials for photothermal therapy of lung, head, and neck tumors. The drug is currently undergoing trials for therapy for prostate cancer. It has been proved that the therapeutic effect of GNPs is based on the effect of narrowing the blood vessels of the tumor and stopping the formation of new blood vessels in the affected organs or tissues. Currently, two drugs with intravenous administration have already been clinically evaluated.
Currently, the most promising and actively developing area of GNPs use in medicine is targeted drug delivery. The most popular objects for targeted delivery are antitumor agents and antibiotics. Many literature sources [48, 49, 50, 51, 52, 53, 54, 55, 56] describe the use of GNPs with such anticancer agents as paclitaxel, methotrexate, daunorubicin, gemcitabine, mercaptopurine, dodecylcysteine, sulfonamide, fluorouracil, cajalalid, tamoxifen, herceptin, doxorubicin, and propidine. Antibiotics and other antibacterial agents are also considered as objects delivered by GNPs: vancomycin, ciprofloxacin, fluorouracil, cefaclor. Table 2 shows examples of current work on the use of GNPs as drug carriers for transport delivery.
Table 2.
Use of GNPs as drug carriers for transport delivery.
In addition to the data presented in Table 2, complexes of ciprofloxacin––a drug and antimicrobial agent from the group of fluoroquinolones of ІІ generation––with gold nano shells were obtained in several works [63]. Such a complex exhibited high antibacterial activity against E. coli. The complex of 5-fluorouracil––an antitumor drug from the group of antimetabolites, antagonists of pyrimidines––with colloidal gold also possesses appreciable antibacterial and antifungal activity against Micrococcus luteus, Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Aspergillus fumigatus and A. niger.
As the analysis of literature data has shown, the main practical applications of GNPs are focused on their use as a carrier for transport delivery [48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]. In recent years, scientists working in this field have devoted their work to the study of the toxicity of GNPs [64, 65]. It has already been established that the organs of tissue macrophages are the main target for the accumulation of GNPs in the size of 10–100 nm. As the size decreases, the uniformity of biodistribution increases. Studies show that the accumulation of them occurs mainly in the liver and spleen. The accumulative effect lasts for 3–4 months. Accordingly, it’s necessary to more carefully study the issue of permissible dosage of the drug, thus preventing possible inflammatory processes [66].
One of the topical issues is the penetration of GNPs into the cell. The main assumption is that the penetration of nanoparticles through the blood-brain barrier critically depends on the size of the NSP. In this case, the upper limit of the average size should not exceed 20 nm [66]. As we discussed earlier, the size effect strongly depends on the nature of the stabilizing agent. Collection and analysis of literature data showed that the optimal ligands for GNPs are SH-containing ligands. For this reason, for creating carriers based on GNPs for transport delivery, it is necessary to cover their surface by ligands with this functional group [67, 68].
In a number of biological studies, it has been shown that GNPs 1–2 nm in size have potentially higher toxicity due to the possibility of irreversible binding to cell biopolymers [69, 70].
Summarizing the facts presented above, the importance of developing new methods for the synthesis of GNPs that will combine both environmental friendliness and proper ligand selection to produce nanoparticles of optimal size should be reiterated. Coordinated efforts are also needed to introduce particle standards and methods used to test the toxicity of nanomaterials.
The development of methods of chemical synthesis of GNPs leads to the possibility of obtaining nanoparticles of different shapes and sizes with different optical properties [34, 71]. “Green synthesis” methods which have advantages over classical chemical methods of GNPs production are becoming increasingly important. For successful use of GNPs in theranostics, it is important to develop effective technologies of their surface modification with various molecules which ensure their recovery and stabilization in vivo and their targeted interaction with biological targets. To date, the best stabilizers are considered to be SH-derivatives of polyethylene glycol and other molecules.
It is generally recognized that GNPs are excellent tags for the clinical diagnosis of cancer and other diseases. Plasmonic photothermal laser therapy of cancer with GNPs has entered the stage of clinical testing the success of which will depend on the development of reliable methods of targeted delivery of GNPs to tumors inside the body and improvement of methods for controlling the process of in situ photo-thermolysis [72, 73].
Summarizing the main results of the chapter, it is worth mentioning once again the broad practical significance of GNPs. A new and innovative approach based on the use of antibiotics and other drugs as reducing agents and stabilizers of GNPs makes it possible to obtain functional materials with enhanced antimicrobial activity, improved biocompatibility, and low toxicity [74]. In this chapter, the authors have reflected the great potential of the simplest GNPs known since ancient times but which have gained new, relevant scientific and practical applications in biomedicine with a promising future. We believe that the creation of new theranostic platforms for targeted drug delivery based on GNPs (especially the use of “green methods” for their preparation) is the most promising direction of nanobiomedicine.
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Written By
Yana A. Gromova and Tatyana I. Shabatina
Submitted: 23 February 2024Reviewed: 03 June 2024Published: 23 July 2024
Open access peer-reviewed chapter - ONLINE FIRST
