Gold Nanoparticles in Cancer Treatment - Molecular Pharmaceutics

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Gold nanoparticles in cancer treatment Krzysztof Sztandera, Michał Gorzkiewicz, and Barbara Klajnert-Maculewicz Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 19, 2018

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Molecular Pharmaceutics

Gold nanoparticles in cancer treatment Krzysztof Sztandera1a, Michał Gorzkiewicz1a, Barbara Klajnert-Maculewicz1,2 1

Department of General Biophysics, Faculty of Biology and Environmental Protection, University of

Lodz, 141/143 Pomorska St., 90-236 Lodz, Poland 2 Leibniz a Both

Institute of Polymer Research Dresden, 6 Hohe St., 01069 Dresden, Germany

authors contributed equally to this work

Abstract Colloidal gold has been studied for its potential application in medicine for centuries. However, synthesis and evaluation of various gold nanoparticles have only recently met with a wide interest of scientists. Current studies confirm numerous advantages of nanogold over different nanomaterials, primarily due to highly optimized protocols for production of gold nanoparticles of countless sizes and shapes, featured with unique properties. The possibility to modify the surface of nanogold particles with different targeting and functional compounds significantly broadens the range of their potential biomedical applications, with particular emphasis on cancer treatment. Functionalized gold nanoparticles exhibit good biocompatibility and controllable biodistribution patterns, which make them particularly fine candidates for the basis of innovative therapies. Considering the high amount of scientific data on nanogold, this review summarizes recent advances in the field of medical application of gold nanoparticles for the therapy of cancer. Graphical abstract

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Keywords Gold nanoparticles, nanogold, nanotechnology, nanomedicine, cancer therapy, cancer treatment 1. Introduction Cancer is a general name for a set of genetic diseases characterized by unrestricted, random cell division and invasiveness. The development of cancer is most often caused by mutations or alterations in the expression patterns of proto-oncogenes, tumor suppressor genes, and those involved in DNA repair. The disruption of pro-apoptotic signaling and overexpression of numerous proteins facilitating cell growth and supplementation hamper the development of efficient anticancer treatment 1. The majority of cancers results from the impact of environmental factors, such as exposure to radiation and pollutants, but most importantly – from unhealthy lifestyle, including lack of physical activity, poorly balanced diet, tobacco smoking and stress. Only 5–10% cancer cases are associated with inherited genetics

2,3.

The risk of cancer increases significantly with age, and many types of this disease occur

more frequently in the developed countries. Cancer is considered one of the main causes of death worldwide. According to National Cancer Institute (NCI) there were 14 million new cancer cases and 8.2 million cancer-related deaths in 2012. The number of new cases is predicted to increase to 24 million within the next two decades, and about 40% of people may be diagnosed with cancer during their life time 1. Taking all these aspects into account, there is a high demand for the development of novel strategies for efficient diagnostics and treatment of cancer. During the past few years an exceptional growth in research and application in the area of nanotechnology and nanoscience brought hope for the circumvention of disadvantages of classical cancer therapies. In general, nanotechnology may be described as engineering of functional systems at the molecular scale. In the context of medicine and biology, nanotechnology includes materials and devices with the structure and function relevant for small sizes, from nanometers (10−9 m) to micrometers (10−6 m). At this level, the properties of objects are determined just above the scale of a single atom. Thus, nano size is associated with specific phenomena in both artificial systems and living organisms. The size of nanomaterials is similar to that of most fundamental biological macromolecules and cells. For instance, the length of typical carbon-carbon bond ranges from 0.12 to 0.15 nm; DNA double-helix has the diameter of approximately 2 nm; the smallest cellular life form, Mycoplasma bacterium, is around 200 nm in length 4. Therefore, nanomaterials with specific properties can be useful for both in vivo and in vitro biomedical research and applications, actively interacting with cellular components or mimicking various chemical and biological compounds. The combination of nanotechnology and biology may contribute to the development of diagnostic devices, contrast agents, drug delivery systems or drugs per se. Even though the first attempt to apply nanotechnology in medicine was made in 1960s at ETH 2 ACS Paragon Plus Environment

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Zurich 5, the discoveries from the very last decades open new perspective in application of nanotechnology in medicine. Currently scientists can design nanoscale particles (1–100 nm) with defined features 5,6, influencing many fields of science, including chemistry and biotechnology. Due to the highly optimized methods of synthesis, nanoparticles may be featured with monodispersity, diminished cytotoxicity, controllable distribution patterns and specific mechanisms of interaction with desired ligands. This makes them potentially finest tools for modern medicine. Considering anticancer applications, it is important to note that nanoparticles have been found to accumulate in tumor tissues through passive mechanism, known as Enhanced Permeability and Retention Effect (EPR), without the addition of targeting ligands 7. This is due to the defective tumor vasculature with irregular epithelium, decreased level of lymphatic drainage and reduced uptake of the interstitial fluid, favoring passive retention of nanoparticles in tumors 8. Nowadays there is an increasing interest in nanoparticles of noble metals 9. The attention of scientists is focused on gold nanoparticles (AuNPs), that versatile properties and possible applications in clinical chemistry, bioimaging and therapy of cancer as well as targeted drug delivery are constantly being characterized. Gold (Au, atomic number 79) was one of the first metals discovered several thousand years ago. In its purest form, it is a bright, yellow, dense, soft and ductile metal, solid under standard conditions. Gold is one of the least reactive chemical elements. From the very beginning, the great value of gold was appreciated due to its infrequent occurrence, facile handling and fabrication, resistance to corrosion and other chemical reactions, and of course its unique color. Gold quickly became the symbol of power and wealth and has been used for coinage and jewellery production. The “gold standard” was for a long time applied as a monetary policy, being abandoned around 1976, shortly after withdrawing gold coins from circulation in 1930s 10. Medicinal application of gold and its complexes also has a long history. The first data on colloidal gold (colloidal suspension of nanoparticles of gold in a fluid) can be found in ancient Chinese, Arabian and Indian papers from V–IV centuries BC, which recommended it for the treatment of various diseases, although the mechanism of action was poorly understood. In medieval Europe, colloidal gold was frequently studied in alchemist laboratories and used for the treatment of mental diseases, syphilis, diarrhea, and even recommended as the elixir of longevity 10. The first scientific article on gold nanoparticles was presented in 1857 by Faraday, which attributed the red color to the colloidal nature of AuNPs and described their light scattering features 11. Fifty years later the visible absorption properties of AuNPs were explained using Maxwell’s electromagnetic equations 11. In 1971 British researchers Faulk and Taylor elaborated a revolutionary method of antibody-colloidal gold conjugation for the direct electron microscopy visualization ofsurface antigens of Salmonellae 12. This discovery initiated several studies over the next 40 years, devoted to biomedical applications of gold nanoparticles, specifically recognizing various 3 ACS Paragon Plus Environment


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biomacromolecules due to the surface functionalization and the characteristic properties. The latter are usually associated with controlled methods of synthesis, allowing to acquire AuNPs with defined shapes and sizes 5,13–15 (Figure 1).

Figure 1. Formation procedure for different shapes of AuNPs. Reprinted from 16 with permission from Elsevier. 1.1.Methods of AuNPs synthesis In general, the techniques of synthesis of AuNPs follow the same rules as for other particles. There are two options for the classification of synthesis methods. The first one is based on the way of synthesis (top-down or bottom-up)

17,

the second involves the methodological approach (chemical,

physical, and biological methods). One of the first and most common chemical methods, developed by Turkevich et al., implies the reduction of chloroauric acid (HAuCl4) by trisodium citrate (playing additional role of the ligand for newly synthesized AuNPs) in 100 oC. This reaction enabled the acquisition of aqueous solutions of modestly monodisperse spherical nanoparticles with the size ranging from 15 to 150 nm, depending on the initial concentration of sodium citrate 18. This method was the basis for the development of further ones, allowing for highly-controlled synthesis of AuNPs in water or organic liquids, utilizing different pH and temperature values, but also a range of reducing agents, like sodium borohydride NaBH4 19–21, aspartate

22

or hydroquinone

23.

The size of AuNPs may be further stabilized using various

capping/stabilizing agents, which are also applied to protect synthesized nanoparticles from aggregation and to control their properties in a precise manner. However, some of them (like cetrimonium bromide in case of synthesis of gold nanorods, see below) may be responsible for nanoparticle-independent toxic effects. While Turkevich-based methods generate mostly spherical AuNPs, gold nanoparticles can be obtained in variety of different shapes, such as rods 24, cages 25, tubes 26, etc. The most suitable method to synthesize different structures of AuNPs is based on seed-mediated growth

27,

involving the 4

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reduction of gold salts with strong reducing agent leading to the production of seed particles, which are subsequently added to the solution of metal salt in the presence of weak reducing agent and structure directing agent. Geometry of gold nanostructures can be altered by varying the concentration of seeds, reducing agents and structure directing agents. Further, physical methods utilizing microwaves 28, ultrasonic waves 29, laser ablation 30, as well as electrochemical and photochemical reduction

31,32

have also been explored for preparing AuNPs.

However, since various chemical and physical techniques adapted for the synthesis of nanoparticles may be quite expensive and harmful to the environment, „green synthesis” methods have become a major focus of researchers in order to elaborate environment-friendly and non-toxic way of AuNPs production

33.

Several substrates and reducing compounds have been successfully applied for safe

synthesis of gold nanoparticles, including chitosan 34, egg shell membrane 35, citrus fruits juice extracts 36,

and edible mushroom 37. Recently, Bacillus licheniformis has been used for the synthesis of 10–100

nm gold nanocubes in much milder conditions in comparison to classical chemical methods

38,

indicating the possibility of application of other bacterial strains for this process. 1.2.General properties of gold nanoparticles Due to the highly optimized methods of synthesis enabling the control of size, shape and dimension of AuNPs, they can be specifically designed to possess particular properties. Size and shape of gold nanoparticles have profound impact on their features, influencing stability, mobility, compatibility etc.

39–45

and should be optimized with regards to the certain biomedical applications.

For instance, nanoparticles designed for drug delivery should be small enough to cross physiological barriers or enter the target cells, and large enough to carry an appropriate amount of therapeutic compounds to the site of action 46,47. It is important to note that physical and chemical characteristics (like fluorescence, electrical conductivity or chemical reactivity) of materials in nano size are usually significantly different than in case of their analogues in bigger forms. For gold, the best example of this hallmark is yellowish color of bulk form and red color (for particles smaller than 100 nm) or blue/purple (for larger particles) of AuNPs, additionally dependent on their shape and properties (Figure 2). Further, colloidal gold, in comparison to bulk gold, is considered to be highly reactive, which greatly broadens its application potential providing optoelectronic, catalytic and antioxidant properties, as well as the possibility of introduction of surface modifications.



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Figure 2. Tunable optical properties of gold nanoshells by changing the shell thickness (A) and gold nanocages by changing the auric acid in the synthetic procedure (B). Top row: TEM; middle row: absorption spectra; bottom row: physical appearance. Reprinted from 48 with permission from Elsevier. An important physical feature of AuNPs involves surface plasmon resonance (SPR). This specific phenomenon occurrs when the frequency of oscillation of free electrons at the surface of nanoparticle resonates with the frequency of incoming light radiation, resulting in a plasmon band. As a result, an electromagnetic field appears at the AuNP surface, enabling surface-enhanced optical properties. The extinction coefficients of the SPR bands are extremely high, up to 1011 M–1 cm–1, which is several orders of magnitude greater than those of common organic dyes. AuNPs provide both absorption and scattering effects which proportions are dependent on the size and shape, but also on the type of solvent, surface ligand, core charge, temperature and the proximity of other nanoparticles 49,50,

influencing the electron charge density on the particle surface. In case of spherical AuNPs with

sizes smaller than 60 nm, the SPR peak absorbance appears around 500–550 nm, contributing to their red color 51. For anisotropic nanoparticles like nanorods (AuNRs), two plasmon bands are observed due to the electron oscillation along the length (longitudinal plasmon band) and the other along the width of the AuNR (transverse plasmon band). The transverse band occurs at ~520 nm, whereas the longitudinal band appears at a longer wavelength depending on the length/width ratio 52. Thus, AuNRs exhibit plasmon bands with maxima ranging from 500 to 1600 nm

53.

Additional interesting effect

dependent on the form of gold nanoparticles and associated with surface plasmon bands involves 6 ACS Paragon Plus Environment

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modulation of fluorescence properties of proximal fluorophores. This is due to the fluorescence resonance energy transfer (FRET) phenomenon, photoinduced electron transfer (PET) process

54–58

and photothermal properties, resulting from light absorption and subsequent non-radiative energy dissipation

59,60.

Thus, altering the shape of gold nanoparticles provides interesting optical properties

that span the broad visible to near-infrared (NIR) spectrum, making them fine tools for bioimaging and theranostic applications

61,

and enabling monitoring of morphological properties of AuNPs during

synthesis. The importance of gold nanoparticles of various shapes and sizes in biological sciences continues to rise because of their compatibility, reactivity and susceptibility to modification, as well as tunable optical features. What is more, AuNPs proved to be both excellent therapeutic agents and drug carriers. In this review, we summarize available data on the possibility of use of AuNPs in the treatment of cancer and highlight the recent achievements in this field. All information included here concerns gold nanoparticles per se, without discussing the topic of their complexes with different nanostructures. 2. Biodistribution, toxicity and functionalization of gold nanoparticles Considering the potential application of gold nanoparticles in anticancer therapy and diagnostics, it is crucial to analyze and understand their biodistribution patterns and overall toxicity, since these two parameters may greatly influence the legitimacy of use of AuNPs. While there are some concerns regarding the inflammatory response or potential accumulation of metal in the organism, they have not been thoroughly tested in long-term in vivo studies. It is only recently that the significance of such experiments has been recognized, and researchers have started to investigate these issues more carefully. Moreover, due to the differences in doses, animal and cellular models, protocols for particles preparation and experiments, as well as possible aggregation of AuNPs in physiological conditions, the data remain inconsistent 62,63. 2.1.Size-dependent properties of spherical AuNPs As mentioned before, many features of gold nanoparticles are associated with their size and shape. This also applies to their biodistribution. The first studies on the biodistribution of colloidal gold in the 1970s and 1980s indicated that after being introduced parenterally, gold nanoparticles are rapidly taken up by liver, secreted through bile, and eliminated with feces 64–66. Later this phenomenon was explained by the significant role of Kupffer cells in the elimination of AuNPs 67. In general, upon single administration (either oral or intravenous), spherical AuNPs localize in liver, kidneys, spleen and lung, and this phenomenon is size- (Figure 3) and shape-dependent (Figure 4), with significantly higher concentrations of smaller particles being found in various organs 68,69.



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Figure 3. Twenty-four hours retention/accumulation of intravenously injected, negatively charged, spherical GNP (1.4 nm, 5 nm, 18 nm, 80 nm, 200 mm coated with TPPMS; 2.8 nm carboxyl-coated); GNP percentages of initial dose are given for whole organs, the entire remaining carcass, total blood and urine; in each panel the respective organ, tissue or body fluid is indicated. Data are mean ± SD, n = 4 rats. Note log scale of x-axis. Reprinted from 70 with permission from Elsevier.


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Figure 4. Biodistribution of gold nanoparticles in non-metastatic orthotropic ovarian tumor-bearing mice. (A) nanorods and (B) nanospheres. n = 3 ± SEM. Reprinted from 69 with permission from Elsevier. It was also noted that the smaller particles permeated into the deep layers of skin whereas the 100 nm and 200 nm particles remained on the surface 71, that further indicates higher bioavailability of AuNPs of small diameters. The particle size also influenced blood concentration and circulation time. For instance, the peak blood concentration of 5-nm AuNPs was 0.53 mg/L ± 0.18 mg/L 10 minutes after injection, and 25-nm AuNPs peaked after 30 minutes at a concentration of 0.11 mg/L ± 0.05 mg/L. Both decreased with time over the next 24 hours 72. Interestingly, since some amount of AuNPs with the upper size limit around 15–20 nm was also found in the brain, it has been concluded that they possess the unique ability to pass blood-brain barrier (BBB) 68,73. The mechanism of crossing BBB by spherical gold nanoparticles was later examined by several research groups, turning out to be dependent on the diameter of AuNPs and involving adsorption-mediated endocytosis, passive diffusion, direct passage by ion channels or tight junction disruption 74. Further, Semmler-Behnke et. al tested if AuNPs can cross the placental barrier, injecting WistarKyoto rats with radiolabeled AuNPs of various sizes (1.4, 18 and 80 nm) and in different doses (5, 3 and 27 μg). 1.4- and 18-nm AuNPs were detected in fetuses, and authors hypothesized that they were able to go through placenta via transcellular processes or transtrophoblastic channels

75.

Also,

materno-fetal transfer of spherical gold nanoparticles was examined in pathological conditions using



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mice with intrauterine inflammation, injected with 3-, 13- or 32-nm AuNPs. The accumulation of 3and 13-nm particles was much higher than in fetuses of healthy mice 76. The size of spherical AuNPs additionally influences their cellular uptake and toxicity. Remarkably, it has been shown that among gold nanoparticles with diameters in a range of 10–100 nm, the maximum uptake occurs for the 50-nm spheres

77–79,

which may be attributed to the fact that

their size is within the range of viruses and lipid-carrying proteins, efficiently endocytosed by the cell 80.

As for the toxicity of spherical gold nanoparticles, assessed mainly by MTT 44, WST-1 81 or LDH 82

assays, but also trypan blue staining 83, impedance spectroscopy and flow cytometry 63,84, the available in vitro data remain inconsistent, indicating either negligible toxicity cytotoxic activity

87–89.

77,84–86

or cell type-dependent

However, the mechanisms of the latter are still poorly understood, although

some data suggest the triggering of oxidative stress 90, irreversible binding to key cellular compounds like DNA 91, cell cycle arrest

89

or caspase-independent apoptosis 92. It is crucial to note that AuNPs

may influence cellular responses without affecting their viability, for example inhibiting proliferation, altering calcium

93

and nitrogen oxide release

94,

stimulating respiratory activity or the activity of

mitochondrial enzymes 95. Interestingly, upon prolonged incubations, in vitro cultured cells were able to transfer endocytosed AuNPs to their daughter cells during division, decreasing the number of accumulated particles in each cell over time. This ultimately led to the reversal of detrimental effects of AuNPs, including changes in the doubling time 96. In vivo tests bring similarly incoherent results. While nanoparticles of sizes 3, 5, 50 and 100 nm did not induce any apparent cytotoxic effects, AuNPs ranging from 8 to 37 nm caused changes in appetite and fur color, bruising, bleeding under the skin and the development of a crooked spine leading to eventual death. Physiological changes were detected in lung, liver and spleen tissue samples taken from mice treated with 8–37-nm AuNPs that were not observed in mice dosed with smaller or larger nanoparticles 97. On the other hand, after repeated administration, the accumulation of 12.5-nm AuNPs in different mice organs did not result in any mortality or toxicity, judging from animal behavior, tissue morphology, serum biochemistry, hematological analysis and histopathological examination. Also, the accumulation rate in organs but not the concentration in the blood was found to be dependent on the administered dose 62. 2.2.Correlation between shape, toxicity and biodistribution of gold nanoparticles Apart from spherical AuNPs, there are numerous reports on biodistribution and toxicity of gold nanoparticles of different shapes, primarily nanorods and nanoshells. The first form has drawn particular attention due to the tunable properties and biodistribution patterns based on the aspect ratios. However, gold nanorods are usually synthesized using cetrimonium bromide (CTAB), cationic surfactant stabilizing nanoparticle and influencing its shape. This compound has been shown to be toxic to in vitro cultured cells above 1 μM concentration 98. Moreover, a decrease in the toxic activity 10 ACS Paragon Plus Environment

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of CTAB-stabilized AuNRs after intensive washing from CTAB molecules has been observed

44,98,99,

indicating that the toxicity of such systems is determined by free CTAB, whereas the nanorods themselves are non-toxic. However, it is difficult to assess the cytotoxicity of AuNRs, due to their low stability and aggregation associated with CTAB release. For this reason, some groups choose to modify gold nanorods, originally synthesized using CTAB, by chemical exchange or surface functionalization to give the particles a new, less toxic coating (see below). Several studies on biodistribution of CTAB-stabilized AuNRs indicate that most of those nanoparticles accumulate in the liver Kupffer cells, and their concentration remains almost unchanged in time. Accumulation in other organs is moderate, with slow kinetics of elimination. Moreover, AuNRs may be found in the brain, indicating the possibility of overcoming the BBB by nanoparticles with a critical size of 20 nm, similarly to spherical AuNPs 100,101. As for the cellular uptake of AuNRs, it was found that nanorods of lower aspect ratios are taken up more efficiently than those with higher aspect ratios

77,

which is not unexpected since spherical

AuNPs (with the lowest possible aspect ratio equal to 1:1) are generally uptaken by cells in much higher amounts (Figure 5).

Figure 5. Uptake of gold nanoparticles by RAW 264.7 macrophages expressed as the amount of gold detected by ICP-MS normalized to mg of protein. n = 3 ± SD. * Significant difference between uptake of rod and spherical particles, p < 0.01.Reprinted from 69 with permission from Elsevier. There is relatively little and inconsistent information on the toxic activity of unmodified nanoshells (AuNSs). The absence of cytotoxicity of these nanoparticles towards human prostate humor cells

102

and hepatocellular carcinoma cells

103

has been reported. On the other hand, a dose-

dependent toxicity of Au-Cu nanoshells at low concentrations was observed during the experiments on African green monkey kidney (Vero) cells

81.

To our knowledge, currently there is no data on the

biodistribution of naked AuNSs.



Among other forms and shapes of nanogold particles, nanoprisms

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104,105

and nanocubes

106,107

have been studied for their potential biomedical use, but only to the limited extent. 2.3.Surface functionalization of gold nanoparticles The vast majority of scientific reports on the toxicity and biodistribution of nanogold relate to functionalized particles. Functionalization of AuNPs is one of the key aspects, along with their size and shape, which determines the fate of particles upon administration. Surface modifications have a pronounced effect on these two parameters, providing protection against aggregation, enhanced biocompatibility, specific interactions with cells, as well as targeted transport and accumulation in desired organs.They may have also a tremendous effect on AuNPs blood half-life, preventing their removal by the cells of mononuclear phagocytic system (MPS), also known as reticuloendothelial system (RES). Unmodified nanoparticles after intravenous administration are very often rapidly recognized and bound by opsonins in the blood, which facilitates their phagocytosis and removal by macrophages. Surface modifications have the potential to “mask” gold nanoparticles from RES, thus ensuring longer blood circulation time and allowing them to reach the site of action 108. It is important to note that surface functionalization can change the optical properties of nanogold particles

109,

which should considered while designing AuNPs for specific applications, for

example in photothermal or radiofrequency therapy (see section 3). Functionalization may be achieved either through physical adsorption or covalent attachment of ligands on the surface of nanoparticles, usually through thiol linkages.One of the most commonly used compound for functionalization of nanogold is poly(ethylene glycol) (PEG), bound covalently with the surface atoms of gold particles. PEGylation has been found to enhance the biocompatibility of various nanoparticles, prolong their blood half-life hydrophilic character

112,113

110,111

and prevent removal by RES increasing their

Spherical gold nanoparticles modified with PEG displayed no cytotoxic

effect against in vitro-cultured human cell lines

86,114,

as well as low uptake by RES, relatively long

blood circulation and enhanced tumor accumulation during in vivo studies on mice

115.

Numerous

studies have been devoted to PEG-coated gold nanorods, primarily due to the possibility of replacing detrimental CTAB on their surface. Nanorods modified with PEG exhibited prolonged blood half-life, much slower accumulation in liver and improved tumor localization, which significantly differentiated them from CTAB-coated particles100,116,117. Niidome et al. demonstrated that the degree of PEG grafting has a tremendous effect on the biodistribution of AuNRs. With an increase of PEG:Au molar ratio, the amount of gold decreased in the spleen but increased in the liver and tumor tissue, proving the significant role of PEG in tumor accumulation 118. Interestingly, the biodistribution of PEG-coated gold nanoparticles (specifically spherical AuNPs and AuNSs), regardless of surface modification, is also size-dependent 119.


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Further, it has been shown that the PEG-modified AuNRs are featured with low cytotoxicity and higher stability in culture medium

120.

Also, several studies report the absence of cytotoxic activity of

gold nanoshells coated with PEG towards human cancer cells

121,122,

as well as enhanced tumor

accumulation 123. However, these nanoparticles were able to induce acute inflammation and apoptosis of liver cells in vivo

124,

as well as macroscopic changes and weight fluctuations of rat organs

63,

indicating that PEG coating not always ensures overall biocompatibility. On the other hand, different surface modifications have been shown to reduce or eliminate the cytotoxicity of gold nanoparticles, thus allowing their safe administration into the organism without harmful side effects. Examples include AuNPs modified with folic acid

125,

polyacrylamide

126,

polyvinylpyrrolidone 127, and AuNRs coated with polyacrylic acid or polyallylamine hydrochloride 128. Reduction of cytotoxic activity of nanorods prepared with the use of CTAB may be also achieved by the substitution with compounds like phosphatidylcholine

129,

aminomercaptotriazole and

mercaptoundecanoic acid 130 or non-ionic surfactant Pluronic F-127 131. It is crucial to note that surface charge of nanoparticles has a tremendous influence on their cytotoxicity. Particles with positive surface charge are usually more toxic, due to non-specific interactions with negatively charged cellular membranes

132.

It has been demonstrated that cationic

AuNPs functionalized with quaternary amines were 7-fold more toxic to in vitro cultured cells than their anionic equivalents, obtained by the substitution of amine groups with carboxyl moieties

133.

Also, the cytotoxic activity of gold nanowires against mouse and human cell lines has been found to be dependent on the type of surface functionalization, with the highest toxicity observed for particles terminated with amino groups, and the lowest for carboxyl-terminated ones. Interestingly, the size of nanowires had no effect on their toxicity 134. Last but not least, surface functionalization of gold nanoparticles is meant to modulate their biodistribution patterns, provide targeted delivery and facilitate cellular internalization. Examples include the use of folic acid antibodies

139–141,

125,

transferrin

135,

carbohydrates

136,137,

oligonucleotides

and specific

coupled on the surface of nanoparticles. Moreover, PEG molecules have been also

used as linkers for different targeting ligands like tumor necrosis factor α (TNFα) 144.

138

142,143

or galactose

However, one should keep in mind that seemingly inert modifications may drastically influence the

accumulation of nanogold in various organs. For example, it has been shown that AuNPs coated with gum arabic or maltose exhibit different biodistribution patterns in blood, urine and tissues. In particular, the highest concentration of gold nanoparticles modified with gum arabic was found in the liver, while those coated with maltose accumulated in lungs

145.

Therefore, while designing

functionalized nanogold for anticancer applications, it is important to take into account not only the targeting properties of surface moieties, but also their potential to direct the particles to different parts of the body.



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3. Gold nanoparticles in anticancer therapy 3.1.Photothermal therapy Due to their unique properties such as absorption and scattering of electromagnetic radiation, gold nanoparticles are of particular interest for the application in photothermal therapy (PTT). This treatment strategy involves the use of electromagnetic radiation to generate heat for thermal destruction of cancer cells

146.

Thermal exposure, both in a form of local heating and hyperthermia of

the entire body, has been used in tumor therapy since the XVIII century

147.

Local and general

hyperthermia causes the disruption of cellular membranes and protein denaturation, leading ultimately to cell death. Unfortunately, healthy tissues are also exposed to damage during this process, which is the main drawback of PTT and significantly hampers its clinical application. This disadvantage has been partially overcome by the use of laser radiation, enabling the controlled and precise destruction of cancer tissue

146,148.

Modern methods of PTT are characterized by improved specificity, negligible

invasiveness and precise spatial-temporal selectivity, and constitute a promising alternative for the treatment of chemotherapy-resistant types of cancer. The efficacy of PTT may be additionally boosted by the application of photothermal agents (especially nanoscale compounds), enabling an enhanced transformation of light into heat. For this purpose, several photothermal nanotherapeutics including nanocarbons, transition metal sulfide/oxide nanomaterials and organic compounds have been extensively tested

149,150.

In this matter, the

advantages of gold nanoparticles of various shapes include a wide spectrum of absorption maxima (from UV to NIR) and high absorption cross sections requiring lower dosage times and lower laser power than conventionally applied dyes

139.

Notably, the NIR region is extremely important as the

light of longer wavelengths can penetrate inside living tissues unlike visible light. The depth of light penetration can reach a few centimeters in the ‘‘biological window’’ (650–900 nm), a region ideal for the SPR absorption of AuNPs, AuNRs and AuNSs. The irradiation in the range of SPR is of particular interest, since it is followed by rapid conversion of light into heat 10. The application of gold nanoparticles in PTT is determined by their size, shape and structure, which greatly influence photothermal properties

151–153.

For this purpose, gold nanorods can be a

valuable tool for modern PPT, since is it possible to manipulate their length and width, thus influencing not only the absorption and scattering band from visible to NIR region, but also increase their absorption and scattering cross sections 154,155. A similar effect may be achieved by changing the relative dimensions of gold nanoshell thickness and core radius

122,156,157.

This gives a possibility of

elaborating AuNRs and AuNSs with specific features adapted to the location and size of the tumor. Further, it has been shown that aggregation of nanoparticles significantly impacts their optical and heating properties. For instance, although different types of AuNSs may be ineffective in the nearinfrared range, their aggregates can be very efficient at significantly small interatomic distances


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(below 10% of their diameter). It has been proved that such clusters can be formed both inside the cell and on its surface, which has to be taken into consideration while planning the PTT experiments 158–161. What is more, the rapid heating of gold nanoparticles causes the formation of vapor bubbles 162 which can cause additional cavitation cell damage upon irradiation with visible light

163.

159

or near-infrared

The capacity of vapor bubbles formation has been shown to increase upon the nanoparticle

aggregation 160. Nevertheless, it has to be noted that irradiation of nanoparticles by high-intensity nanosecond IR pulses may cause their rapid destruction, in some cases even after the first dose 164. On the other hand, the application of femtosecond pulses does not solve this problem since the provided energy is too low. Thus, it is crucial to precisely control the nanoparticles’ properties for the particular irradiation strategy. The first study on the possibility to apply gold nanoparticles in photothermal therapy was presented by Hirsch et al. in 2003. They used PEG-modified gold/silica nanoshells with a 110 nmdiameter core and a 10 nm-thick shell providing a peak absorbance at 820 nm. Upon incubation of SKBR-3 human breast epithelial carcinoma cells with such constructs and subsequent irradiation, enhanced morbidity was observed. By contrast, untreated cells subjected the same conditions showed no loss in viability. Further in vivo studies revealed that exposure of solid tumors treated with AuNSs to low doses of NIR light caused significant temperature rise capable of inducing irreversible tissue damage

121.

Those studies were further developed in murine xenograft model of colon carcinoma, in

which complete removal of tumor was noted upon treatment with PEG-coated gold/silica AuNSs and subsequent irradiation

165.

Considering great potential of application of such gold nanoshells in PTT,

they were additionally conjugated with anti-human epidermal growth factor receptor (EGFR2/HER2) antibody via PEG linker (150 antibody molecules per nanoshell), in order to enable tumor-specific delivery. In vitro studies on HER2-expressing SK-BR-3 cells confirmed the possibility of selective induction of cell death with the photothermal interaction of immunonanoshells and NIR light, without any detrimental effect on co-cultured human dermal fibroblasts (HDFs). By contrast, control nanoshells conjugated with non-specific antibody or PEG did not induce cell death upon NIR irradiation

122,166.

These observations were confirmed in Daoy.2 medulloblastoma cell line with

increased expression of HER2. Further, in an analogous set of experiments, gold/silica nanoshells were conjugated with antibody against interleukin-13 receptor-alpha 2 (IL13Rα2) frequently overexpressed in gliomas. These immunonanoshells were able to efficiently induce cell death in U373 and U87 glioma cell lines expressing IL13Rα2, but not in A431 epidermoid carcinoma cells due to low expression of interleukin-13 receptor 167. Similar approach has been applied by El-Sayed et al. for spherical gold nanoparticles. They analyzed SPR absorption spectra from both naked AuNPs and AuNPs conjugated with monoclonal anti-EGFR antibody in non-cancerous epithelial cell line (HaCaT) and two malignant oral epithelial 15 ACS Paragon Plus Environment


Page 16 of 53

cell lines (HOC-313 and HSC-3). Colloidal gold nanoparticles were found in dispersed and aggregated forms inside the cells but displayed no cancer-specific uptake. As expected, anti-EGFR antibodymodified AuNPs specifically bound to the surface of the cancer type cells with 600% greater affinity than to the non-malignant cells

168.

This resulted in the increased rate of cancer cell death upon

irradiation after treatment with antibody-conjugated gold nanoparticles 169. It has been also shown that due to the specific binding of antibody-modified AuNPs to the EGFR overexpressed on cancer cells, lower laser power threshold is required for cell destruction

170.

Further, anti-EGFR antibody-

conjugated AuNRs exhibited analogous properties towards HaCaT, HOC-313 and HSC-3 cell lines. The use of gold nanorods enabled the application of NIR irradiation, since they exhibit strong longitudinal absorption at approx. 800 nm, in comparison to spherical AuNPs with plasmon band maximum at approx. 530 nm 139. Several other research teams also concentrated on the photothermal potential of gold nanorods and NIR-induced nanoshells. Stern et al. investigated unmodified 110-nm AuNSs with a 10-nm gold shell, which were able to induce cell death in two human prostate cancer cell lines (PC-3 and C4-2) upon exposure to NIR light (810 nm), whereas cells exposed to the radiation alone did not show any decrease in viability 102. This outcome was confirmed during in vivo studies on mice injected with PC3 cells

171.

In vivo tests on rodent models evaluating PEG-modified NIR-inducible gold/silica AuNSs

showed the disruption of muscle tissue upon irradiation in the region of nanoparticle localization, without any damage to other tissues 157. What is more, such gold/silica nanoshells functionalized with PEG exposed to near-infrared illumination were able to increase tumor perfusion, leading to the reduction of a hypoxic fraction of tumors in mice inoculated with human colorectal cancer cells (HCTs). Further radiation caused vascular disruption and extensive tumor necrosis, indicating multilevel anticancer activity of gold nanoshells specifically designed for PTT 170. Von Maltzahn et al. proposed a computationally guided strategy for photothermal anticancer therapy using gold AuNRs modified with PEG. These nanoparticles have been shown to possess better spectral and photothermal properties and longer circulation time in vivo than gold/silica AuNSs. A single intravenous injection of PEG-AuNRs enabled the destruction of all irradiated human xenograft tumors in mice 118. Moreover, CTAB-coated and folate-conjugated AuNRs exhibited different surface adsorption and internalization patterns in KB cells, however in both cases making them similarly susceptible to photothermal damage through laser-triggered cell membrane disruption. Authors speculated that hyperthermic effects might be induced at much lower power when nanorods were adsorbed on the cell membrane, since it appeared to be the region most susceptible to thermal ablation 172.

3.2.Radiofrequency therapy


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Radiofrequency ablation (RFA) is one of the least invasive methods of cancer treatment. It involves the damage of cancer tissue by heat generated via medium frequency alternating current. During the RFA procedure, a needle-like probe is being inserted into the tumor bulk and used to increase its temperature, leading ultimately to its destruction by radiofrequency diathermy

173

(Figure

6). RFA is especially useful for the treatment of both primary and metastatic tumors of small sizes in lungs, liver and kidneys. It has been also proposed for the therapy of pancreatic and bile duct cancer 174,175.

Further, the application of RFA enables gentle but efficient removal of benign bone tumors,

providing less bone destruction and fewer relapses in comparison to surgical techniques 176.

Figure 6. (A) Kocher mobilization and RFA of tumor of the head of pancreas. (B) RFA with cluster electrodes of the tumor of the body of the pancreas. Reprinted from 174 with permission from Elsevier. The advantages of the radiofrequency therapy include minimal invasiveness with no skin incision and facile execution compared to surgical resection. It is relatively safe and poses minimal risk for patient’s overall condition, since it does not directly stimulate heart muscle or nerves and therefore can be used without general anesthetic. This method may be applied several times in case of cancer recurrence and enables the treatment of tumors which are difficult or impossible to be removed surgically. However, the application of RFA may be limited due to the necessity of accurate needle placement, tumor size and location, insufficient destruction of cancer tissue (usually 5–40%) and low specificity

175.

Thus, non-invasive and precise technique for acquisition of radiofrequency-induced

local heating in required. Due to the ability of gold nanoparticles to absorb x-rays, upon localization in tumor cells they may serve as target molecules to produce increased heat when exposed to the external radiofrequency field 177. As mentioned before, visible and NIR light can induce surface plasmon resonance in nanogold particles, which provokes photothermal heating through well-known mechanisms. However, in the case of radiofrequency irradiation, the mechanism of nanoparticle-enhanced heating is poorly understood. Three possible modes of action have been proposed so far: Joule or inductive heating, magnetic heating and electrophoretic heating. Each mechanism is strongly dependent on the frequency of the applied irradiation, as well as the size and shape of gold nanoparticles 178. 17 ACS Paragon Plus Environment


Page 18 of 53

For the radiofrequency-based anticancer therapy, spherical AuNPs are most commonly studied. These nanoparticles were tested on several in vitro cultured human cancer cell lines. Upon exposure to radiofrequency field, the increased rate of cell death has been noted due to the heat-induced destruction of intracellular structures

179,180.

Moreover, a significant temperature increase and thermal

injury were confirmed in rat models injected with gold nanoparticles and exposed to RF field at the power of 35 W 179. For the targeted delivery of AuNPs, they were conjugated with cetuximab, an EGFR-specific antibody, and evaluated for radiofrequency ablation both in vitro and in vivo (Figure 7). It has been shown that these nanogold particles were rapidly internalized in epidermal growth factor receptorexpressing cancer cell lines, and subsequent exposure to RF resulted in almost complete heat-induced cell death. By contrast, no destruction was observed for cell lines which were not characterized by EGFR expression

181–184.

These results were confirmed in in vivo models. Pancreatic carcinoma

xenografts in mice upon treatment with cetuximab-conjugated AuNPs were exposed to radiofrequency field and evaluated for tumor size, necrosis rate and cleaved caspase-3 level. The RF field-induced destruction of pancreatic carcinoma xenografts has been noted, with no sign of injury to healthy organs. Additionally, increased level of cleaved caspase-3 and enhanced necrosis in treated tumors were observed 185.

Figure 7. The slight shift of the plasmon peak (left) is indicative of successful conjugation of the antibody to the AuNPs. Transmission electron microscopy (right) demonstrates cetuximab-targeted AuNPs in a Panc-1 cell. Reprinted from 184 with permission from Elsevier. An interesting approach has been proposed by Roa et al., who used glucose-functionalized AuNPs to enhance the sensitivity of radiation-resistant human prostate cancer cells. This group of scientists has been able to prove that spherical gold nanoparticles surface-modified with glucose decrease the p53 expression and trigger the activation of cyclin-dependent kinases (CDKs) with subsequent cell cycle arrest in the G2/M phase, which leads to sensitization of cells to radiation

186.


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Similar results, obtained a few years later by Wang et al. additionally proved the deregulation of Bcl-2 with simultaneous upregulation of Bax and activation of caspase-3 by glucose-functionalized AuNPs, leading to increased apoptosis of lung cancer cells exposed to RF field

187.

This outcome shows that

lack of biocompatibility of gold nanoparticles may be an advantage in some cases, enabling differentapplications of nanogold. 3.3.Gold nanoparticles as drug carriers Although chemotherapy is the most common method approved for the treatment of cancer, full exploitation of its potential is in many cases limited, mainly due to numerous side effects resulting from non-specific interactions of drugs with cells and tissues, as well as their low solubility or disadvantageous biodistribution. Further, efficacy of chemotherapy may be additionally hampered by changeable tumor microenvironment and cellular drug resistance. Since the development, full testing and approval of new anticancer chemotherapeutic is extremely costly and labor intensive, it is reasonable to improve already existing therapies. One of the promising approaches involves the application of drug delivery systems which could provide efficient targeted transport and overcome limitations of standard anticancer therapy. Such carrier systems must be capable of holding an adequate amount of the drug, bypassing mechanisms of drug resistance, improving biodistribution and preventing fast removal of the therapeutic from the organism. Further, drug delivery devices should be featured with prolonged blood half-life, tumor accumulation, efficient cellular uptake and controlled release patterns 188. Currently several compounds are under evaluation for potential drug delivery, particularly for cancer treatment

189.

It has been proved that nanoparticles may shield therapeutics from degradation,

enhance their solubility and extend bloodstream circulation time, at the same time providing targeted transport and controlled release of therapeutics 190. For the nanoparticle-based drug delivery system, passive targeting (utilizing EPR effect), active targeting (by conjugation of small targeting molecules) or a combination of these strategies can be used to enhance tumor accumulation. The therapeutic may be bound with nanocarrier either through physical encapsulation or chemical (covalent or non-covalent) bonding. In the latter strategy, a prodrug approach may be applied, with the therapeutic compound being converted into an inactive form or attached to a linker that is cleaved only in the tumor microenvironment or inside cancer cells. This method takes advantage of pathophysiological differences between normal and malignant cells, such as acidic pH or overexpression of various cellular components 191. An interesting strategy ensuring intracellular delivery of active compounds involves their conjugation to the surface of gold nanoparticles through thiol groups. This enables the release inside the cell due to the glutathione (GSH) activity. Glutathione is an important cellular antioxidant which concentration in the cell reaches 10 mM. This compound is responsible for removing free radicals and 19 ACS Paragon Plus Environment


Page 20 of 53

maintaining cellular redox homeostasis due to the ability to reduce disulfide bonds. Inside the cell, glutathione ‘replaces’ molecules conjugated on the surface of AuNP, thus contributing to their efficient release 192 (Figure 8).

Figure 8. a) A schematic depiction of the GSH-mediated payload release via place-exchange reaction. b) Bright field and fluorescence micrographs of human HepG2 cells after incubation with AuNPs (GNPs) for 96 h. c) Fluorescence images showing dose-dependent release of the payloads after the addition of glutathione monoester (GSH-OEt) modulating cellular GSH levels. Reprinted from 192 with permission from Elsevier. Additionally, the release or activation of the drug may be triggered by external stimuli, such as light (Figure 9) or temperature. Thus, the exploitation of cellular characteristics provides the control of drug release and activity in biologically relevant manner, while the external stimuli enable spatiotemporal regulation

192.

The merge of both tactics may result in significantly higher specificity of

anticancer therapy.


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Figure 9. a) A schematic illustration for nuclear delivery of DNA using photolabile nanoparticles. b) Light-induced surface transformation. c) Fluorescence and bright field microscopy images after photorelease of DNA from the complex. To clarify the overlap of F-DNA and nuclear stain DAPI; green channel (Fluorescein) and blue channel (DAPI) are depicted with red and yellow, respectively. d) Confocal micrographs illustrating the accumulation of photo-released DNA inside the nucleus. Panels 1, 2, 3 and 4 show four consecutive slices of middle sections of z-series confocal images (interval = 1.0 µm). Reprinted from 192 with permission from Elsevier. All these aspects result in nanoparticles being excellent candidates for drug carriers. Several molecules such as liposomes, dendrimers, silicon nanostructures, solid lipid nanomolecules, micelles or carbon nanomaterials have been tested for the application in drug delivery. However, only a small number of polymers and liposomes have been clinically approved

193.

Gold nanoparticles have been

recently examined for the anticancer drug delivery potential, primarily due to their biocompatibility, as well as the ability to form stable complexes with DNA and small interfering RNA (siRNA) and possibility of covalent bonding with therapeutics and targeting molecules 194. These features enable the utilization of two approaches: drug delivery and nucleic acid delivery. 21 ACS Paragon Plus Environment


Page 22 of 53

3.3.1.Drug delivery In general, anticancer drugs may be classified as phase-specific/cell cycle-specific (providing the destruction of rapidly proliferating cells, usually during the specific stage of cell cycle) or cell cycle-non-specific (having an equal effect on tumor and normal cells regardless of the growth phase or division rate). These include alkylating agents, heavy metals (causing the formation of cross-links between the DNA strands, leading to inhibition of DNA replication and induction of apoptosis), antimetabolites, cytotoxic antibiotics, spindle poisons (influencing assembly and disassembly of microtubules) and topoisomerase inhibitors

195.

A separate category of anticancer drugs involves

photosensitizers for photodynamic therapy (PDT). This treatment method is based on light-sensitive compounds acquiring cytotoxic properties upon exposure to light of a specific wavelength. Such therapeutics (like rose bengal or phthalocyanine) contain chromophore moieties (like cyclic tetrapyrrolic molecule), which upon irradiation transfer its energy to the cellular O2 to form singlet oxygen and other reactive oxygen species (ROS), significantly harmful to cellular structures 196. The examples of anticancer drugs conjugated with gold nanoparticles are summarized in Table 1. In several cases not listed in Table 1, AuNPs have been covalently conjugated with compounds of antiangiogenic or angiogenesis modulating activity (for the detailed information, see subsection 3.4). It is worth noting that the vast majority of research on covalent conjugates concerns spherical gold nanoparticles, most probably due to their ability to undergo facile surface chemistry and efficient cellular uptake compared to nanogold of more complicated shapes. The activity of conjugates was evaluated both in vitro on tumor cell models, and in vivo on mice with induced tumors of different origin, showing an increased cytotoxic effect in comparison to free drug. In several cases, the addition of targeting molecules provided specific recognition and better penetration of drug-nanogold covalent formulations into target cells. Nevertheless, surface functionalization seems not to be indispensable, since even the simplest drug-nanogold conjugates show increased cytotoxic activity and enhanced intracellular accumulation compared to free therapeutic compound (Figure 10).


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Figure 10. Intracellular distribution of Au-PEG-SS-DOX in HepG2-R cells. (A) Confocal images of cells treated with Au-PEG-SS-DOX showing distribution of DOX-derived fluorescence (red). (B) Distribution of lysosomes (green) in cells labeled with Lysotracker. (C) Merged image of A and B showing almost a complete co-localization of LysoTracker and DOX-derived fluorescence. (D) Intracellular DOX fluorescence intensity in HepG2-R cells after exposure to free DOX and Au-PEGSS-DOX for 24 hours. Reprinted from 197 with permission from Elsevier. Chemical conjugates are usually highly stable due to the permanent covalent bond (usually through thiol, amino or carboxylate functional group) between the drug and the nanoparticle. However, this approach requires the choice of proper linker, undergoing specific cleavage and releasing the therapeutic at the site of action. Moreover, in some cases, permanent bonding may decrease the therapeutic effect of the attached compound. Table 1. Examples of anticancer drug-nanogold conjugates Nanoparticle type

Surface functionalization/targeting molecule

Drug

Reference

PEG, folate

doxorubicin

198

doxorubicin

199

PEG

doxorubicin

200

poly(L-aspartate), PEG, folate

doxorubicin

201

PEG

doxorubicin

197

3-mercaptopropionic acid (MPA)

daunorubicine

202

thioalkyl tetra(ethylene glycol)lyated trimethyl ammonium or thioalkyl tetra(ethylene spherical AuNPs

glycol)lyated carboxylic acid



Page 24 of 53

PEG, tumor necrosis factor alpha (TNFα)

paclitaxel

203

PEG

tamoxifen

204

-

methotrexate

205

cetuximab

gemcitabine

206

-

6-mercaptopurine

207

5-fluorouracil

208

-

dodecylcysteine

209

-

sulfonamide

210

-

kahalalide F

211

photocleavable and zwitterionic thiol ligands (alkyl and tetra(ethylene glycol) components with terminally anchored orthonitrobenzyl (ONB) group)

amine-terminated oligonucleotide

AuNRs

platinum (IV)

212

complex

-

phthalocyanine

213

-

rose bengal

214

The formation of less stable but easier to prepare non-covalent complexes between gold nanoparticles and therapeutics may be possible due to the introduction of surface hydrophobic or hydrophilic monolayer, which generates pocket-like cavities enabling drug encapsulation. Noncovalent complexes provide direct delivery of unmodified drugs, that eliminates potential problems associated with prodrug strategy (e.g. inactivation or insufficient drug release). However, it is difficult to predict the stability of non-covalent formulations in different temperature, pH and environmental conditions, which may significantly limit their efficacy in vivo. Thus, the number of reports on this subject is significantly limited. For instance, PEGylated spherical AuNPs were used for the improvement of solubility and tumor accumulation of above-mentioned phthalocyanine, hydrophobic PDT drug 215. This system was further developed by the attachment of epidermal growth factor (EGF) peptides, providing 10-fold enhanced transport of phthalocyanine to the brain tumor 216. An interesting solution was proposed by Brown et al., who prepared gold nanoparticles non-covalently modified with PEG monolayer carrying oxaliplatin. Such formulation exhibited better cytotoxic effect than free oxaliplatin and ability to penetrate into the nucleus of lung cancer cells

217.

Spherical AuNPs coated

with (poly(N-isopropylacrylamide)-co-oleic acid)-g-chitosan ((PNIPAAm-co-OA)-g-CS) were also examined in lung cancer cell line model for the delivery of erlotinib. These complexes showed high cellular uptake and enhanced cytotoxicity due to the release of the drug in a thermo-responsive manner 218.


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Modification of AuNPs with tetra(ethylene glycol) (TEG) units terminated with zwitterionic moieties enabled the formation of a hydrophobic alkanethiol interior with hydrophilic shell. These nanoparticles have been used to entrap a fluorescent probe (4,4-difluoro-4-bora-3a,4a-diaza-sindacene, BODIPY) and two anticancer drugs: tamoxifen and β-lapachone (Figure 11). The compounds were stably encapsulated in the hydrophobic pocket of AuNPs and released into the cell by membrane-mediated diffusion without uptake of the carrier nanoparticle

219.

Additionally, the

introduction of surface negative charge eliminated non-specific, toxic interactions of nanoparticles with cellular membrane. Such an approach allows for the elaboration of multimodal delivery system with numerous different functions, based on gold nanoparticles loaded with several therapeutic and auxiliary or targeting agents.

Figure 11. (A) Structure of particles and guest compounds: BODIPY, tamoxifen (TAF), and βlapachone (LAP) with the number of encapsulated guests per particle (B) Cytotoxicity of complexes measured by Alamar blue assay after 24 h incubation with MCF-7 cells. IC50 of AuNP (NP), equivalent drugs (Drug), and free drugs are shown in the table. Reprinted from 194 with permission from Elsevier. 3.3.2.Nucleic acid delivery Both chemical conjugation and physical complexation have been used for the delivery of nucleic acids by nanogold particles in order to improve gene therapy. Nucleic acids, applied for repair of defective genes (DNA) and regulation of cellular division and homeostasis (siRNA) constitute 25 ACS Paragon Plus Environment


promising anticancer therapeutics

220.

Page 26 of 53

In comparison to small-molecule drugs, nucleic acids require

delivery devices for the protection against nuclease activity and environmental degradation, as well as to facilitate cell entry. These delivery vehicles are generally classified into two groups: biological and synthetic vectors. Among the first category, viral vectors are the most popular. However, they may possess immunogenic, carcinogenic and pro-inflammatory properties, hampering their clinical use 221. To overcome these problems, several types of synthetic vectors have been proposed (e.g. lipids, polymers or dendrimers), which application, despite their good transfection efficacy and facile production, is still limited due to their low storage stability, weak targeting potential and difficult in vivo tracking

222,223.

Thus, in order to elaborate an efficient delivery system for nucleic acids, the

attention of scientists focused on gold nanoparticles. Covalent conjugation of nucleic acids to AuNPs is primarily used for the delivery of genesilencing oligonucleotides, where the modification does not reduce biological activity 224. This strategy is based on the occurrence of RNA interference (RNAi) phenomenon, in which RNA molecules inhibit gene expression or translation, through the formation of double-stranded hybrids with targeted mRNA. The application of gold nanoparticles in this field mainly involves the transport of microRNAs (miRNAs) and small interfering RNAs (siRNAs)

225,226.

AuNPs covered with thiolated

oligonucleotides exhibited higher affinity constants for their complementary nucleic acids than their linear counterparts, as well as rapid cellular uptake (dependent on the density of the surface siRNA shell) and efficient endosome escape

227.

Similar constructs additionally modified with thiolated

cationic ligand poly(ethylene glycol)-poly(2-N,N-dimethylamino)ethylmethacrylate) (SH-PEGPAMA) showed efficient gene knockdown in HuH-7 human hepatic cell line and prolonged serum half-life. Moreover, SH-PEG-PAMA may act as a stabilizer and provide further protection against RNases and facilitate endosomal escape via the “proton sponge” effect 228. The addition of hybridizing monoclonal antibody-DNA conjugates on the surface of gold particles in RNA-AuNP constructs provided targeting properties and selective cell recognition resulting in enhanced activity 229. RNA-AuNP conjugates were tested in experiments involving knockdown of luciferase green fluorescent protein (GFP)

224

225

and

expression in cell line models, demonstratingincreased efficacy

compared to free oligonucleotides. Again, the decrease in gene expression was dependent on the level of oligonucleotide modification. The nanocarriers were able to protect RNA molecules against nuclease degradation and showed efficient cellular uptake despite surface negative charge 224. Spherical gold nanoparticles have been also used as carriers for tumor-suppressive miRNA (miR-205), showing enhanced inhibition of miRNA target protein expression 226. The delivery of nucleic acids is also possible through the application of non-covalent complexes with surface-functionalized gold nanoparticles. The strong negative charge of nucleic acids makes cationic AuNPs the most obvious choice to form stable complexes 230 with both siRNA 231 and doublestranded DNA plasmids

232,233.

For the purpose of generating surface positive charge, AuNPs were 26 ACS Paragon Plus Environment

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modified with quaternary ammonium 231,

232,

poly(ethylenimine) (PEI)

but also glycine, arginine, leucine, phenylalanine, tryptophan

with triethylenetetramine

235).

233

234

or amino acids (mostly lysine

or glutamic acid functionalized

Interestingly, nucleic acids have been showed to wrap around

positively-charged spherical gold nanoparticles in a form similar to the structure of chromatin, which provides protection from degradation by nucleases and other chemical agents

236.

However, it should

be noted that the formation of such complexes triggers reversible changes in nucleic acids conformation 192,233,234,

237.

Non-covalent formulations showed enhanced delivery and increased activity

with the strength of these effects dependent on AuNP:nucleic acid ratio, surface charge

coverage and hydrophobicity of nanosystems 232. The release of DNA from complexes with AuNPs may be enhanced by the application of photocleavable linkage, like o-nitrobenzyl ester bond cleaved upon near-UV irradiation (> 350 nm). This leads to the release of cationic alkyl amine, leaving behind a negatively charged carboxyl moiety. Such reversal in electrostatic charge causes efficient release of DNA from AuNPs complexes, resulting in effective DNA accumulation inside the cells, with significant nuclear localization 238. The synthesis of so-called ‘layer-by-layer’ modified nanoparticles seems to be promising, versatile approach for DNA and RNA transport and controlled release. In this strategy, AuNPs may be coated with subsequent layers of modifying molecules with different properties. For instance, mercaptoundecanoic acid-stabilized gold nanoparticles were repeatedly coated with layers of positively charged PEI and negatively charged siRNAs. The constructs with different degrees of surface coating exhibited nominal cytotoxicity and various intracellular localization patterns, which translated into different levels of GFP expression knockdown

239.

Also, pH-responsive AuNPs coated

with layers composed of PEI, cis-aconitic anhydride-functionalized poly(allylamine) (PAH-Cit) and siRNA showed facile endosomal escape and enhanced gene silencing 240. 3.4.Gold nanoparticles as therapeutics – modulation of angiogenesis Using gold nanoparticles as therapeutic molecules in their own right is another potential strategy for medical treatment of cancer. As mentioned before, AuNPs may exhibit cytotoxic properties against certain types of cancer cell lines. Surface functionalization with targeting ligands may additionally improve the specificity of action of nanogold particles, at the same time decreasing their non-specific interactions with healthy tissues and cells. However, since the mechanisms of cytotoxicity of nanogold particles are not fully recognized and characterized, their use as anticancer therapeutics per se requires further research. The inhibition of angiogenesis is one of the most promising strategies for application of gold nanoparticles in anticancer therapy. This process involves growth and expansion of new blood vessels through the degradation of extracellular matrix, as well as activation, migration, proliferation and differentiation of endothelial cells

241

(Figure 12). Tumor growth heavily depends on blood vessels 27



Page 28 of 53

formation providing constant flow of nutrients and oxygen, as well as metabolic wastes removal. The growth of cancer cells typically follows a sigmoidal-shaped curve, with doubling time dependent on tumor bulk 195. Solid tumors can reach the size of 1–2 mm without the necessity of blood supply, since at the beginning the diffusion processes are sufficient for the exchange of compounds between the environment and the cells. Upon further growth, tumor enters the phase of cellular hypoxia, thus initiating the process of angiogenesis, which is crucial for cancer progression and metastasis 242. Thus, the inhibition of angiogenesis is one of the main strategies of current anticancer therapy. Several antiangiogenic compounds have been identified so far, and they are currently under clinical evaluation 243,244.

Figure 12. Normal angiogenesis and tumor angiogenesis. Endothelial cells covering the innermost layer of the blood vessel are producing new capillaries. Reprinted from 245 with permission from Elsevier. The main target for inhibition of angiogenesis is a group of growth factors, including fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and most importantly vascular endothelial growth factor (VEGF), well-known angiogenesis activators overexpressed during tumor growth and metastasis. These factors play critical role in proliferation of endothelial cells via interactions with tyrosine kinase receptors. VEGF is the key factor involved in the development of cancer and metastasis, therefore the most comprehensively investigated

246.

However, anticancer

treatment taking advantage of inhibition of angiogenesis is far from satisfactory. Insufficient formation of blood vessels may slow down the delivery of drugs to cancer cells and decrease their therapeutic effect

247.

Further, tumors can develop resistance mechanisms against antiangiogenic therapy,

primarily through the accumulation of particularly aggressive cells 248,249. 28 ACS Paragon Plus Environment

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Naked spherical AuNPs have been shown to interact with heparin-binding growth factors like VEGF165 and basic FGF (bFGF), thus inhibiting their activity. It has been hypothesized that this phenomenon is primarily based on the interactions between heparin-binding domain of growth factors (presumably through cysteine and/or lysine residues) and -NH2 or -SH groups of gold nanoparticles. This theory finds support in the observation that AuNPs do not inhibit the activity of non-heparinbinding growth factors like VEGF121. The binding of VEGF165 and bFGF by nanogold resulted in inhibition of endothelial/fibroblast cell proliferation in vitro through the reduction of phosphorylation rate of key proteins responsible for angiogenesis. This effect was dose-dependent, with almost complete inhibition being observed at 335–670 nM concentrations. Moreover, AuNPs inhibited VEGF-induced permeability and angiogenesis in vivo in mouse ear and mouse ovarian tumor models 245,250.

Later, it has been shown that the inhibitory effect of AuNPs is caused by the change in the

conformation or denaturation of heparin-binding growth factors, whereas the conformations of nonheparin-binding proteins remains unchanged (Figure 13). Interestingly, authors have demonstrated that the inhibition processes are size-dependent (Figure 14), and the surface of naked AuNPs plays an important role in observed phenomena. They used thiolated tetra(ethleyene glycol)-modified gold nanoparticles with different surface charges to investigate the role of electrostatic interactions between AuNPs and heparin-binding domains in inhibition of growth factors activity. It has been proved that bare gold surface is essential to inhibit the function of VEGF165

251.

Additional experiments

performed by the same group have shown that internalized gold nanoparticles may alter intracellular signaling and block MAPK pathway, thus inhibiting metastasis via interference with epithelialmesenchymal transition (EMT). This process, in which heparin-binding growth factors play important roles, is crucial for metastatic potential of tumor cells 252.

Figure 13. Binding of heparin-binding growth factors (HB-GFs) to gold nanoparticles leads to the inhibition of their function due to change in the protein structure. Reprinted from 251 with permission from Elsevier.



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Figure 14. AuNPs affect the phosphorylation of VEGF165 receptor. (A) Serum-starved HUVECs were stimulated for 5 mins with VEGF165 (10 ng/mL) that was preincubated with or without AuNPs (GNPs) and then immunoblotted with antibodies to phophotyrosine KDR (pKDR) and total KDR levels in the cell extracts. (B) Densitometric scanning of phosphotyrosine blots using NIH Image, expressed in percentage. Reprinted from 251 with permission from Elsevier. The ability of AuNPs to inhibit VEGF165-induced cell migration and tube formation has been further explored using human umbilical vein endothelial cell line model (HUVEC). Gold nanoparticles significantly slowed down both processes by affecting the structure of cell surface and cytoskeleton and influencing the Akt pathway 253. AuNPs have been also used as carriers or platforms for angiogenesis modulating compounds. For instance, they have been covalently conjugated with quercetin to improve its solubility and anticancer potential. Quercetin regulates proliferation, survival and differentiation of tumor cells, and plays an important role in modulation of EGF-induced EMT process. AuNPs-quercetin formulations reduced viability and capillary-like tube formation in HUVEC cell culture. Also, conjugates were able to suppress new blood vessel formation both in vitro and in vivo, and slow down tumor growth in mammary carcinoma rat models 254. Spherical AuNPs proved to be efficient nanocarriers for endostatin, an antiangiogenic agent widely applied in clinical treatment. Such conjugates reduced cell migration and tube formation in in vitro cultured HUVECs, and increased pericyte expression while inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) and anterior gradient 2 (AGR2) expression in metastatic colorectal cancer xenografts

255.

Interestingly, similar PEGylated formulations exhibited increased

tumor accumulation and promoted temporary tumor vascular normalization in H22 xenograft models. They were able to reduce permeability and hypoxia, strengthen blood vessel integrity and increase blood-flow perfusion, thus increasing the delivery of 5-fluorouracil into the tumor


256.

PEG-coated 30

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AuNPs were also conjugated with antiangiogenic agent semaphorin 3F (Sema 3F), which resulted in improved cell uptake and significant reduction of VEGF165-induced cell proliferation in HUVECs culture compared to free semaphorin 257. An interesting strategy involves the functionalization of gold nanoparticles with peptides designed to selectively interact with cell receptors responsible for activation or inhibition of angiogenesis. Bartczak et al. designed three types of peptides: binding to the vascular endothelial growth factor receptor and activating the expression of proangiogenic genes (P1, KPQPRPLS), binding to neuropilin-1 receptor and promoting its internalization (P3, KATWLPPR) and P2 (KPRQPSLP) as control, not interacting with those receptors. These peptides were covalently bound to oligo(ethylene glycol)-capped AuNPs, which were subsequently evaluated for the modulation of blood vessel growth in vitro. As expected, depending on the peptide function, AuNPs promoted or blocked the capillary formation without causing toxicity to the cells, and both activators and inhibitors caused barrier dysfunction following different mechanisms

258.

These properties were subsequently

confirmed in vivo in chick embryo model 259. 4. Conclusions and critical remarks Thanks to the rapid development of nanotechnology and nanoscience over the past few decades, a great variety of particles of different sizes, shapes and structures are now available to researchers. Due to their unique properties, gold nanoparticles are of particular interest for medical applications, especially for anticancer therapy. A wide range of possible synthesis methods allows obtaining nanogold particles with specific architecture and characteristics, depending on the intended use. Moreover, their reactivity enables further modification and functionalization, additionally improving bioavailability and broadening the scope of medical applications of AuNPs. Numerous and diverse physicochemical properties of nanogolds (highlighted in this review), distinguishing them from other nanoparticles, give hope for their use especially as drug delivery devices, modulators of angiogenesis or heat-activated factors destroying tumor tissue. This brings hope for the development of innovative cancer treatment methods, providing a good alternative for the most commonly used chemotherapeutics. However, there are still many questions and inconsistencies in currently available scientific reports regarding biological impact of gold nanoparticles. These are mainly due to the differences in in vitro and in vivo models, experimental procedures, applied doses or synthesis methods. Possible aggregation of AuNPs and difficulties in their visualization without additional labeling may constitute further obstacles in the interpretation of the experimental results. All those aspects significantly hamper drawing unambiguous conclusions about the biological activity of gold nanoparticles and their application in anticancer treatment. In order to fully exploit their therapeutic potential, there is a strong



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need to continue and broaden the studies both on simple cellular models grown in vitro and in more complex animal systems. It is still a great challenge to develop and optimize non-toxic methods of AuNPs synthesis, providing monodisperse nanoparticles of high purity and enabling their use for in vitro screening tests in sterile conditions. The precise control of nanogold synthesis is extremely important due to the fact that even a small change in size and shape can drastically affect the properties of AuNPs. Further, the chemical characterization of AuNPs is another important stage, allowing for obtaining nanoparticles with the same physical and chemical properties ensuring the repeatability of experiments. A separate but not less important issue is to comprehensively evaluate the correlation between particle features (size, shape and surface modification) and observed biological effects. In particular, compounds selected for functionalization/coating of gold nanoparticles should be thoroughly tested for possible side effects or systemic toxicity in living organisms. The assessment of biocompatibility of nanogold, not only at the level of cytotoxicity, but also subcellular processes is crucial. Although the initial claim of absence of AuNPs cytotoxicity has raised understandable enthusiasm, numerous studies concerning this subject indicate the multilevel nature and complexity of this issue. Therefore, it is a must to better understand cellular and molecular mechanisms triggered by exposure to AuNPs. Here, the inflammatory properties of gold nanoparticles, as well as their impact on genomics (complete set of genetic information provided by the DNA), transcriptomics (gene expression patterns) proteomics and metabolomics (the content of cellular proteins and metabolites, respectively), as well as epigenetics (heritable changes in gene expression occurring without changes in DNA sequence) should be highlighted as residual challenge. This is particularly important due to the fact that such effects may cause long-term changes or toxicity, similarly to the prolonged accumulation of metals in the organism. Especially the epigenetic alterations are able to promote phenotype modifications not only in the individual exposed but also in subsequent progeny and successive generations. This has important implications on the way scientists assess the safety of chemical compounds. Unfortunately, all mentioned fields of study and associated techniques are not yet routinely implemented in nanotoxicology. Last but not least, several problems exist regarding the delivery of drugs or active compounds by AuNPs, both in the form of a complexes and conjugates. At this point, the kinetics of the release of therapeutic and its interaction with gold itself should be thoroughly tested. There are numerous reports on the decrease of the activity of compound upon complexation/conjugation with nanocarriers, which may significantly hamper the delivery potential of nanogold. Such formulations should be also comprehensively evaluated for their stability in different environmental conditions. Taking all those aspects into account, it can be assumed that the clinical use of gold nanoparticles still requires a lot of effort and can be far from the ultimate success. Nevertheless, in this work we have made an in-depth review of the available data on the possible use of AuNPs in various 32 ACS Paragon Plus Environment

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anticancer therapies. The number and variety of available reports on the biological activities of nanogold, which stands out significantly from other nanoparticles, allows us to hope that in the future we will be able to develop effective methods of cancer therapy based on AuNPs.

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825x425mm (96 x 96 DPI)


Gold Nanoparticles in Cancer Treatment - Molecular Pharmaceutics

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