Nanoparticles: synthesis and applications (2024)

7.2.1. Chemical Reduction

Chemical reduction is an effective wet-chemical method for making zero-valent nanoparticles based on chemical-reducing aqueous salts of metals, such as silver nitrate (AgNO₃) in the case of synthesis of silver nanoparticles, for instance. To reduce the precursor metal salt, at least one reducing agent is used to produce electrons for metal ions that reduce them to become zero-valent. Commonly used reductants are borohydride, citrate, and ascorbate. Reduced nanoparticles are stabilized by a stabilizing agent. An example of a stabilizing agent is cetyltrimethylammonium bromide [(C₁₆H₃₃)N(CH₃)₃Br; CTAB], which is widely used in gold nanoparticle synthesis. The stabilizing agents can be reducing agents themselves, such as citrate of sodium in making silver nanoparticles (Shenava Aashritha, 2013). For more details the reader is referred to the review paper by Alaqad and Saleh (2016) and references therein.

7.2.2. Coprecipitation

Precipitation is the carrying down by a precipitate of soluble substances under certain conditions (Patnaik, 2004). Generally, when the concentration of substances reaches supersaturation, a nucleation suddenly appears in solution. The nucleation will be grown by the diffusion on to its surface which then becomes nanoparticles. During the growth, the nucleation needs to be slowed down in order to get uniform nanoparticles. Several methods can be listed as precipitation: coprecipitation, microemulsion/inverse microemulsion, polyol, etc. Coprecipitation is a convenient way to synthesize Fe₃O₄ nanoparticles (Lu et al., 2007, Quy et al., 2013, Dung et al., 2016, Khalil, 2015, Mascolo et al., 2013). The mixture of two chloride salts of FeCl₂ and FeCl₃ with 1:2 molar ratios of Fe²⁺/Fe³⁺ was vigorously stirred and kept at 70°C before NH₄OH was added resulting in the black color precipitation. The Fe₃O₄ nanoparticles were collected after purifying through magnetic separation with ethanol and distilled water several times to decontaminate the residual chemicals. By modifying the pH and ion concentration in solution, the size of nanoparticles can be controlled.

7.2.3. Seeding

The seeding method was discovered by Frens, 1972, Frens, 1973, where nanoparticles are grown by the reduction of salt in aqueous solution which contains seed nanoparticles. In this method, the stabilizers are used to control the size and shape of growing nanoparticles. This method was developed over the years using various types of seeding, reductant agents, and stabilizers (Xu et al., 2007, Han et al., 2009, Perrault and Chan, 2009, Ziegler and Eychmuller, 2011, Rioux and Meunier, 2015). For example, the method which was developed by Perrault and Chan in 2009, reduces HAuCl₄ in gold nanoparticles seed-contained aqueous solution using hydroquinone. The gold nanoparticle seed can act in conjunction with hydroquinone to catalyze the reduction of gold ions into their surface. If the stabilizer is citrate, typically the seed nanoparticles were prepared by the citrate method. Using this method, the size of nanoparticles can be grown at least 30–300nm.

7.2.4. Microemulsion and Inverse Microemulsion

Microemulsion is a popular method to synthesize nanoparticles, where microemulsions are an isotropic and thermodynamically stable mixture of “oil,” water, and surfactant, or in combination with a cosurfactant. The basic types of microemulsions are direct (oil dispersed in water) and reverse (water dispersed in oil). The small drops of aqueous phase (micelles) may contain salts and/or other ingredients, and the “oil” may actually be the mixture of the surfactants. The reaction to form nanoparticles also can be realized when the micelles mix with each other and the growth of the nanoparticles is controlled by the surfactants in “oil” (Lopez-Quintela and Rivas, 1993). Using this method, the Fe₃O₄ nanoparticles can be synthesized (Feltin and Pileni, 1997) and also can be functionalized with a silica layer. This method can also be used to prepare Fe₃O₄/Au core–shell nanoparticles to prevent the oxidation of magnetic nanoparticles (MNPs) as well as form the biocompatibility (Boutonnet et al., 1982). Furthermore, the inverse microemulsion method is the simplest way to produce multifunctional nanoparticles by creating the silica matrix in aqueous phase, which will fix the single particles inside (Dung et al., 2016).

7.2.5. Hydrothermal Method

In the hydrothermal method, the crystals of nanoparticles are grown by heterogenous reaction under conditions of high temperature and high pressure from substances which are insoluble at normal temperature and pressure (Byrappa and Adschiri, 2007). The crystal growth is carried out in an apparatus consisting of a steel pressure vessel called an autoclave, in which nutrients are supplied along with water. Hydrothermal synthesis is usually carried out below 300°C. The critical condition gives a favorable reaction field for formation of nanoparticles, owing to the enhancement of the reaction rate and large supersaturation based on the nucleation theory. This method has been used to synthesize metal oxide nanoparticles in supercritical water (Hayashi and Hakuta, 2010), metal nanoparticles (Kim et al., 2014), and semiconductor nanoparticles (Bui et al., 2014, Hoa et al., 2011, Williams et al., 2007).

7.2.6. Sonoelectrodeposition

Sonoelectrodeposition is a useful synthesis method for nanoparticles and has been successfully applied to prepare metallic nanoparticles such as FePt and CoPt (Luong et al., 2011, Nam et al., 2012; and references therein). Sonoelectrodeposition is a technique combining the advantages of electrodeposition and mechanical waves of ultrasound to produce metallic nanoparticles (Zhu et al., 2000). In Section 7.4 we discuss silver nanoparticles. One of main disadvantages of the conventional synthesis methods for silver nanoparticles, including chemical reduction, is the presence of unexpected toxic ions in the final products. The toxic ions in the product are mostly the ions of the silver precursor, such as nitrate and thiolsulfate. A good silver precursor such as silver acetate can be used (Irzh et al., 2007), however, this chemical is expensive and manipulation is difficult under ambient conditions. Tuan et al. (2011) reported a modified sonoelectrodeposition technique to obtain silver nanoparticles in a nontoxic solution. The modification is that a silver plate was used as the cathode instead of silver salts thus allowing the avoidance of unexpected ions from the salts.

7.3.1. Functionalization of Nanoparticles

Functionalization of nanoparticles can be defined as the addition of a chemical functional group on their surface in order to achieve surface modification that enables their self-organization and renders them compatible (Subbiah et al., 2010). The most widely used functional groups are amino, biotin, steptavidin, carboxyl, and thiol groups (Bruce and Sen, 2005). The main purpose of functionalizing nanoparticles is to cover their surface with a molecule that possesses the appropriate functionality needed for the designed application. For many biomedicine applications, nanoparticles need to be functionalized in order to conjugate with biological entities such as DNA, antibodies, and enzymes. For more details on the functionalization of nanoparticles, its methods, and class, as well as its implications in biomedical sciences, the reader may be referred to, for instance, the review by Subbiah et al. (2010).

We focus here on the functionalization of gold nanoparticles and MNPs discussed in Section 7.4. For application in detecting breast cancer cells, gold nanoparticles synthesized by a chemical reduction were functionalized with 4-aminothiolphenol (4-ATP, sometimes called p-aminothiolphenol [PATP]). For basal cell carcinoma (BCC) detection, different amounts of 4-ATP solutions were added to gold nanoparticles coated by CTAB. CTAB on the surface of gold nanoparticles was replaced by 4-ATP to form gold nanoparticles functionalized with 4-ATP (Au-4ATP). Fe₃O₄ nanoparticles were functionalized using 3-aminopropyl triethoxysilane (APTS). APTS is a bifunctional molecule, an anchor group by which the molecule can attach to free –OH surface groups. The head group functionality –NH₂ is for conjugating with biological objects. The amino-NP is ready to conjugate with the DNA of the herpes virus and with the antiCD4 antibody.

7.3.2. Silica Coating of Magnetic Nanoparticles

Maintaining the stability of MNPs for a long time without agglomeration or precipitation is an important issue (see, for instance, Lu et al., 2007). The protection of MNPs against oxidation by oxygen, or erosion by acid or base, is necessary. The common method is protection by a layer which is impenetrable, so that oxygen, for example, cannot reach the surface of the particles. It is noted that the stabilization and protection of particles are often closely linked with each other. One of the ways to protect MNPs is coating them with silica. A silica shell not only protects the magnetic cores, but can also prevent direct contact of the magnetic core with additional agents linked to the silica surface that can cause unwanted interactions. The coating thickness can be controlled by varying the concentration of ammonium and the ratio of tetraethylorthosilicate (TEOS) to H₂O. The surfaces of silica-coated MNPs are hydrophilic, and are readily modified with other functional groups (Ulman, 1996). Quy et al. (2013) and Hieu et al. (2017) have prepared Fe₃O₄/SiO₂ nanoparticles by coating MNPs with silica using TEOS.

7.3.3. Multifunctional Nanoparticles

Recently, multifunctional nanoparticles have gained wide attention due to their advantages in the goal of applications. Potentially, multifunctional nanoparticles which include individual physicochemical properties of nanoparticles, such as plasmonic metallic nanoparticles, photoluminesable semiconductor nanoparticles or quantum dots, and MNPs, can complement some of the limitations of conventional applications using single nanoparticles, particularly in biomedicine. For example, bifunctional nanoparticles which are composed of MNPs and metallic nanoparticles not only can be used as optical labels in bioimaging, diagnosis and therapy, but also allow some biomolecules to be tagged and separated, together with targeted drug delivery and magnetic resonance imaging under the induction of an external magnetic field (Cai et al., 2014, Sotiriou et al., 2011, Ilovitsh et al., 2015, Giani et al., 2012, Sun et al., 2006). Multinanoparticles can be in core–shell structures or in the complex structures which are a combination of at least two types of single nanoparticles.

Core–shell structured nanoparticles can be classified into inorganic/inorganic, inorganic/organic, organic/inorganic, organic/organic, core/multishell, and movable core/hollow shell nanoparticles (Chaudhuri and Paria, 2012). The synthesis approaches to nanoparticles can be divided into top-down and bottom-up methods. The top-down approaches often use externally controlled tools to cut, mill, and shape materials into the designed nanoscale structures, for example, lithography methods, laser beams, mechanical techniques. The bottom-up approaches exploit the chemical properties of the molecules to cause them to self-assemble to become nanoparticles, such as chemical synthesis discussed above. The bottom-up methods can produce much smaller nanoparticles and are cost-effective, compared to the top-down methods. Both methods are used in the synthesis of core–shell structured nanoparticles. However, since ultimate control is needed for achieving a uniform coating of the shell, the bottom-up approach has proven more suitable. A combination of the two methods can also be utilized, for example, core particles synthesized by the top-down method but then coated by the bottom-up approach in order to maintain precise shell thickness. In general, various methods were used to prepare core–shell nanoparticles. For example, to produce iron oxide@Ag core–shell nanoparticles, several methods were used including impregnation (Liu et al., 2012), surface functionalization followed by deposition (Liu et al., 2010), solvo-thermal reduction (Liu and Li, 2009), and chemical reduction (Hu et al., 2010, Sun et al., 2012). Reducing agents such as glucose and sodium borohydride are used for the reduction of silver salts, and the surface functionalization of iron oxide nanoparticles by different surface-modifying agents is required. Hu et al. (2010) used glucose for the reduction of Ag(NH₃)₂⁺ to Ag, which is adsorbed onto the surface of silica-coated iron oxide which is prepared by the coprecipitation method. Liu et al. (2010) have reported the surface functionalization of Fe₃O₄ surface by APTS followed by reduction of AgNO₃ using sodium citrate and sodium borohydride. Sun et al. (2012) have used sodium borohydride as the reducing agent for the reduction of Ag(NH₃)₂⁺ to obtain Fe₃O₄@Ag core–shell nanoparticles. Dung et al. (2016) used ultrasound to assist in the reduction of silver ions following this strategy. Liu and Li (2009) have used dimethylformamide as the reducing agent during solvo-thermal synthesis of γ-Fe₂O₃@Ag microspheres. In parallel, one-step synthesis using thermal decomposition of silver acetate in the presence of iron oxide microspheres is also applicable and does not require the addition of any external reducing agent or surface modification of iron oxide (Sharma and Jeevanandam, 2013). To control the overall size and the shell thickness, a microemulsion method, where water droplets act as a template or nanoreactor, is preferable to a bulk medium.

Other types of multifunctional nanoparticles are the complex structures of materials, which is the combination of at least two types of single nanoparticles. Similar to a core–shell structure, the nanomaterials used in complex structures can be categorized by two types of nanoparticles: organic, which includes micelles, liposomes, nanogels, dendrimes, and inorganic, which includes magnetic, semiconductor, lanthanide, and metallic nanoparticles. The combination can be achieved in many ways, however it is needed to fulfill the requirements of the applications. For example, the multifunctional nanoparticles should have superparamagnetic properties in order to be applied in drug delivery and DNA separation, and they should have plasmonic properties in order to be applied as biolabeling agents, and they should also be biocompatible. The simplest combination which fulfills these requirements is the complex of Fe₃O₄ nanoparticles with superparamagnetic properties and Ag nanoparticles with plasmonic properties in a matrix of SiO₂ which provide the biocompatibility and also improve the stability of Ag and Fe₃O₄ nanoparticles. Surface activator polyvinylpyrrolidone (PVP) was used to control the size of silver nanoparticles, which were synthesized by a wet-chemical reduction method with NaBH₄ as reductant. The synthesized nanoparticles were coated with 4-ATP to form functionalized Ag-4ATP nanoparticles. These functionalized nanoparticles were combined with the above-prepared Fe₃O₄ nanoparticles by an inverse microemulsion method to form multifunctional nanoparticles (Dung et al., 2014). In this method, the microemulsion was created by mixing the hydrophilic phase of the mixture of Ag-4ATP and Fe₃O₄ solution and the hydrophobic phase of toluene. The mixture of Ag-4ATP/Fe₃O₄ with different mass rates was moderated under a sonic bath for 2hours, then TEOS was added to react with water in solution as in reaction (7.1). The formed SiO₂ coating layer in amorphous conformation covers both initial particles.

The multifunctional composites were also successfully prepared in a complex form using an ultrasound-assisted chemical method (Dung et al., 2017a). MNPs were firstly prepared by the coprecipitation method, then coated by a silica layer. The silica layer, after that, was modified by APTS. Silver ions were then absorbed on the surface of APTS-functionalized silica-coated MNPs. Under the ultrasonic wave of 200W acting for 60minutes these silver ions were reduced by sodium borohydride. In XRD characterization after synthesis, the relative intensity of diffraction peaks of silver crystals increases when the atomic ratio of silver to iron increases from 0.208 to 0.455. In parallel, all nanoparticles showed superparamagnetic properties with the saturation magnetization decreased from 44.68 to 34.74emu/g with increasing silver:ion atomic ratio. The coexistence of strong surface plasmon absorption at 420nm and these superparamagnetic properties make these particles promising for biomedical applications.

In another way, MNPs can be directly functionalized with an amino group without coating by silica layer (Dung et al., 2017b). In this way, Fe₃O₄-ZnO multifunctional nanoparticles were successfully synthesized in aqueous solution by ultrasound-assisted thermolysis. The as-prepared Fe₃O₄ MNPs were modified by APTS to have free amine (−NH₂) groups on their surface. Zn²⁺ ions then were added and stirred to adsorb onto the surface of Fe₃O₄-NH₂ nanoparticles in alkaline solution at pH 11. The solution was decomposed through thermolysis in an ultrasound bath. The characterization shows that photoluminescence of Fe₃O₄-ZnO multifunctional nanoparticles was enhanced in visible light at a wavelength of 565nm to allow detection, labeling, diagnosis, and therapy in biomedicine. Furthermore, they exhibit superparamagnetic properties of Fe₃O₄ with high saturation magnetization, which can be used for separation applications in biomedicine under an external magnetic field.

7.4.1. Application of Gold Nanoparticles for Breast Cancer Cell Detection

Gold nanoparticles are promising candidates for cell imaging and tumor-targeted drug delivery (Sokolov et al., 2003, Paciotti et al., 2004, Jain, 2005), breast cancer diagnosis, and targeted therapy (Yezhelyev et al., 2006). Being a member of the epidermal growth factor receptor tyrosine kinase family, HER2 is found to be overexpressed in 20%–30% of human breast cancers (Harries and Smith, 2002; and references therein). Therefore, HER2 is an interesting target for breast cancer therapies. Anti-HER2 (trastuzumab, trade name Herceptin) is a humanized monoclonal antibody (mAb) designed specifically for antagonizing the HER2 function. Quynh et al. (2011) and Nguyen et al. (2015) have synthesized gold nanoparticles by a chemical reduction then applied them for imaging KPL4 breast cancer cells after conjugating them with trastuzumab.

Fig. 7.1shows the bright-field and dark-field microscopy images of breast cancer cells after being incubated with gold nanoparticles nonconjugated with trastuzumab as well as conjugated with trastuzumab (Nguyen et al., 2015). As can be seen from Fig. 7.1, when the gold nanoparticles were not conjugated with trastuzumab, the dark-field image showed no signal of the gold nanoparticles (A₂). When the gold nanoparticles were directly conjugated with trastuzumab, the gold nanoparticles were bound onto cancer cells and these cancer cells were clearly observed in the dark-field image (A₄) through the scattering light from the gold nanoparticles. When the 4-ATP functionalized gold nanoparticles (amino-gold nanoparticles) were covalently conjugated with trastuzumab through l-ethyl-3-(3-dimethylaminopropyl) ethylcarbodiimide (EDC) connection, the gold nanoparticles also concentrated on the cancer cells, but these cancer cells were observed with slightly lower intensity in the dark-field image (A₆) compared to those in image A₄. Nguyen et al. (2015) pointed out, however, that the gold nanoparticles directly conjugated with trastuzumab could be stored in a freezer for only about 2 weeks before they lost their activity, while the gold nanoparticles covalently conjugated with trastuzumab were stable with storage for about two months.

7.4.2. Basal Cell Carcinoma Fingerprinted Detection

Skin cancer is the most common cancer in humans and its incidence is increasing (Baxter et al., 2012). Worldwide, BCCs constitute about 74% of skin cancer cases (NCIN, 2013). Among the treatments for “high-risk” BCCs (i.e., BCCs on the face and neck, or recurrent BCCs), Mohs micrographic surgery (MMS) is the most efficient (Mohan and Chang, 2014). This procedure helps to maximize the removal of tumor cells, while spares as much healthy tissue as possible. However, the need for a pathologist or specialized surgeons to diagnose frozen sections during surgery has limited the wider use of MMS, which leads to cases of inappropriate inferior treatment. Frozen-section histopathology also requires arduous and time-consuming procedures, increasing the costs compared to standard methods of BCC excision.

For skin cancer diagnosis, Raman spectroscopic imaging is a promising technique, because of its high sensitivity to molecular and structural changes associated with cancer. However, raster scanning Raman mapping requires long times for data acquisition, typically days for tissue specimens of 1cm×1cm. Recently, multimodal spectral imaging based on Raman spectroscopy and tissue autofluorescence was used to reduce the BCC diagnosis time to only 30–60minutes, which becomes suitable for use during MMS (Kong et al., 2013, Takamori et al., 2015).

An alternative method that could allow to reduce data acquisition and BCC diagnosis times during MMS is surface-enhanced Raman spectroscopy (SERS). It was discovered that strongly increased Raman scattering signals can be obtained in the very close vicinity of metal nanostructures, which are mainly due to resonances between optical fields and the collective oscillations of the free electrons in a metal. Thus SERS has attracted great interest in the biolabeling field because significant enhancement of the labeling signals of molecular vibrations on the metallic nanoparticles surface can be obtained. Quynh et al. (2016) studied surface-enhanced Raman (SER) signal of 4-ATP that was linked to the surface of gold nanoparticles conjugated with skin carcinoma cell antibody BerEP4. Gold nanoparticles with sizes ranged from 2 to 5nm were prepared by a wet-chemical method using CTAB. The Au-4ATP-antibody solutions were dropped on the surface of the tissue sample and the SER scattering signals were collected and analyzed. Fig. 7.2shows the fingerprinted landscape of SER signals of Au-4ATP-antibody on a BCC tissue. Fig. 7.2A shows the colored image of a Gram-stained tissue, where the cancer cell area may be the dark-colored regions, for example, region A1, A2. However, the result of diagnosis essentially depends on the subjective decision of the pathologists because this nonspecific method may lead to misinterpretation of noncancer regions as cancer ones. Fig. 7.2B shows a bright-field microscopy image of the tissue, where B1 region corresponds to a hair follicle position, and B2 does not, although B1 and B2 have the same position on the tissue as regions A1 and A2 in Fig. 7.2A. Fig. 7.2C shows the result of an SER signal obtained by the principal component analysis (Quynh et al., 2016). Fig. 7.2D shows the result of the SER signal analyzed using only the intensity of SER peaks at 1075cm⁻¹. The Au-antibody colloids are oriented close to the BCC surface by the antigen–antibody coupling. The carcinoma sections act as a dock where a high concentration of Au-4ATP-antibody particles is distributed, then the SER peak intensity at 1075cm⁻¹ will be higher in these areas. InFig. 7.2C, the colored areas such as C1 and C2 can be considered as cancer regions. However, in Fig. 7.2D the area D1 does not show the high intensity of the peak at 1075cm⁻¹, while the others, such as the D2 area, indicate very high intensity of the peak at 1075cm⁻¹. From Fig. 7.2, only A2, B2, C2, and D2 regions can be definitely considered as the cancer areas, while A1, B1, C1, and D1 may assigned as the position of hair follicles where the cell concentration is higher than in other parts. Quynh et al. (2016) pointed out that, while the whole SER map collecting time should be longer than 2hours (the collecting time of each spectrum was nearly 5seconds), the fingerprinted image using peak height at 1075cm⁻¹ can be observed in around 5minutes. Hence, this method may represent a solution for quick diagnosis, even during operation.

7.4.3. Antibacterial Test Using Silver Nanoparticles

Silver nanoparticles (AgNPs) are commonly utilized nanomaterials due to their antibacterial properties, high electrical conductivity, and unique optical properties that can be used in various applications (Sondi and Salopek-Sondi, 2004). It is believed that the high affinity of Ag toward sulfur or phosphorus is the key element of its antibacterial property. As sulfur and phosphorus are found in abundance throughout cell membranes, AgNPs react with sulfur-containing proteins inside or outside the cell membrane, which in turn affects cell viability (Pal et al., 2007, Elechiguerra et al., 2005). Another theory proposed that Ag⁺ ions released from AgNPs can interact with phosphorus moieties in DNA, resulting in inactivation of DNA replication, or can react with sulfur-containing proteins to inhibit enzyme functions (Sharma et al., 2009). These properties allow the incorporation of AgNP into various matrices such as activated carbon (AC), polymer networks, textiles, and wound dressing materials (Sedaghat and Nasseri, 2011).

Many approaches have been developed to obtain AgNP of various shapes and sizes, including chemical reduction, laser ablation, gamma irradiation, electron irradiation, chemical reduction by inorganic and organic reducing agents, photochemical method, microwave processing, thermal decomposition of Ag oxalate in water and in ethylene glycol, and sonoelectrochemical method (see references in Tuan et al., 2011). As pointed out in Section 7.2.6, one of main disadvantages of those methods is the presence of unexpected toxic ions in the final products. Tuan et al. (2011) report a modified sonoelectrochemical technique to obtain AgNP in a nontoxic solution. The silver particles are then directly loaded on AC produced by thermal activation of coconut husk. Here we concentrate to their work on the antibacterial properties of AgAC examined by inhibition growth of Escherichia coli. Fig. 7.3shows the quantitatively antibacterial study of AgNP in Luria-Bertani (LB) broth. It presents the dynamics of E. coli growth in only LB broth (negative control), TSC control [LB broth supplemented with 120µL trisodium citrate (TSC) solution], and AgNP antibacterial tests (LB broth supplemented with AgNP of concentration from 2 to 200µg/mL). In this figure, OD₅₉₅ represents optical density at 595nm (1 optical density at 595nm, OD₅₉₅, equals the concentration of 1.7×10⁹ cells/mL). The initial number of E. coli inoculated into 2mL LB medium of the tested tube was 1.7×10⁶ cells, giving the final bacterial concentration of 8.5×10⁵ cells/mL. It is observed that E. coli grew normally in the negative control and the TSC control. After 30hours in the TSC control, the concentration of E. coli (OD₅₉₅=2.5) is higher than that in the negative control (OD₅₉₅=1.5) which suggests that TSC was not toxic to E. coli and may be even enabled for the growth of the bacteria. With the presence of AgNP, the situation is different because of the well-known antibacterial property of AgNP (Kim et al., 2007). When AgNP concentration was 2µg/mL, the result is similar to that of the negative control because the low value of AgNP could not inhibit bacterial growth. With a higher AgNP concentration, the inhibitory effect appeared within 8hours even at a low AgNP concentration of 4µg/mL. Fig. 7.3 clearly shows that, with the concentration of AgNP>16µg/mL, the E. coli growth was inhibited.

7.4.4. Magnetic Nanoparticles

MNPs are of great interest in biomedicine applications. In the applications described below these nanoparticles were synthesized by the coprecipitation method.

7.4.5. Applications of Multifunctional Nanoparticles

Multifunctional nanoparticles are gradually attracting more and more attention because of their ability to combine numerous properties, such as electronic, magnetic, optical, and catalytic. They are highly functional materials with modified properties which can be quite different from those of the individual materials. The properties of core–shell nanoparticles can be modified by changing either the constituting materials or the core-to-shell ratio (Oldenburg et al., 1998). Multifunctional nanoparticles show distinctive properties of the different materials employed together to meet the diverse application requirements. The purpose of the functionalization is manyfold, such as surface modification, the ability to increase the functionality, dispersibility, and stability, controlled release of the single nanoparticles, reduction in consumption of materials, etc. Applications of different multifunctional nanoparticles are summarized in review articles by Karele et al. (2006), Seleci et al. (2016), Jia et al. (2013), and Bao et al. (2013). The multifunctional nanoparticles are widely used in various applications such as pharmaceutical applications (Caruso, 2001), biomedical (Balakrishnan et al., 2009, Salgueirino-Maceira and Correa-Duarte, 2007), catalysis (Daniel and Astruc, 2004, Phadtare et al., 2003), electronics (Kortan et al., 1990, Qi et al., 1996), enhancing photoluminescence (Mews et al., 1994, Kamat and Shanghavi, 1997), creating photonic crystals (Scodeller et al., 2008), etc. Especially in the biomedical field, these nanoparticles are used for bioimaging (Laurent et al., 2008, Babes et al., 1999, Dresco et al., 1999), controlled drug release (Dresco et al., 1999), targeted drug delivery (Laurent et al., 2008, Gupta and Gupta, 2005, Dresco et al., 1999, Yan et al., 2009), cell labeling (Laurent et al., 2008, Jaiswal et al., 2003, Michalet et al., 2005), and tissue engineering applications (De et al., 2008). For instance, core–shell nanoparticles have attracted considerable attention in clinical and therapeutic applications (Hirsch et al., 2003, Loo et al., 2004). Core–shell nanoparticles, which are strong absorbers, can be used in photothermal therapy, while those which are efficient scatterers can be used in imaging applications. Silica core–gold shell nanoshells, a novel core–shell nanostructure, which either absorb or scatter light effectively, can be designed by varying their core-to-shell ratio (Loo et al., 2004). In imaging applications of core–shell nanoparticles, they can be conjugated with specific antibodies for diseased tissues or tumors. When conjugated nanoparticles are inserted in the body, they get attached to diseased cells and can be imaged. In parallel, when the tumor has been located, resonance wavelength absorption of the core–shell nanoparticles will lead to localized heating of the tumor and it is destroyed. In other words, the imaging and photothermal therapy can be carried out together with core–shell or multifunctional nanoparticles. In drug-delivery systems using core–shell nanoparticles, the drug can be encapsulated or adsorbed onto the nanoparticle surface (Sparnacci et al., 2002) via a specific functional group or by an electrostatic stabilization technique. The nanoparticles will come into contact with the biological medium, and then direct the drug. For instance, the enzyme- and antibody-conjugated core–shell nanoparticles, which are strong absorbers with gold shells, can be embedded in a matrix of the polymer, such as nisopropylacrylamide (NIPAAm), and acrylamide (AAm) (West and Halas, 2000). These polymers exhibit a melting temperature which is slightly above body temperature. If the core–shell nanoparticles absorb heat from the illumination with resonant wavelength, the heat will transfer to the local environment, then cause collapse of the polymer matrix and release of the drug. Furthermore, when the core is MNPs, the core–shell nanoparticles with the bifunction of magnetic and gold nanoparticles can drive the drug and kill the tumor under the external magnetic field as well as by the irradiation of resonance wavelength. The usual methods of tumor treatment, such as chemotherapy or radiotherapy, have various side effects such as substantial loss of hair, lack of appetite, diarrhea, etc. The process of attacking the tumor also leads to the loss of many healthy cells. Core–shell or multifunctional nanoparticles offer an effective and relatively safer strategy to cure these ailments by significantly reducing the amount of chemicals or radiation using local treatments.

Another strategy of using multifunctional nanoparticles is using multiple types of nanoparticles in one application, such as in fast DNA diagnosis (Quynh et al., 2014). This fast DNA kit created from NH₂-modified SiO₂-coated Fe₃O₄ nanoparticles and highly fluorescent Mn-doped ZnS nanoparticles in a sandwich structure, which can be seen in Fig. 7.6. The sandwich configuration attached the fluorescent particles to the docking matrix of MNPs with the complementary hybridization of the detector probe–target–capture probe structure. In one side of this sandwich structure, SiO₂-coated Fe₃O₄ nanoparticles, which were modifed by the NH₂ group, were employed as a docking matrix. The docking matrix was linked with a capture probe oligonucleotide chain, which specifically identifies the target DNA. In the other side of the sandwich, the detector probe formed by the signaling semiconductor nanoparticles contacted with another oligonucleotide chain. This sandwich configuration was applied to detect DNA of EBV using separation function of MNPs and the signaling function of semmiconductor nanoparticles. The kit firstly was stored as three separated solutions containing magnetic probe nanoparticles, semiconductor detector nanoparticles, and target DNA molecules, respectively. In order to measure the target DNA concentration, those solutions were mixed to assemble the magnetic donor–target DNA–semiconductor detector complexes via the specific hybridization of catcher probe and detector probe with the target DNA. The complexes, then, are easily collected by an outside magnetic field. The other components, which do not contain MNPs will be washed out. The collected complexes were redistributed in solution and measured by photoluminescence. The luminescent intensity at 586nm of Mn-doped ZnS nanoparticles changes with changing the initially added DNA target concentration. The detection limit of target DNA is around 2×106 copies/mL (~0.3fM), showing the ability of using the named multifunctional magnetic–semiconductor sandwich structure for fast KIT DNA detection during scene investigation and viral DNA detection.

Finally, in addition to the improved material properties, multifunctional materials are also important from an economic point of view. Multifunctional nanoparticle-based drug-delivery systems have been developed to improve the efficiency and reduce the systemic toxicity of a wide range of drugs, where additional capabilities like targeting and image contrast enhancement added to the nanoparticles. However, additional functionality means additional synthetic steps and costs, more convoluted behavior and effects in vivo, and also greater regulatory hurdles. The tradeoff between additional functionality and complexity is discussed by Cheng et al. (2012).

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