Applications of metallic nanostructures in biomedical field

CHAPTER 14

Applications of metallic nanostructures in biomedical field Petronela Pascariu*, Emmanuel Koudoumas†, Valentina Dinca‡, Laurentiu Rusen‡ and Mirela Petruta Suchea†,§ *

“Petru Poni” Institute of Macromolecular Chemistry, Iaşi, Romania Center of Materials Technology and Photonics, School of Engineering, Technological Educational Institute of Crete, Heraklion, Greece ‡ National Institute for Lasers, Plasma and Radiation Physics, Magurele, Romania § National Institute for Research and Development in Microtechnologies (IMT-Bucharest), Voluntari, Romania †

Chapter outline 14.1 Metallic nanostructures—Overview 14.1.1 Review of the most usual metallic nanostructures, properties and their use in biomedical applications 14.1.2 Specific properties 14.1.3 Methods of fabrication 14.2 Biomedical applications 14.2.1 Biosensors and detectors 14.2.2 Drug delivery and nanomedicine 14.2.3 Germicidal action 14.2.4 Other biomedical applications 14.3 Conclusive remarks References Further reading

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14.1 Metallic nanostructures—Overview In recent years, metallic nanostructures with controlled size, shape, architecture, composition, and properties are ideal building blocks for engineering and tailoring specific applications, attracting extensive attention from both scientific and industry community. Taking in consideration their properties that include high surface area, good crystallinity, and improved optical and electric properties as compared with those of metal oxides or other kinds of materials, metallic nanostructures hold potential use in a wide variety of research and industry field, such as catalysis, photography, energy harvesting, and optoelectronics (Verellen et al., 2011; Liu et al., 2011; Zahmakiran and Ozkar, 2011; Adeyemi and Sulaiman, 2015a, b; Daraee 2016; Linic et al. 2011; McKenzie and Graham, 2009). Various studies are focused on obtaining gold, silver, gadolinium, and platinum with improved optical and electric properties that are directly correlated with their size, shape, dimensionality, crystallyne phase, and surface properties (Gerard and Gunko, Functional Nanostructured Interfaces for Environmental and Biomedical Applications https://doi.org/10.1016/B978-0-12-814401-5.00014-1

© 2019 Elsevier Inc. All rights reserved.

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Fig. 1 Schematic representation for different methods used for noble metal nanostructures synthesis.

2013; Huang and El-Sayed, 2011; Hazra et al., 2017), which are also dependent on the different biological, physical, and chemical preparation methods. A diagram of such examples related to the processing methods is shown in Fig. 1, discussed in detail in the second part of the chapter. Nevertheless, some of their characteristics make them, especially in the case of the noble metals (i.e., gold, silver, and platinum in different shapes and sizes), suitable for biomedical and environmental applications such as biosensors, tissue engineering, drug delivery system, cancer diagnostics, detectors and sensors, UV protection, and air/water/ soil purification (Conde et al., 2012; Alaqad and Saleh, 2016; Hong et al., 2015; Malekzad et al., 2016; Singh et al., 2016). As an example, it was shown that noble metal-based nanostructure optical properties can be tuned by changing their shape (nanoparticles (NPs), nanorods, nanotubes, and so on.), size (from 1 to 100 nm), and composition (e.g., core/shell or noble metal alloy structures). This characteristic is particularly interesting for photothermal applications, as the nanostructures absorb/emit/transmit/reflect a desired wavelength enabling their imaging within native tissue ( Jain et al., 2008). Besides the abovementioned characteristics, these types of nanostructures have low toxicity in vivo, and their surface can be

Applications of metallic nanostructures in biomedical field

functionalized with either biomolecules (e.g., antibodies, peptides, and/or DNA/RNA to specifically target different types of cells) (Sperling and Parak, 2010) or biocompatible polymers (e.g., polyethylene glycol, PEG). In this way, their in vivo circulation is prolonged, enhancing their characteristics for drug and gene delivery applications (Ghosh et al., 2008; Nishiyama 2007). Within biomedical applications, two of the most used noble metal nanostructures are gold and silver NPs. For example, if Au NP applicability ranges from cancer radiation therapy (Ganeshkumar et al., 2012) to protein labeling and biomolecular detection platforms or therapeutic and drug loading agents (Lan et al., 2013; Mendoza et al., 2010; Giljohann et al., 2010; Amjadi and Farzampour, 2014), for Ag, the applications are directed more toward cosmetics, electronic application, antimicrobial surfaces, and environmental protection (Krutyakov et al., 2008; Murawala et al., 2014). This is due to Au-based NP material low cytotoxic effect as compared with those based on Ag NPs that are relatively toxic to mammalian cells (Bechet et al., 2008). However, Ag nanoparticles are frequently used not only in the antimicrobial applications to eliminate pathogens like fungi, viruses, and bacteria (Monteiro et al., 2009; Sharma et al., 2009, Ahamed et al., 2010) but also in different other types of applications: colloidal coatings, textile industry, paints, etc. Due to the special chemical and physical properties of these types of nanostructures (i.e., surface-enhanced Raman scattering and optical behavior, electric conductivity, high thermal and chemical stability, and catalytic activity), these nanomaterials can be successfully used in nanomedicine, research, and industry, described in the next parts of the chapter.

14.1.1 Review of the most usual metallic nanostructures, properties and their use in biomedical applications 14.1.1.1 Au nanostructures In recent years, due to specific characteristics related to large surface area and high electric conductivity, Au nanostructures have been widely used in catalysis, optical molecular sensing, drug delivery systems, cancer therapeutics, and construction “blocks” in nanotechnology (Fig. 2) (Tiwari et al., 2011; Xu et al., 2006; Adeyemi and Sulaiman, 2015a, b; Tedesco et al., 2010). Fabrication of Au NPs can be performed to have a different size from 1 to 150 nm (Liu et al., 2007; Zuber et al., 2016) depending on the synthesis method. An advantage is represented by the fact that Au NPs can have different forms (e.g., rod and dot) (De Jong and Borm, 2008) and are easily detectable within micromole concentrations, warranting their use in imaging applications (Fadeel and Garcia-Bennett, 2010). These nanostructures exhibit also good biocompatibility, and the cells have been shown to intake gold NPs without cytotoxic effects (Chen et al., 2008; Fadeel and Garcia-Bennett, 2010). Lai et al. demonstrated a median lethal dose (LD50) of over 5 g/kg of body weight using a nano-Au suspension with a particle diameter of 50 nm (Lai et al., 2006). Moreover, starting with

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Fig. 2 Types of functionalization of gold NPs and their potential biomedical applications. Reproduced from (Tiwari et al., 2011).

1920, the colloidal Au NPs have been used in medicine for the treatment of tuberculosis (Mottram 2003). Since then, colloidal Au NPs prepared by different methods (e.g., citrate reduction method) have been widely researched as drug and gene delivery vehicles (Vasir et al., 2005; Pissuwan et al., 2006; Saleh 2011; Chen et al., 2008). 14.1.1.2 Silver NPs Specific properties as high conductivity, chemical stability, and improved catalytic and antimicrobial activity (Frattini et al., 2005; Li et al., 2005; Singh 2015) make Ag NPs attractive for applications in environmental purification (water and air filtration) and various biomedical biointerfaces and antiviral therapies. Besides the abovementioned applications, due to individual plasmonic activity in optical spectra, Ag NPs are also used in

Applications of metallic nanostructures in biomedical field

biosensing (Choi et al., 2016). In the last decade, another important use of Ag NPs as antiviral agent against various resistant viral strains was demonstrated (e.g., human immunodeficiency virus, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkey pox virus). Considering the fact that metals are able to attack a wide range of targets in the virus, the risk related to developing resistance is very low as compared with conventional antivirals, which makes the use of metal nanoparticles a good alternative for new therapies against pathogenic viruses (Galdiero et al., 2011; Tran et al., 2013). A general view on some of the most important applications of Ag NPs is schematically represented in Fig. 3. Moreover, different systems of hybrid materials containing silver NPs with amphiphilic hyperbranched macromolecules are synthesized for use in surface coatings with good antibacterial activity (Aymonier et al., 2002). In the work from (Le Pape 2002), antimicrobial properties of activated carbon fibers with Ag NPs were evaluated, and it was found that the use of such composites as membranes can improve the microbial quality of the drinking water. In other work (Yoon et al., 2008), it was studied how Ag NPs deposited on carbon fiber filters were effective for the removal of bioaerosols by inhibition of the survival of microorganisms, Bacillus subtilis and Escherichia coli, being completely inhibited within 10 and 60 min, respectively. These bioaerosols are airborne particles that can cause chronic affections, which are developed in the ventilating, heating, and air conditioning system in atmosphere with high content of humidity. When used for wound treatment, nanocrystalline Ag can be used in wound dressings for ulcers, while Ag sulfadiazine is used in pastes or creams for treating burned wounds (Bhattacharya and Mukherjee, 2008). However, the antibacterial activity of silver NPs can decrease due to oxidation (Huang et al., 2017). As a drawback, it should be mentioned that a diameter of Ag NPs smaller than 20 nm could be very dangerous for environment because these can accumulate in the plants and inhibit the plant growth and development. Ag NPs can have a negative effect on aquatic organisms and mammals due to the fact that these can represent a source of silver ions, leading to potentially toxic results (Malysheva et al., 2016). Strategies to reduce the toxicity of Ag NPs include the synthesis of various organic and inorganic supporting materials. Very extensively studied are the compounds based on carbon nanotubes and titanium dioxide (Siddhartha Sankar et al., 2016; Hao et al., 2017). Furthermore, some researchers have found that nanocomposite systems based on graphene oxide and Ag improve antimicrobial properties compared with pristine Ag NPs. These hybrid nanostructures show a nontoxic effect on the rat skin (Xu et al., 2011). Recently, it was reported that graphene oxide-Ag NP nanocomposites have good dispersibility in water without any further modification (Chen et al., 2016). These nanostructures have improved antimicrobial activity at an exceedingly low concentration (9.37 μg/ mL) compared with the pure Ag NPs (12.45 μg/mL) and graphene oxide nanosheets (250 μg/mL). Graphene oxide/Ag NP composite with antibacterial property was effective

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Fig. 3 Diagram with Ag NP applications.

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at a relatively low concentration (2.5 μg/mL) against Xanthomonas oryzae pv. Oryzae (Xoo) (Liang et al., 2017).

14.1.2 Specific properties The optical, mechanical, electronic, chemical reactivity and catalysis properties of noble metal-based nanomaterials are the result of their size, shape, dimensionality, crystal phase, and surface properties (Fig. 4). Among the most studied nanostructures related to biomedical field are Au nanostructures. Properties of Au nanostructures depend on size, shape, degree of aggregation, and local environment. For example, Brioude and coauthors report in their studies that Au nanorods possess two different surface plasmon resonance bands (one band corresponds to the transverse plasmon and the other one to the longitudinal plasmon). The longitudinal localized surface plasmon resonance (along the long axis) can be tuned from the visible to the near-infrared region (Brioude et al., 2005). The ability to modify the plasmonic characteristics of anisotropic Au nanocrystals is an important way to design surface-enhanced Raman scattering (SERS) substrates (Hong et al., 2011a, b). Likewise, Andoy et al. demonstrated that shape-controlled metal nanocrystals are a new generation of nanoscale catalysts and they find that Au nanoplates exhibit different catalytic activity regarding the sites where the reductive N-deoxygenation reaction takes place (Andoy et al., 2013). The biological interactions and impact of Ag NPs depend on the physicochemical properties such as size (surface area), shape, surface charge and coating, agglomeration,

Fig. 4 Properties of noble metal nanostructures.

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and dissolution rate. Thereby, particles having small size and larger surface area render high toxic behavior ( Johnston et al., 2010). Also, the shape of Ag nanostructures can influence in important manner their physical and chemical properties. There are a wide range of Ag nanostructures used in biomedical field, namely, spherical NPs, nanowires, nanorods, nanoplates, and nanocubes (Rycenga et al., 2011). Studies have shown that the biological activity of Ag NPs depends on the surface charge load of their coatings, with direct impact on the living systems (Powers et al., 2011). The agglomeration phenomenon of NPs is known to occur frequently, being observed in culture media and inside the cytoplasm or nuclei of HepG2 cells (Kim et al., 2009). The oxidation of the Ag NP surface leads to dissolution and generation of ionic silver. The chemical and surface properties of the particle, including their size, can influence the dissolution rate, which further can affect the surrounding media (Misra et al., 2012). 14.1.2.1 Optical properties Au NPs exhibit characteristic colors and great optical properties being linked to their size, shape, and the dielectric constant of the neighboring medium. The specific wine-red color of spherical Au NP stems leads to a phenomenon termed localized surface plasmon resonance (LSPR) ( Jain et al., 2008; Willets and Van, 2007). Au nanostructures exhibit this phenomenon by light irradiation that induces collective oscillation of free electrons on their surface (Xia and Halas, 2005). This can exceed into the dielectric over nanometer length domain and hence can induce an improvement on the incident field up to several orders of magnitude, leading to new properties of NPs. Moreover, the electronic vibrations are restricted by the size and shape of the metal nanoparticle, which gives rise to the size- and shape-dependent optical properties of gold and silver NPs. Early investigations aiming the behavior of the light in the presence of NPs were made by Faraday on Au colloids. For example, spherical Ag and Au NPs have a single plasmonic absorption band at λ ¼ 400 and 510 nm, respectively. Instead, the 1D nanorods/nanowires of Ag and Au exhibit two surface plasmonic resonances, namely (1) the band at higher energy attributed to the absorption and the scattering over the short axis of the nanorod/nanowire and (2) the lower energy band attributed to the absorption and the scattering over the long axis of the nanorod/nanowire. The longitudinal specifies that 1D nanostructure band can be modulated ranging from visible to near-infrared domain, with applicability in nanomedicine (Bridges et al., 2012). Au nanostructures are classical examples to demonstrate the shape-dependent LSPR properties. Fig. 5 shows the absorption spectra for the nanospheres with different shapes. The absorption spectra of Au nanospheres with spherical shape have only one well-defined resonance peak compared with the

Applications of metallic nanostructures in biomedical field

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Au with rod shape that in their optical spectrum shows two bands in the visible or near-infrared domain. Theoretically, the first band around 530 nm (viz., transverse LSPR) corresponds to electron oscillation perpendicular to the long axis of the NR, and the other one appearing at a longer wavelength (viz., longitudinal LSPR mode) corresponds to the oscillation parallel to the long axis (Fig. 5) (Lu et al., 2009). The anisotropic NPs with disk and triangular prism shape have LSPRs split into distinctive dipole and quadrupole plasmonic modes (Nelayah et al., 2007). Another type of studied metallic nanostructures is Au with nanobelt shapes and presents tunable plasmon resonance (Anderson et al., 2011). Plasmonic nanowires with sub-100 nm rectangular cross sections exhibit strong transverse plasmon peak at visible wavelengths. This type of nanostructures can have applications in plasmonic circuits or nanomedicine. In the case of 2D Au nanoplates, broad charge separation can appear when polarization takes place along their edges. Dipole resonance and in-plane quadrupole modes correspond with the simulated spectrum following the calculations of the discrete dipole approximation (DDA) (Millstone et al., 2005). Hong and coauthors assumed that the surface plasmon resonance (SPR) of Au nanoplates is strongly influenced by the dielectric surroundings and the shift of SPR is of great interest in developing chemical and biological sensors with high efficiency (Hong et al., 2011a, b). 14.1.2.2 Electronic properties Due to the fact that Au nanostructures exhibit good conductivity, they are used as electrodes or are incorporated into electronic devices. Unidimensional nanostructures (1D) have been extensively studied regarding their integration into microdevices/nanodevices. For example, stretchable, conductive circuits and electrodes made of multilayers

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of Au nanosheets have been developed, and the resistivity of each Au nanowires of 350 nm is around 29 Ω nm, value comparable with bulk Au (Moon et al., 2013; Smith et al., 2000). Sun et al. obtained ultrathin Au nanowires (9 nm) and investigated the electronic properties of a single nanowire obtaining good electron conductivity with its resistivity at 260 Ω nm (Wang et al., 2008). 14.1.2.3 Mechanical properties Study of mechanical and structural properties of these nanostructures is important to properly evaluate the performance and their integration in devices. By means of experimental techniques, the metal nanowire strength, elastic modulus, and hardness can be evaluated from modified atomic force microscope or lateral force microscope. Wu et al. developed a standard method to evaluate the mechanical properties of nanowires using a modified atomic force microscope or lateral force microscope (Wu et al., 2005). The authors measured yield strength of Au nanowires (40 nm) and find it is 5.6 GPa, being 10 times higher compared with bulk Au. Likewise, they proved that Au nanowires don’t have a near-perfect elastoplasticity encountered to NPs, instead having a more elastoplastic behavior compared with bulk Au. Lee et al. have evaluated the deformation behavior during the uniaxial loading of [110]-oriented Au nanowires using in situ TEM (Lee et al., 2014). The authors show that the cyclic uniaxial loading presents a reversible plastic deformation by twinning and consecutive detwinning in tension and compression, respectively. Strength and tensile ductility can be modulated through engineering nanoscale twinning in Au nanowires. Wang reported that Au nanowires with angstrom-scaled twins having 0.7 nm in thickness exhibit near-ideal theoretical tensile strength up to 3.12 GPa with a remarkable ductile-to-brittle transition by decreasing twin size (Wang et al., 2013). 14.1.2.4 Stability, chemical reactivity and catalysis The surface structure can be modified depending on the shape and dimensions and can involve distinct stability of 1D and 2D noble nanostructures under unique conditions such as electron irradiation and high temperature. NP chemical reactivity is linked to their surface area. The structure of NPs is compressed up to several thousands of atoms. Individual nanoparticle combines a hybrid electronic structure of both discrete energy levels typical for atoms/molecules and the band structure encountered in metals. By going down to 2 nm, Au and Ag NPs have a substantial loss of their metallic behavior and start to undergo molecular-like transitions under normal conditions. NPs with size below 2 nm do not have continuous band structure compared with bulk Au and will start to show different electronic behavior. Noble metals are considered to be the most stable of all metallic elements, while NPs containing them have proved to possess important catalytic activity.

Applications of metallic nanostructures in biomedical field

Au nanocrystals are one of the most attractive catalysts to facilitate a wide variety of chemical reactions. For example, Grirrane et al. reported that Au NPs supported on titanium dioxide (TiO2) can catalyze the aerobic oxidation of aromatic anilines to aromatic azo compounds with high yields (98%) under mild conditions (Grirrane et al., 2008). Moreover, the catalytic properties of Au nanocrystals depend on their size and shape, as well as the interaction between Au NPs and metal oxide supports (Corma et al., 2013). Many studies reported the influence of particle size and found that the maximum activity at optimum diameter has been reported for CO oxidation, alkane oxidation, and other reactions (Corma et al., 2013; Chen and Goodman, 2006). On the other hand, the reactivity and selectivity of catalyst also depend on its shape and the surface facets (Hong et al., 2012; Wu 2012; Zhou et al., 2012a, b). Wang obtained two-dimensional Au nanosheets with high catalytic activity and stability in the solvent-free selective oxidation of carbon-hydrogen bonds with molecular oxygen (Wang et al., 2015). Recently, dendritic Au nanostructures were fabricated in which graphene oxide was used as a morphology-controlling agent with excellent electrocatalytic activity and could be used for the determination of Fe(III) in real coastal water samples (Han et al., 2017).

14.1.3 Methods of fabrication Generally, metallic nanostructured materials can be obtained by several synthesis methods but divided into two broad categories: physical and chemical routes. The methods of physical synthesis would be the following: (1) high-energy ball milling, (2) wire explosion, (3) arc discharge, (4) inert-gas condensation, (5) laser ablation, and (6) ion sputtering. These physical methods can produce large quantities of materials but with large particle size variation (Sreeprasad and Pradeep, 2013). In chemical methods, nanomaterials are made starting from atoms generated from ions, in solution, and are assembled to make nanomaterials. Several methods come under this category: (1) chemical reduction, (2) electrochemical synthesis, (3) photochemical synthesis, (4) sonochemical routes, (5) solvothermal synthesis, (6) interfacial synthesis, (7) micelles and microemulsions, (8) biological methods, (9) thermolysis, (10) arrested precipitation, (11) hybrid methods, and (12) solvated metal atom dispersion. The shape and size of NPs depend on the method of synthesis. Various chemical technologies were elaborated for the synthesis of noble metal nanostructures using different methods, namely, reduction method (a), Brust-Schiffrin reduction (b), hydrothermal method (c), galvanic replacement reactions (d), photochemical synthesis (e), electrochemical synthesis (f and g), and template-mediated synthesis (h), which can lead to different shapes as can be seen from Fig. 6.

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Fig. 6 Typical TEM/SEM images of noble metal nanostructures obtained by different methods. (Based on Sreeprasad T.S., Pradeep T. 2013. Noble metal NPs. In: Vajtai R. (Ed.), Springer Handbook of Nanomaterials. Springer, pp. 303–388, https://doi.org/10.1007/978-3-642-20595-8_9.)

Applications of metallic nanostructures in biomedical field

14.2 Biomedical applications 14.2.1 Biosensors and detectors Recently, noble metal nanostructures for biosensors have attracted much interest for use as biosensors and biodetectors due to their biocompatibility, chemical stability, electrochemical activity, high electron mobility, ease of synthesis by diverse methods, and high surface-to-volume ratio. Working principle of noble metal nanoparticle-based biosensors/biodetectors is presented in Fig. 7. It is known that the quality of a biosensor depends on their components. For example, the layer (matrix material) between the recognition layer of biomolecule and transducer is correlated to the stability, sensitivity, and shelf-life of a biosensor. Biosensor research aims at “developing miniaturized, integrated systems that can rapidly and inexpensively detect trace amounts of analyte(s) in minute and small volumes with high sensitivity and specificity.” By detecting the pathogens and disease markers from early time, there is an increased chance to improve treatment efficiency and the chances of full recovery. This is applicable especially in cases of cancer or infections (e.g., viral hepatitis and HIV). Among the noble metal NPs, Au nanostructures with nanowire shapes represent excellent nanoelectrode candidates in electrochemical applications (pressure sensors, DNA detector, interconnects, and nanoelectrodes) due to the fact that 70% of the gold atoms are at the surface (Zhang et al., 2014). Garcia obtained sensors based on Ag-loaded hematite (a-Fe2O3) NPs for methyl mercaptan detection at room temperature prepared by the coprecipitation method. Based on Au and Ag NPs, good electronic properties and conductivity (Garcia et al., 2017), as well as the unique spectral properties, make them a material of choice for a variety of electrochemical and colorimetric sensors (Du 2007; Petkova et al., 2012). Moreover, the inclusion of various noble metal NPs with desirable plasmonic and/or electrocatalytic

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Fig. 7 Working principle of noble metal nanoparticle-based biosensors/biodetectors. (From Malekzad H. et al. 2016. Nanotechnol. Rev. 6(3), 301–329.)

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properties in electrospun polymer nanofibers yields to novel hybrid nanoscale systems with synergistic properties and functions. For example, electrospun polymer nanofibers decorated with noble metal nanoparticle (e.g., Au and Ag NPs) can be used in chemical sensing based on surface-enhanced Raman scattering (SERS) and electrochemical sensing applications (Malekzad et al., 2016). Cellulose nanofibers coated with silver NPs were used in SERS analysis to detect thiabendazole pesticides in apples (Liou et al., 2017). Au NPs attached on 3D poly(acrylic acid) (PAA)/poly(vinyl alcohol) (PVA) nanofibrous membrane showed high sensibility for the detection of trace amount of analytes such as 4-aminothiophenol and rhodamine 6G (Liu et al., 2017). Au NPs/poly(vinyl alcohol) nanofibrous composite mats were embedded with horseradish peroxidase (HRP) by electrostatic interactions and used as biosensor substrate materials for H2O2 detection (Wang et al., 2012). This biosensor (HRP-Au NPs/PVA) showed a highly sensitive detection of H2O2 with a detection limit of 0.5 μM at a signal-to-noise ratio of 3.

14.2.2 Drug delivery and nanomedicine Another important application of metallic nanostructures is the promise of targeted, sitespecific drug delivery. Performances of intelligent drug delivery systems are continuously improved with the purpose to maximize therapeutic activity and to minimize undesirable side effects. Au NPs have been frequently used in drug delivery due to their favorable optical and chemical properties, including tunable sizes in the range of 0.8–200 nm, easy surface modification with different functional groups, good biocompatibility, and visible light extinction behavior. These nanostructures can be conjugated with polyethylenimine (PEI) to deliver genes (Thomas and Klibanov, 2003) and be modified and conjugated with suitable proteins/peptides to target the cell nucleus (Tkachenko et al., 2004). Likewise, these NPs can be easily functionalized with various moieties, such as antibodies, peptides, and/or DNA/RNA to specifically target different cells (Sperling and Parak, 2010), and with biocompatible polymers (e.g., polyethylene glycol, PEG) to prolong their in vivo circulation for drug and gene delivery applications (Ghosh et al., 2008).

14.2.3 Germicidal action It is known that the gram-negative bacteria are the main cause of the most severe infections. The main issue is related to multidrug-resistant (MDR) bacteria to drugs, causing every year more than two-thirds of the hundreds of thousands of deaths even in most of developed economies. There are new drugs to treat MDR gram-positive bacteria but essentially none to treat MDR gram-negative bacteria. The most preferred treatment method for bacterial infections was antibiotics due to their cost-effectiveness and powerful outcomes. However, many studies have been reported that widespread use of antibiotics has led to the emergence of multidrug-resistant bacterial strains. In fact,

Applications of metallic nanostructures in biomedical field

superbacteria that are resistant to nearly all antibiotics have recently developed due to abuse of antibiotics. Therefore, attention has been focused on new and exciting nanostructure-based materials with antibacterial activity (Wang et al., 2017). Metal nanostructures, such as Ag, Au, and Zn nanostructures, are the subject of intensive research in science and technology being extensively used as bactericidal and bacteriostatic agents (Silver et al., 2006). So far, Ag NPs have proved to be the most effective against a broad spectrum of microorganisms. Therefore, these NPs can be used in medicine for burning therapy, dental materials, water treatment, lotions, etc. (Rai et al., 2009; Sondi and Salopek-Sondi, 2004). Some authors (Shrivastava et al., 2009) suggested that the activity of Ag NPs against Gram-negative bacteria is concentration-dependent and that the concentration of Ag NPs that prevents bacterial growth is different for each type of bacterium. There are bacteria like Pseudomonas aeruginosa and Vibrio cholerae that have proved to be more resistant to Ag NP exposure than E. coli and Salmonella typhi (Ingle et al., 2008; Tran et al., 2013). However, at concentrations above 5 μg/ml, growth of all bacteria was completely inhibited. The antimicrobial activity was shown to be dependent on the shape of Ag NPs and has found a high activity value for triangular nanoparticle shapes investigated against the gram-negative bacterium E. coli (Pal et al., 2007; Mohanpuri et al., 2008). Other works demonstrated the antimicrobial activity of Ag NPs synthesized by tea leaf extract against the pathogenic V. harveyi and its protective effects on Feneropenaeus indicus in shrimp culture environments (Vaseeharan et al., 2010). Au NPs are also highly investigated for the bactericidal activity, which involves inactivation of bacteria by interaction with functional groups on the bacterial cell wall (Niemirowicz et al., 2014). The antimicrobial activity of Au nanostructures may be attributed to their toxic effects on bacterial cells. Au NPs showed higher activity against gram-negative bacteria than against gram-positive bacteria. Au NPs at room temperature using Solanum nigrum (S. nigrum) leaf extract were used as reducing agent (Muthuvel et al., 2014). These nanostructures significantly inhibited the growth of medically important pathogenic gram-positive bacteria (Staphylococcus saprophyticus and B. subtilis) and gram-negative bacteria (E. coli and P. aeruginosa) and could have a high potential for use in the preparation of drugs used against various diseases and also promising candidate for many medical applications. Recently, Shamaila and coauthors reported data getting Au NPs with 6–40 nm size showing high antibacterial activity compared with other studies (Shamaila et al., 2016; Zhou et al., 2012a, b; Prema and Thangapandiyan, 2013; Ali et al., 2011; Belliraj et al., 2015).

14.2.4 Other biomedical applications Except the already presented biomedical applications of metal NPs, remarkable progress was made also on applications such as fluorescent biological labels, cancer therapy, MRI contrast enhancement, and phagokinetic studies.

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14.2.4.1 Fluorescent biological labels Recent advances in nanotechnology generated a new class of fluorescent labels and fluorescent metal nanoclusters, for example, Au and Ag. These nanoclusters represent an important class of materials that connects the atomic and nanoparticle behavior in metals. Compressing up to hundred atoms, their sizes equal the Fermi wavelength of electrons, leading to molecule-like behavior including discrete electronic states and size-dependent fluorescence (Shang et al., 2011). Fluorescent metal nanoclusters have distinct set of features, such as ultrasmall size and strong photoluminescence, combined with good photostability, large Stokes shift and high emission rates, and biocompatibility, making them ideal fluorescent labels for biological applications (Zheng et al., 2012; Wolfbeis 2015). As a plus, in the last years, a new class of ultrasmall, biocompatible fluorophores by the synthesis of water-soluble fluorescent metallic nanostructures with different ligands and tunable emission colors was established. In the work of Shang et al., synthesis strategies developed for these fluorescent metallic nanostructures are summarized, highlighting especially the advances in biological imaging and in the application to the detection of various analytes (i.e., metal ions, proteins, and nucleic acids) (Shang et al., 2011). 14.2.4.2 Cancer therapy It is well known that NPs having small dimensions (<100 nm) possess high vascular permeability and decrease lymphatic function of tumors. By attaching these NPs to cancer cell, targets with noninvasive implementation can increase cellular uptake efficiency, selectivity, and localization in tumor cells and tissues. By incorporating metallic NPs into tumors, as light-activated heating nanosystems, one can allow high heat administration in the tumor area in hyperthermia treatment by lowering the negative effect on the surrounding healthy tissue. The photothermal therapy via heating (hyperthermia) is an efficient way to eliminate the cancer cells or tumor tissue (Huang and El-Sayed, 2011). Among the different types of NPs, Au has been highlighted in the field of the cancer research due to their highly improved and tunable optical properties. Au NPs can assemble in the tumor areas via the passive mechanism known as “enhanced permeability and retention effect” (Maeda 2001) or by active targeting through chemical conjugation in cancer cells (monoclonal antibody and folic acid for cancer treatment). By using systemic route, NPs must fulfill several major prerequisites in order to accumulate in the target cells. Among these prerequisites, the following can be included: (a) Their outer layer must be inert in order to bypass the activation of the reticuloendothelial system; (b) their size must be around 100 nm in order to brake the blood vessels and localize the affected cells; and (c) after the establishment in the pathological cells, the NPs must overcome different obstacles including (i) cell surface binding; (ii) cellular uptake; (iii) escape from lysosomes/endosomes; and

Applications of metallic nanostructures in biomedical field

(iv) association with a particular subcellular location, such as nuclei or mitochondria (Kodiha et al., 2015). As an example, Au nanoshells having diameters ranging between 100 and 300 nm have SPR peaks in the NIR region. In one early study, human breast carcinoma cells incubated with gold nanoshells were found to determine photothermally induced morbidity by irradiating with NIR light. Stern et al. showed that 93% of tumor necrosis and regression was observed in high quantities of nanoshell (8.5 mL/g) administration (Stern et al., 2008). 14.2.4.3 MRI contrast enhancement NPs containing metal and metal alloy are today considered as novel particulate contrast agents. These types of NPs are known for their exceeding high saturation magnetism by comparing them with oxides even if their stability and potential toxicity in biomedical applications have to be taken in consideration. Metallic Fe NPs synthesized by Hadjipanayis et al. (2008) have higher magnetic properties compared with iron oxide NPs. The analysis of the MRI contrast effect (measured at 1.5 T) indicates that the pristine Fe NPs are strong contrast agents due to their higher relaxivity (129 mM1 s1) of pristine Fe NPs, compared with IONPs with a similar size (Hadjipanayis et al., 2008). Seo and coworkers have reported an improvement on metallic alloy NPs for MRI contrast. They prepared FeCo/single-graphitic-shell nanocrystals and measured their magnetic characteristics as MR contrast agents. They reported a high relaxivity of FeCo NPs at 1.5 T (R1 ¼ 70 mM1 s1 and R2 ¼ 644 mM1 s1 for 7 nm FeCo NPs) having high Ms (215 emu g1) (Seo et al., 2006). Likewise, FePt NPs exhibit high R2 relaxivity (122.6 mM1 s1 for 4 nm FePt NPs at 0.5 T) being superior to T2 contrast agents (Hao et al., 2010). 14.2.4.4 Phagokinetic studies It is crucial to have a good understanding on how cellular motility can influence tissue development, immune processes, and wound healing. For evaluating cell motility, microscopy techniques are usually used, but it is difficult and time- and resourceconsuming to follow and obtain a quantitative measurement of cell migration (Nogalski et al., 2012). Developing simple methods that allow performing such measurements of cell motility in a cost-effective way leaded to the development of phagokinetic track motility assay. This analysis exploits the moving characteristic of cell to clear Au particles from its way to induce a quantitative approximation on a colloidal Au-coated glass plate. By using free available software, multiple tracks can be monitored for each treatment to fulfill statistical demands. The analysis can be used to evaluate motility of various cell types, among them being cancer cells, fibroblasts, neutrophils, skeletal muscle cells, keratinocytes, trophoblasts, endothelial cells, and monocytes (Nogalski et al., 2012).

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14.3 Conclusive remarks Metallic nanostructures are an interesting class of nanomaterials with various attractive properties including low toxicity and possibility to be obtained in different shapes and sizes (e.g., ultrasmall size) that make them suitable for a wide variety of biological applications, such as intracellular drug delivery, ultrasensitive molecular diagnostics, and image-guided therapy, just to mention a few. Taking in consideration the recent advances in the synthesis of metallic NPs by a multitude of approaches, a significant progress was made toward the fundamental understanding of the specific properties directly correlated to the development of applications in biomedical field. Within this context, this chapter presented a short overview of the most used metallic NPs and their biomedical applications, giving a very narrow opening to the huge range of their potential achievements. Nevertheless, despite their already proved potential future for this field, an in-depth understanding of their interactions with various biological compounds, cells, tissues, or bioenvironment is still necessary for a safe use. However, taking in consideration the continuous progress in design and synthesis of multifunctional metal nanostructures, their spreading use in the near future of nanobiomedicine application is expected.

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