Noble Metal-Based Plasmonic Nanoparticles for SERS Imaging and Photothermal Therapy

C H A P T E R

4 Noble Metal-Based Plasmonic Nanoparticles for SERS Imaging and Photothermal Therapy Yula´n Herna´ndez, Betty C. Galarreta Science Department - Chemistry, Pontifical Catholic University of Peru, Lima, Peru

4.1 INTRODUCTION

The great impact that these two techniques have in the area of bioapplications is due to the possibility of having a unique system that may be used both for diagnosis and therapy (area currently known as theragnostics).

Noble metals’ excellent optical properties have been known since ancient times and their use has been very spread for different applications such as decoration, where the best example is the Lycurgus cup that dates from the 5th century BC, and medicine. These astonishing optical properties appear when dimensions are scaled down to the nanoscale, reason why noble metal nanoparticles have attracted a lot of attention during last decades as the base for the development of new analytical techniques and novel therapies among others. Two of these promising tools are:

4.2 PLASMONIC PROPERTIES OF METALLIC NANOPARTICLES Noble metals nanoparticles, such as gold and silver, have unique optical properties arising from their interaction with an incoming electromagnetic field that leads to localized surface plasmon resonance (LSPR) modes. The physical origin of this interaction is the collective oscillation of the electrons in the conduction band in a metal in response to an electromagnetic field, which is defined as the quantum quasi-particle called plasmon [1,2]. When this excitation is confined to the interface between a conductive material—with a complex dielectric function [εm ¼ Re(εm) + iIm(εm)]—and a dielectric medium with a real permittivity (εd), it receives the name

– Surface-Enhanced Raman Spectroscopy (SERS), a variant of Raman spectroscopy that has proven itself as a great alternative as it induces the enhancement of Raman signals up to 10 orders of magnitude. – Photothermal therapy (PTT), a novel type of therapy based on the efficient generation of heat that these nanostructures have shown when irradiated at selected wavelengths.

Nanomaterials for Magnetic and Optical Hyperthermia Applications https://doi.org/10.1016/B978-0-12-813928-8.00004-1

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of surface plasmon resonance (SPR). Materials that at certain wavelengths of light have a negative real part and a small positive imaginary part in the dielectric function show a SPR signal (e.g., gold and silver, shown in Fig. 4.1A and B). At nanoscale, when an incoming wavelength of light (λ), larger than the size of a nanoparticle (diameter: d < λ), interacts with the free electrons of the metallic particle such collective oscillation leads to a plasmon that resonates locally around the nanoparticle, and that is, defined as the LSPR [1, 4]. Two main effects are associated with the LSPR: the modulation of the LSPR frequency and the enhancement of the electric field. First, like SPR, the LSPR is sensitive to the dielectric environment and the complex dielectric function of the metal [5]. This leads to optical extinction bands (λLSPR) that in the case of gold and silver nanoparticles has a maximum within the visible (Vis) and near-infrared (NIR) region of the electromagnetic field [1,5,6]. The second effect of the LSPR refers to a change in amplitude of the electromagnetic field near the nanoparticle surface, which can be greatly enhanced by several orders of magnitude at specific regions in the surface. These regions are often

referred as hot spots and present an evanescent nature, as the intensity of the field rapidly decays with distance [1, 6]. The LSPR mode is not only susceptible to changes in the dielectric environment and the conductive material, but also to the size, the geometry, and the proximity between two or more nanostructures, defined as the interparticle distance [5]. Different theories have tried to explain this susceptibility [1,5,7,8]. A simplified example using the Mie theory for gold nanospheres is shown here to emphasize some of the different parameters that must be considered to determine the optical properties relating to the LSPR on nanoparticles. Mie developed an analytical solution to predict the extinction (σ ext), scattering (σ sca), and absorption (σ abs ¼ σ ext  σ sca) cross section. Eqs. (4.1) and (4.2) are simplified expressions of the equations used for small nanoparticles (d < < λ) with only one LSPR mode active [1,5, 7]. These two equations show how the optical properties of the nanoparticles strongly depend on the dielectric function of the metal (εm) and the dielectric constant of the medium (εd), as well as to the geometry (χ: shape factor), and the size or volume (V) of the nanoparticle [1].

FIG. 4.1 Real (A) and imaginary (B) components of the complex dielectric function of gold (black curve) and silver (dotted curve) [3]. (C) Calculated extinction (black curve), scattering (dotted curve), and absorption (dashed curve) cross section of gold nanospheres surrounded by water according to the simplified equations from the Mie’s theory. A. PRINCIPLES OF HYPERTHERMIA

4.2 PLASMONIC PROPERTIES OF METALLIC NANOPARTICLES

σ ext ¼

18πεd 3=2 V Imðεm Þ (4.1) 4 λ ½ Reðεm Þ + χεd 2 + ½ Imðεm Þ2

σ sca ¼

32π 4 εd 2 V 2 ½ Reðεm Þ  εd 2 + ½ Imðεm Þ2 λ4 ½ Reðεm Þ + χεd 2 + ½ Imðεm Þ2 (4.2)

Thus, if gold nanospheres (χ ¼ 2) of 20 nm diameter are surrounded by water (εd ¼ 1.7), then the LSPR extinction band (λLSPR) is predicted at 520 nm, as shown in Fig. 4.1C, after using Eqs. (4.1) and (4.2). This calculation is in good agreement with the experimentally observed extinction spectrum of a colloidal solution of gold nanospheres that has a distinctive red color [1]. For anisotropic nanostructures, beyond nanospheres, the Mie’s theory is limited, and numerical methods are generally required to predict the optical behavior of other kind of geometries. Electrodynamic calculations, such as finitedifference time domain (FDTD) method, discrete dipole approximation (DDA), or finite element method (FEM), have been used by different groups to model the LSPR bands and the hot spots of metallic nanostructures and to correlate with the experimental results [9,10]. Both, simulations and experimental results, highlight how the plasmonic properties of these nanostructures depend on the material of the metal, the surrounding medium as well as the size and geometry of the particle. Each of these parameters could be modulated to finely tune the LSPR bands at specific wavelengths to greatly enhance the electric field at specific locations and to further promote SERS clinical diagnosis and PTT therapeutic processes.

4.2.1 Surface-Enhanced Raman Scattering The SERS process was discovered in 1974 by Fleischmann, who observed a strong increase in the Raman signals (around 105 times) of pyridine adsorbed onto rough silver electrodes [11]. The unusual intensity was attributed, at that moment, to an increase in the number of

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excitable molecules because of the larger surface area offered by the electrodes. However, in 1977, two independent groups led by Albrecht and Van Duyne [12,13] recognized that this marked enhancement could not be explained simply by the increased surface area and SERS was subsequently proposed [7]. Within the last 10 years, surface-enhanced Raman scattering (SERS) detection technologies and imaging have emerged as a powerful tool in biomedical research [14,15] offering several advantages over other optical detection methods such as fluorescence. Besides the fact that Raman scattering is a technique that provides vibrational spectral bands that are narrow and unique for each molecular system, SERS is ultrasensitive, it is suitable for multiplexing analysis, its reporters tend to be highly photostable, and it could use a light source in the NIR region, very useful for biological imaging due to a deeper penetration in the skin and with a minimum energy loss or damage to normal tissues [14–17].

4.2.2 Raman Scattering: A Molecular Vibration “Fingerprint” The Raman spectrum of a molecule is the result of photons that are inelastically scattered due to the excitation or relaxation of the vibrational modes of such molecule. From a classical point, the incoming electromagnetic wave, defined by its energy (E) as the product of the Planck’s constant (h) and the frequency of that radiation (νL): E ¼ hνL, induces a dipole moment in the molecule, that is, modulated by its molecular vibrations. Each atom, bond strength, and arrangement in the molecule contributes to different vibrational molecular modes and their interaction with the incoming field yields to a sum of different frequencies between the incoming field and the molecular vibrations [18–20]. The scattered photons that loose energy (hνs) by exciting a molecule in the vibrational ground state are known as the Raman Stokes (hνs < hνL).

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Anti-Stokes (hνa), on the other hand are much less common and occur when the photon interacts with a molecule in an excited vibrational state, gaining energy (hνa > hνL) and leaving the molecule in the ground state. In both cases, the Raman scattering signals provide a chemical specificity, with vibrational bands with narrow linewidth (1 nm) [21] and where the Raman spectrum of each molecular system is considered as their vibrational “fingerprint.”

4.2.3 Enhancement Mechanisms of SERS: Ultrasensitivity Despite its benefits, conventional Raman scattering has poor sensitivity. As shown in Eq. (4.3), the intensity of the Raman Stokes signals [I(νs)R] is directly proportional to the number of molecules probed (N), the intensity of the incoming source—usually a laser [I(νL)]—and the Raman scattering cross section (σ Rfree), which are typically 14–15 orders of magnitude smaller than those of fluorescence [20,22]. These Raman signals could be slightly improved by 3–6 orders of magnitude by using an excitation source in resonance with the electronic transition of the molecular system, process known as resonance Raman scattering (RRS) [23]. Iðνs Þ R ¼ Nσ Rfree IðνL Þ

(4.3)

Fortunately, the poor sensitivity of conventional Raman could be overcome by SERS. Eq. (4.4) shows how the SERS intensity [I(νs)SERS] depends on the amplification of the laser source [A(νL)] and of the Raman scattered signals [A(νs)], as well as on the number of molecules (N´) that have been adsorbed on the surface of the metallic (σ Rads) nanoparticle and that take part of SERS [18,23, 24]. 2 2 (4.4) Iðνs Þ SERS ¼ N0 σ Rads AðνL Þ Aðνs Þ IðνL Þ The enhancement of the SERS signals has been well explained in the literature [7,25–29]. It is considered that the large SERS signal enhancement

could be explained by two main mechanisms: the electromagnetic mechanism (EM) and the chemical mechanism (CM). The former one relies on the LSPR of metallic nanoparticles, is considered the dominant factor and its enhancement factor (EFEM) is in the range of 105–1010 [5,30–32]. The latter factor considers the interaction between the metal and the adsorbed molecule, or the chemical nature of the adsorbed molecule itself, it is typically considered the smallest contributor of the enhancement factor (EFCM  10–100), and it explains some inconsistencies that cannot be interpreted by the electromagnetic mechanism. From the mathematical analysis of the LSPR extinction cross section of nanoparticles, Eq. (4.1), one can infer that the electromagnetic field intensity due to the LSPR is sensitive to a change in wavelength of light [ILSPR(λL)] and it could be modulated. Therefore, when a molecule adsorbed on the surface of a metallic nanostructure is irradiated with an excitation laser source, the intensity of the incident field (j Io(λL)j2) is enhanced [ILSPR(λL)], as well as the Raman scattering light [ILSPR(λs)], as described in Eq. (4.5) [4,5, 33]. EFEM ðλL Þ ¼

jILSPR ðλL Þj2 jILSPR ðλs Þj2 jIo ðλL Þj4

(4.5)

The maximum enhancement will occur when both the incident Raman beam and the Raman scattering signals are close to the LSPR resonance wavelength (λLSPR). Studies done in this field suggest that the highest enhancement will be observed when the LSPR band is positioned between the Raman excitation wavelength and the Raman shift of the molecule of interest [5, 34]. Although the electromagnetic mechanism explains most of the enhancement of SERS, some observations cannot be explained by this theory, suggesting there are other factors. Three examples of this inconsistency are: (i) the difference within the SERS spectrum of a molecule and its normal Raman spectrum, (ii) the inconsistent

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4.2 PLASMONIC PROPERTIES OF METALLIC NANOPARTICLES

enhancement factor obtained when different kinds of molecules have been studied under the same experimental conditions, and finally (iii) the discrimination in the enhancement of the different bands in a SERS spectrum. Such observations can be better apprehended by the chemical mechanism. The nature of the chemical mechanism is a combination of contributions that could come from the metal-molecule complex formation (charge transfer and resonant Raman scattering), molecular orientation, and surface selection rules [25, 35]. Charge transfer considers that molecules are strongly adsorbed by the metallic cluster and allow the formation of an adsorbate–surface complex. This complex then produces a charge-transfer mode with a larger Raman cross section than the one from the original Raman signal of the adsorbate [18,26]. Thus, when the original energy difference of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the adsorbate is too high to be excited with a convenient laser, the formation of the adsorbate-metal complex allows a charge-transfer interaction through the overlap HOMO and LUMO of the metal at the Fermi level. As a result, the energetic distance between bands is reduced and the excitation probabilities are increased. In other words, the cross section of the scattered light is enhanced by this new complex [18,26]. On the other hand, RRS can increase the intensity of the Raman signals, when the incident Raman beam matches or is close to an allowed electronic transition of the studied molecules. The presence of the metallic structure alters the excitation energies of the molecule and leads to the formation of surface-enhanced resonance Raman scattering (SERRS) [4,10, 26]. Finally, the molecular orientation and surface selection rules are responsible for the shift in frequency and intensity of the Raman spectrum [4, 10]. In the last couple of years, SERS has emerged as a suitable alternative to fluorescence-based (bio) detection analysis and imaging [14,15, 36–38]. In

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contrast to fluorescence, a single excitation source is required to collect the unique and narrow (linewidths 1 nm) vibrational bands of any Raman-active molecule. Thus, multiple molecules with large Raman scattering cross section, such as rhodamine 6G (Rh6G), p-aminothiophenol (pATP), malachite green isothiocyanate (MGIC), iodide and 3,30 -diethylthiatricarbocyamine (DTTC), shown in a box in Fig. 4.2, and many others, can be detected simultaneously in a mixture as far as they have distinctive vibrational signals that do not overlap with each other. Another great advantage is the possibility to use a laser source in the visible or NIR region, making a system compatible with biological applications and with optical microscopy. The combination of a Raman system together with confocal microscopy allows one to conduct measurements with a spatial resolution limited by the Rayleigh criterion, which is about half the wavelength of the excitation light [39]. Although multiplex diagnostics have been reported to discriminate cancerous cells using conventional Raman spectroscopy, the process is intrinsically weak and it requires a chemometric analysis to treat and process the data [40–42]. Most of the diagnostics systems are based on SERS nanoprobes or nanotags, a system made of strong Raman-active molecules bound to a plasmonic nanostructure and a shell that stabilizes the system. As with quantum dots or fluorescent probes, these strong Ramanactive molecules behave like reporters, but with the advantages of being highly stable, biocompatible and with minimal photobleaching. Furthermore, the surface of these SERS nanotags could then be modified if needed, to induce a selective interaction with a specific target or it could also be used as a passive probe. Two recent reviews have summarized the synthesis, characterization, and requirements of the different SERS tags available in the literature [17] and their application in diagnostics, multimodal sensing, and imaging [17,38]. A schematic representation of the steps required to design and

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FIG. 4.2 Design criteria and general steps required for the preparation of surface-enhanced Raman spectroscopy (SERS) nanoprobes for biomedical applications: (A) the selection of the nanoparticle substrates with the appropriate localized surface plasmon resonance (LSPR) resonant wavelength; (B) the adsorption of a Raman reporter with a large scattering cross section, such as the ones shown in a box; (C) the surface coating or encapsulation to stabilize the probes with (i) a silica shell, (ii) a layer of biomolecules like bovine serum albumin (BSA), (iii) a polymer like thiolated polyethylene glycol (SH-PEG) or (iv) an amphiphilic diblock copolymer like polystyrene block-poly(acrylic acid) (PS154-b-PAA60), or with (v) a liposome coating. Finally, (D) the specificity to a biological target with antibodies, aptamers, peptides, or small molecules that cross-links to the surface of the SERS nanotags. Adapted with permission from Y. Wang, B. Yan, L. Chen, SERS tags: novel optical nanoprobes for bioanalysis, Chem. Rev. 113 (2013) 1391–1428. https://doi.org/10.1021/cr300120g (web archive link). Copyright 2013 American Chemical Society.

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4.3 OPTICAL HYPERTHERMIA

prepare such SERS nanoprobes is shown in Fig. 4.2. Different studies have shown multiplex detection in vitro and in vivo SERS imaging with multiple SERS nanotags (4–10 different kinds), and where SERS imaging has been combined with other imaging or detection modes [15,38], such as optical hyperthermia.

4.3 OPTICAL HYPERTHERMIA Since ancient times, the increase of the body temperature has been used as therapy mimicking the body reaction to an infection (fever). During the 19th and 20th centuries, doctors triggered those temperature increases by infecting patients with different viruses or bacteria, or even by administering them with toxins [43]. Obviously, this practice had many drawbacks and side effects, but the idea remained as a goal for researchers until the 21st century, when scientific breakthroughs such as nanotechnology emerged as a potent solution. Some of these nanomaterials proved themselves as good sources of heat when in the presence of a magnetic field (magnetic hyperthermia) or when irradiated with light (optical hyperthermia). These phenomena in combination with all the other advantages of nanostructures rose as a very promising tool in the fight of wide spread diseases, such as cancer. The increase of the temperature represents an effective tool for therapy as it triggers the denaturalization of proteins what can be used either to kill damaged cells (process known as thermoablation), to induce drug release, or to weaken those target tissues for increasing the impact induced by traditional treatments such as radiotherapy or chemotherapy, reducing this way the needed dose and so their side effects (this last approach will be discussed later in Chapter 11). What makes hyperthermia very interesting for cancer treatment is the fact that tumors are characterized by a disordered growth that involves chaotic vasculature and deficient blood

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supply. This disorganization makes tumors hypoxic and leads to acidic regions, which makes them more susceptible to heat than healthy tissues. On the contrary to traditional ways of increasing the temperature, such as laser fibers, ultrasound, and infrared devices, nanomaterials are a good alternative as they are able to reach deep tumors and generate localized heat avoiding side effects on normal cells. Besides, they are known to be good targeting systems, both because of their size that enables them to accumulate in those chaotic tumoral tissues [enhanced permeability and retention (EPR) effect] and their multifunctional features, which allows attaching targeting biomolecules such as antibodies.

4.3.1 Mechanism of Heat Generation As described previously, noble metal nanomaterials present very interesting optical properties due to their special interaction with light in the UV–Vis–NIR region. Basically, these nanostructures can go through two different phenomena when irradiated, they absorb part of the incident light and scatter the rest of it. Usually, the analyzed phenomenon is due to the sum of both effects, what is known as extinction. When a photon with a frequency that matches the resonance of the oscillation electrons of the metallic material is absorbed, this energy induces the jump of these electrons to an excited state. This energy can be returned through a radiative decay, which means, that a photon is emitted either with the same frequency as the incident one (Rayleigh) or not (Raman). On the contrary, other times the energy absorbed is returned by a nonradiative decay, which does not involve the emission of a photon and is the cause of the heat generation associated with noble metal nanoparticles. Once the photon has been absorbed, the excited electrons possess higher energy than lattice (phonons), which leads to a nonequilibrium state within the

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nanoparticle. This imbalance triggers an energy transfer through electron–phonon relaxation, process in the picosecond timescale. Finally, the energy of the phonons is dissipated via phonon–phonon scattering to the surrounding media, leading to the enhancement in the temperature, process that can last between 100 picoseconds and a few nanoseconds [44, 45]. The heat generated by these nanomaterials may be characterized by the specific absorption rate (SAR), which can be calculated with Eq. (4.6):   ΔT (4.6) SAR ¼ Cρmedium Δt initial SAR ¼ NQnano ¼ NCabs I

(4.7)

In Eqs. (4.6) and (4.7), C is the concentration of the nanoparticles used and the medium the density of the surrounding media, which is directly related to the efficiency of the phonon–phonon relaxation process. On the other hand, in Eq. (4.7), N represents the number of nanoparticles per cubic meter and Qnano represents the heat generated by each nanoparticle, which can also be calculated by the absorption crosssection area of each nanoparticle (Cabs) multiplied by the power density (I). From these equations, we can extract three basic ideas: – Increasing the number of nanoparticles results in higher heat generation. – The bigger the absorption cross section, the higher the temperature reached. – A more powerful irradiation leads to an increased SAR.

4.3.2 Noble Metal Nanoparticles What makes noble metal nanoparticles very attractive tools for bioapplications based on optical hyperthermia, is the fact that the plasmonic band, frequencies at which the absorption of these materials is maximum and, in consequence, their light-to-heat conversion, can be tuned in the NIR region. The NIR light is able to penetrate

several centimeters and depending on the target tissue it may reach even 10 cm deep, which allows to get to zones inaccessible by other techniques [46,47]. Besides, the NIR region is also known for being the “biological window” (also “therapeutic window”), the region of the electromagnetic spectrum where tissues and blood are semitransparent, as water, hemoglobin, and melanin show very little absorption of this kind of radiation (Fig. 4.3) [48]. This is why anisotropic noble metal nanoparticles whose LSPR band may be modulated along the Vis–NIR region of the spectra are especially important. As previously described, the position of this LSPR band depends on the parameters that change the dielectric constant of the material and the surroundings such as the metal used, the size, shape, aggregation state, and the surrounding medium. The morphologies whose LSPR bands lie within the NIR window and have been used for this aim are, mainly, nanorods, nanoprisms, nanocubes, nanocages, nanostars, and core-shell nanostructures. Although gold is the most spread option due to its biocompatibility and inert nature (less prone to be oxidized than other noble metals) [49,50], silver has also started to play a more active role when coated by a silica shell, common step in improving its biocompatibility. These anisotropic nanostructures behave in a different way depending on the incident angle of the radiation with respect to the nanoparticles [1]. That is, why several LSPR bands may be found in the UV–Vis–NIR spectrum due to the different modes and that have been described both experimentally and theoretically. Since first implemented in vitro by Hirsch and coworkers in 2003 [51], PTT has been successfully applied both in vitro and in vivo proving itself as a very potent therapeutic tool and inducing cell death only when irradiating and leading to promising results in tumor reduction and increase in survival rates in mice. It should also be highlighted that this heat generation has also been applied as an

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FIG. 4.3 UV–Vis-near-infrared (NIR) spectrum of the absorption of water (H2O), hemoglobin (Hb), oxyhemoglobin (HbO2) and melanin, and the biological window (λ ¼ 700–1100 nm). Based on the data compiled by Scott Prahl at Oregon Medical Laser Center (http://omlc.ogi.edu/spectra/).

antibacterial system using silver nanoparticles not only because of the damage produced by the increase in temperature but also due to the oxidation of Ag and liberation of Ag+. These ions are responsible for cellular damages because of their role in the production of reactive oxygen species (ROS) that lead to mitochondrial dysfunction and DNA damage [49,52, 53].

4.4 SYNTHESIS METHODS Several geometries of noble metal nanoparticles have been used for both SERS and optical hyperthermia; in particular anisotropic nanostructures because all of the advantages previously described: appearance of hot spots, tunability of plasmonic bands in the NIR region and efficient light-to-heat conversion, among others (Fig. 4.4). Despite the fact that silver presents better optical properties, gold is the preferred option for these theragnostics systems due to its biocompatibility and relative inertness (Ag is prone to be oxidized to Ag+, highly cytotoxic).

However, a good inert shell may overcome this drawback, which has enabled the appearance of some works using also Ag nanoparticles. Due to higher reproducibility and versatility, nanoparticles used for these bioapplications are usually synthesized by bottom-up techniques. In the last decades, several methods have developed in order to obtain monodisperse nanostructures of a wide range of morphologies for both gold and silver. The synthetic routes of both materials have many aspects and reagents in common; therefore, they will be described together within this section. In general, all the approaches are based on the reduction of the precursor, HAuCl4 or AgNO3, in the presence of a reducing and a capping agent that stabilizes the surface.

4.4.1 Spherical Nanoparticles The synthesis of spherical—more accurately said truncated octahedral—gold and silver nanoparticles has been known for many years and these NPs can be obtained in a reproducible fashion, with high monodispersity and a very good control of the size. In the case of gold

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FIG. 4.4

Different types of nanoparticles classified according to their morphology.

NPs, since first reported in 1857 by Faraday [54], different approaches have been described, two of them being highlighted according to the medium of dispersion: – Aqueous media: the method proposed by Turkevich [55] using sodium citrate as reducing and stabilizing agent due to electrostatic repulsion. This method was lately refined by Frens [56], who proposed that by varying the ratio between the precursor and the citrate, gold nanoparticles of different sizes could be achieved. – Organic solvents or biphasic systems: the method reported by Brust using NaBH4 as reductant and alkanethiols as capping agents [57]. Apart from varying the ratio between reactants, the size of the spherical nanoparticles can be controlled depending on the strength of the reducing agent. In this aspect, the use of a strong reductant like NaBH4 leads to obtaining little nanoclusters; when employing mild reducing agents as citrate or ascorbic acid, the slower rate of reduction gives as a result bigger nanostructures. The synthesis of silver spherical nanoparticles has evolved in the same direction, being the method described by Lee and Meisel [58], analogous to Turkevich’s, the most common.

4.4.2 Anisotropic Nanoparticles Despite the well-established syntheses of gold and silver nanospheres, their use is limited to the visible region and their photothermal conversion is not as efficient as other, which has encouraged the development of efficient synthesis methods of more complex morphologies, anisotropic nanoparticles, with at least one plasmonic band in the NIR region. It is important to keep in mind that the synthesis of anisotropic nanoparticles is not thermodynamically favored—they present higher surface energy, different growth rates of crystallographic facets, etc. Therefore, these synthesis methods need to be kinetically controlled (parameters such as reactant concentration, reaction rate, diffusion, solubility, etc., are going to be crucial) and, most of the times, the use of specific stabilizers is required. These capping agents specifically attach to certain facets, breaking the symmetry, inhibiting the growth process in those directions, and forcing the gold or silver atoms to deposit in other planes [59]. Most anisotropic nanoparticles are synthesized through seed-mediated processes with two well distinctive steps: a nucleation one, where a strong reductant and a rapid growth of all crystal facets are needed; and a growing

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step, defined by slower reaction rates and selective facets’ growth. In this kind of synthesis, small and homogeneous seeds are first formed and then followed by a drastic change in conditions, in particular the reducing and the capping agents. 4.4.2.1 Nanorods Maybe the most common anisotropic nanoparticles used in SERS and PTT are nanorods (NRs) due to their well-established synthesis protocols with high yields and excellent size control especially on their aspect ratio (length/ diameter). The synthesis of gold NRs was first reported by Masuda [60] and Martin [61] through electrochemical reduction of gold electrodes onto nanoporous aluminum oxide membranes, leading to large nanostructures and quite low yield. Based on their work, Wang and coworkers introduced the immersion of a silver plate in the electrolytic solution and the presence of surfactants like cetyltrimethylammonium bromide (CTAB), which improved the control over the aspect ratio [62]. However, the major breakthroughs in the synthesis of AuNRs were done by Murphy’s and El-Sayed’s groups in 2001 [63] and 2003 [64], respectively, with a seed-mediated process. First, the gold seeds were synthesized by reduction of HAuCl4 with NaBH4 in the presence of citrate, as described by Jana et al. [63], and of CTAB, in the synthesis described by Nikoobakht [64], both acting as stabilizing agents. Once obtained the seeds, these were added to a growth solution containing more Au(I), CTAB, AgNO3, and ascorbic acid as a mild reductant. As they reported, the presence of small amounts of Ag+ was critical to successfully control the final shape of the nanoparticle, its concentration, and different aspect ratios (Fig. 4.5A). This synthesis has been revisited since then, and nowadays, Ag+ and Br ions are thought to attach selectively to the surface of the nanoparticles, directing the elongated growth of NRs [65].

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Similarly as reported for AuNRs, in 2001 Jana et al. described this type of nanoparticles made of silver (AgNRs) by using AgNO3 as precursor and adding NaOH to control the reaction pH [66]. More recently, Mahmoud et al. reported the controlled synthesis of AgNRs by the polyol method, which will be described in next section [67]. These seed-mediated processes described for AuNRs have been the base for the development of many other methods for the synthesis of the morphologies described in next sections. 4.4.2.2 Nanocubes and Nanocages The most reproducible method for the synthesis of noble metal nanocubes was introduced in 2002 by Xia et al. [68], when they reported the synthesis of Ag nanocubes using the polyol process described by Fievet et al. [69]. Briefly, a polyol such as ethylene glycol, 1,2-propylene glycol, and others, is used in this method as a reducing agent, a stabilizer, and a solvent. These polyols allow, near reflux, to reach temperatures much higher than in aqueous phase. Xia et al. discovered that Ag nanocubes could be obtained with a high yield, using AgNO3 as precursor, ethylene glycol as polyol, and poly(vinyl pyrrolidone) (PVP) as stabilizer and shape-control agent, as it is known that the adsorption of the carbonyl group of the pyrrolidone ring on metal surfaces is highly selective toward {111} and {100} planes. The synthesis of silver nanocubes is achieved by controlling the ratio between ethylene glycol and PVP, and changes in the precursor concentration and the growth time can modulate the size of the cubes obtained. As they stated, aspects such as the injection time, reactants concentration, and temperature, are critical for the synthesis of the nanocubes. Following the same methodology, gold nanocubes were successfully obtained by Kim et al. [70] but using HAuCl4 and traces of AgNO3. In 2005, Xia’s group went one step further and reported the use of their Ag nanocubes as templates for the synthesis of hollow gold

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FIG. 4.5

(A) TEM images of gold nanorods (NRs) with plasmon band energies at 700 (left) and 1250 nm (right) (the scale bar is 50 nm) (Adapted with permission from B. Nikoobakht, M. A. El-Sayed, Preparation and growth mechanism of gold nanorods (NRs) using seed-mediated growth method, Chem. Mater. 15 (2003) 1957–1962. https://doi.org/10.1021/cm020732l (web archive link). Copyright 2003 American Chemical Society). (B) SEM image of the silver nanocubes (image above) and gold nanocages (bottom) (the scale bar is 20 nm) (Adapted with permission from J. Chen, F. Saeki, B.J. Wiley, H. Cang, M.J. Cobb, Z.-Y. Li, L. Au, H. Zhang, M.B. Kimmey, Li, Y. Xia, Gold nanocages: bioconjugation and their potential use as optical imaging contrast agents, Nano Lett. 5 (2005) 473–477. https://doi.org/10.1021/nl047950t (web archive link). Copyright 2005 American Chemical Society). (C) UV–Vis–NIR spectra of gold nanoprisms with tunable edge lengths and their corresponding SEM images (the scale bar is 100 nm) (Adapted with permission from B. Pelaz, V. Grazu, A. Ibarra, C. Magen, P. del Pino, J.M. de la Fuente, Tailoring the synthesis and heating ability of gold nanoprisms for bioapplications, Langmuir 28 (2012) 8965– 8970. https://doi.org/10.1021/la204712u (web archive link). Copyright 2012 American Chemical Society).

nanocages using a revolutionary method, the galvanic replacement [71]. The method takes advantage of the lower reduction potential of silver (0.22 V) in comparison with gold’s (0.99 V), and when the Ag nanocubes are in the presence of HAuCl4, the silver ions are spontaneously oxidized and the gold ions are reduced and deposited on the surface of the nanocubes (Fig. 4.5B). Due to the stoichiometry of the reaction (see Eq. 4.8), each three silver atoms are replaced by only one gold atom, inducing the formation of holes that finally led to the synthesis of these hollow structures. By controlling the

amount of gold salt used in the process, different nanoframes can be prepared. 3AgðsÞ + AuCl4  ðaqÞ➔AuðsÞ + 3Ag + ðaqÞ + 4Cl ðaqÞ

(4.8)

Furthermore, this group was also able to induce the formation of holes in the faces of the nanocubes by etching the silver with Fe(NO3)3 and/or NH4OH [72]. Although less common, the synthesis of gold nanocubes was also described by Zhang et al. following the methodology used for the

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4.4 SYNTHESIS METHODS

synthesis of AuNRs but using the chloride analog of CTAB instead, the cetyltrimmetylammonium chloride (CTAC) [73]. By varying the amount of seeds added to the growth solution, the authors were able to control the edge lengths of these nanocubes that ranged from 38 to 269 nm. 4.4.2.3 Nanoprisms The most spread methods rely on varying the conditions described for AuNRs such as variation of the pH, surfactant concentration, or the addition of more halide ions. Although the desired morphology was obtained, all of these methods needed a purification step due to the relative low yield in comparison with the NRs synthesis [65]. Millstone et al. [74] described the synthesis of controlled gold nanoprisms by carrying out a fractionate addition of three stages using gold citrate-capped seeds as starting point and a mix of CTAB, ascorbic acid, and NaOH as growth solution. The addition of traces of KI at pH 4 has also proved to increase the yield of nanoprisms, although an excess may suppress the formation of these nanoparticles [75]. In 2008, Mirkin’s group also reported the effect of iodine, describing that in its absence, exclusively polyhedral NPs were obtained, whereas an increase in its concentration changed the final shape of the nanoparticles from NRs (2.5– 5 μM) to a mixture of NRs, nanospheres (10 μM), nanoprisms (50 μM), and finally, rounded disk-like nanostructures [76]. In 2012, Pelaz et al. [77] reported the synthesis of gold nanoprisms without CTAB using only HAuCl4 and adding sodium thiosulfate acting as both reducing and stabilizing agent in two separate steps. As described by the authors, by varying the amount of thiosulfate added in the last addition, the size and sharpness of the edges could be controlled, allowing to tune the position of the plasmonic band along the NIR region from approximately 785 to 1100 nm (Fig. 4.5C).

95

Regarding the synthesis of silver nanoprisms, the most spread approach is the use of photochemical methods, described for the first time by Jin et al. in 2001 [78] and obtaining highly monodisperse nanoprisms after irradiation with UV light for several hours. However, it has also been reported the chemical reduction of AgNO3 by citrate and NaBH4 at high temperatures [79] or in combination with H2O2 and PVP [80] although the results obtained are not as reproducible nor monodisperse as the nanoprisms synthesized by photochemical methods. 4.4.2.4 Branched Nanoparticles The synthesis of this type of nanostructures (nanostars, nanoflowers, nanopods, etc.) is one of the most complex as their surface energy is really high in comparison with other morphologies. The method described by Sau and Murphy [81], using AuNPs seeds, CTAB, ascorbic acid, and NaBH4, was the first report of this type of nanoparticles with yields around 50%. Nehl et al. [82] used a similar approach but using 10-nm gold seeds as starting point and Langille et al. [83] reported the effect of using CTAC instead of CTAB, ascorbic acid, and NaBr. Both of them obtained branched nanostructures as a result. As described for other morphologies, the addition of PVP may enhance the anisotropy of the synthesized nanoparticles by selective adsorption. This approach combined with dimethylformamide (DMF) and NaBH4 was used by Liz-Marzan et al. [84] to obtain high yields of gold nanostars. Many other examples have been reported in last few years [85–90]. In 2013, Yuan et al. [91] reported a surfactantfree synthesis by using citrate as stabilizing agent in the presence of silver ions and ascorbic acid under very controlled conditions. Another ligand-free synthesis was the one described by Keunen et al. [92] in 2016 using HAuCl4 and H2O2 as reductant in basic medium. They also observed that the addition of iodide ions led to less branched structures, enabling tuning the plasmonic band along the Vis–NIR region.

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4.4.2.5 Hybrid Nanoparticles Probably, the most important hybrid nanoparticles used for SERS and PTT are the ones described by Halas et al. [93] consisting of a dielectric core made of silica (prepared by St€ ober hydrolysis [94]) and a metallic shell grown by the addition of aged chloroauric acid and potassium carbonate reduced by NaBH4. By varying the relative dimensions of the core and the shell, their optical properties can be controlled and their plasmonic band may be tuned from 700 to 1100 nm. The preparation of this type of nanostructures has also been reported through the electrostatic adsorption of tin [95] or gold nanoparticles [96] on the surface of the silica cores, acting as nucleation sites for the growth of the shell using formaldehyde or carbon monoxide [97]. The same idea has been used for the synthesis of the so-called “nanomatryoshkas,” concentric nanoshells alternating SiO2, and metallic layers. One curious approach was the one described by Gao et al. [98] where gold nanoparticles were synthesized and coated with organosilica, followed by the in situ reduction of HAuCl4 with NaBH4 for the formation of seeds on top of the silica layer, which were finally grown until obtaining a homogenous gold layer. Bimetallic nanoparticles have also been described for bioapplications being the most common systems the one formed by Au/Ag [99,100] for increasing the optical properties of the nanostructures, and the tandem Fe3O4/ Au [16] which introduces magnetic properties that could be used for magnetic resonance imaging (MRI) or magnetic hyperthermia, among others.

4.5 FUNCTIONALIZATION Despite the good results obtained during the synthesis of anisotropic nanoparticles, some of the surfactants used in the described methods, such as CTAB, are cytotoxic, which limits their

application in vitro and in vivo. Most of the times, the synthesized nanoparticles need to be functionalized before their use in bioapplications in order to: (i) increase the biocompatibility of the system (e.g., SiO2); (ii) avoid the recognition by the reticuloendothelial system (RES) and increase their halftime in the bloodstream (e.g., PEG); (iii) target the nanoparticles so they can be directed to the damaged zone (e.g., antibodies or aptamers); and (iv) provide the system with a new functionality (e.g., Raman reporters or Gd chelates for MRI contrast). The strategies used for the functionalization can be summarized as follows: – Chemisorption: direct attachment of the molecules to the nanoparticles through quite strong interactions. In the case of noble metals, the most exploited interaction is the strong interaction established with sulfur which occurs spontaneously and at room temperature [101]. – Electrostatic interactions: it occurs between charged species but is very susceptible to pH and ionic strength [102, 103]. – Covalent attachment: couplings established between functional groups on the nanoparticle [104], being the most common, the formation of amides (carboxyl + amine) [105], thioethers (thiol + maleimide) [106], and cycloadditions (azide + alkyne) [107], among others. It should also be included the silanization of surfaces which increases both the solubility and biocompatibility of nanostructures. – Affinity interaction: established between pairs of ligands based on their molecular recognition. The most spread example is biotin and avidin, being one of the strongest non-covalent interactions known [108–110]. The most common ways for increasing the biocompatibility of the system and introducing more functional groups on the surface for further modification are the addition of a silica coating or derivatives of PEG. In the first case, the ober hydrolysis SiO2 is deposited through the St€

A. PRINCIPLES OF HYPERTHERMIA

4.6 THERAGNOSTICS (SERS + PTT)

[94] and not only provides functional groups for the attachment of other ligands such as Raman reporters, but also allows their entrapment due to its porous structure [111]. The second one, the PEGylation process is usually carried out by using thiolated PEGs due to the strong interaction with gold and silver. The nature of PEG is known to mask the surface charge and ensure steric stabilization avoiding opsonization, which is a main goal to decrease the recognition of the nanomaterials by the immune system [112,113]. Lately, some other biocompatible polymers like chitosan have emerged as a good option for the coating of silver nanoparticles, for example, in order to avoid the oxidation of silver atoms in the system [114–116]. Although nanoparticles have proven themselves to be good candidates for passive targeting due to their accumulation in tumoral tissues by EPR effect [117], the possibility of using them to develop multifunctional platforms in the same scale as biomolecules, gives the opportunity of an efficient conjugation of molecules for active targeting. As damaged cells suffer from changes in the regulation of membrane receptors, it is possible to select the most adequate targeting unit in each case for different cell lines. Some molecules used for active targeting are antibodies [118–120], aptamers [121– 123], folic acid (FA) [124–126], the arginine–glycine–aspartic acid (RGD) motif [127–129], etc. Finally, there is a group of peptides frequently used in bioapplications known as cellpenetrating peptides (CPPs) [130,131], group formed by peptides like TAT [132,133] or penetratin [134] which are known to enhance the internalization of nanoparticles and, in some cases, its transport to the nucleus. They are also important because they can “select” the internalization route, which is a key parameter for the final success of the system. The RGD motif, previously mentioned, can also be included in this group as it is known to selectively bind to some integrins, a group of receptors present in the cell membrane of certain cell lines. This motif binds

97

to αvβ3 y αvβ5 integrins known for being overexpressed in endothelial tumoral cells and enhances the crossing of the cell membrane [135, 136].

4.6 THERAGNOSTICS (SERS + PTT) It has already been stated that the combination of SERS and PTT techniques presents several advantages. However, the field is quite new, as the first work that combines both techniques was reported in 2009. Since then, many other groups have developed systems for their combination (Table 4.1). Many different types of noble metal nanoparticles have been used but most of them are anisotropic due to their advantages in both techniques. On one side, the anisotropy leads to the presence of hot spots which favors very high enhancement of SERS signals. On the other hand, the position of their plasmonic bands in the NIR region is really convenient for in vitro and in vivo applications as all the incident radiation may be absorbed by the nanoparticles and not by water, tissues, or hemoglobin. Although not applied to in vitro or in vivo systems, the work reported by Rycenga et al. [150] in 2009 entailed a big step in the combination of both techniques. They used Ag/Au nanocages with their plasmonic band at three different points 525, 620, and 790 nm and functionalized them with the Raman reporter 1dodecanethiolate (1-DDT) which shows two intense signals corresponding to the carbon–carbon stretch bands: one due to the gauche conformation (G at 1080 cm1) and another one due to the trans conformation (T at 1125 cm1). Interestingly, the ratio between the intensities of these two bands depends on the temperature, so through SERS measurement the authors were able to establish the temperature generated in the media when the nanoparticles were irradiated with a laser at 514 nm and another one at 785 nm. As it was expected, the higher

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TABLE 4.1 Summary of reports where gold and silver nanostructures have been used for both SERS and PTT Nanoparticle

a

PPy/Fe3O4-core/Au-Nshell

SERS

PTT

Ref.

[3ATP]

In vitro

[137]

Au-NBPs

[2NT] and folic acid

In vitro and in vivo

[138]

rGO@CPSS-AuNPs

[Rh6G] Anti-EGFR

In vitro

[139]

CaMoO4:Eu@SiO2@Au nanorods

[PB]

In vitro

[140]

CaMoO4:Eu@Au nanorods

[4MBA]

In vitro

[141]

Au-NPs

Protein structure at nucleus

In vitro

[142]

Au-nanostar

[4MBA]

In vitro and in vivo

[143]

Au-NR/Ag

[4MBA], [PATP], [PNTP], [4MSTP])

In vitro

[144]

Au-nanoshell nanomatryoshka

[4MBA]

In vitro and in vivo

[98]

Chit-AgNTs

[3ATP] conjugated with Folic acid

In vitro

[124]

Popcorn-shaped iron magnetic core-gold plasmonic shell

MDR Salmonella DT104

MDR Salmonella DT104

[16]

Au-NPs

[4MBA]

In vitro

[145]

Au-nanostars-SiO2

[4MBA]

In vitro

[146]

Ag/Au nanostructures

[Rh6G]

In vitro

[147]

Pd hexagonal nanoplates@Ag (-SiO2)

[4PDT]

In vitro

[148]

Au-nanopopcorn

[Rh6G]

In vitro

[89]

Au-NRs/CTAB/PEG

[DTTC]

In vitro and in vivo

[149]

Ag-nanocubes

1-DDT

Effect of the temperature

[150]

Au-Ag-nanocages

1-DDT

Effect of the temperature

[150]

Au-NRs/PEG

[CV], [MGIC], [NB], [DTTC], [Al-PPC], [IR-792], [DTDC], [DTC]

In vivo

[151]

Au nanostars

[ICG]

In vitro

[152]

Double-walled Au nanocage/SiO2 nanorattles

[pATP]

In vitro

[153]

Au nanostar

[4MBA]

In vitro and in vivo

[143]

Au-popcorn/SWNT

[SWNT]

In vitro

[154]

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4.6 THERAGNOSTICS (SERS + PTT)

TABLE 4.1 Summary of reports where gold and silver nanostructures have been used for both SERS and PTT—cont’d Nanoparticle

SERS

PTT

Ref.

GO@AuNRs

[GO]

In vitro and in vivo

[155]

Au nanostar/SiO2

[DTTC]

In vitro and in vivo

[156]

Au nanorods

[4MBA]

In vitro

[157]

Au nanorods

Squaraine dye

In vitro

[158]

AuNP/CNT

CNTR

In vitro and in vivo

[159]

AgNP/PANI

ICG

In vitro and in vivo

[160]

Ag/SWNT and Au/SWNT

SWNT

In vitro

[161]

Au/Ag core-shell

Rh6G

In vitro

[162]

BP-AuNPs

Aminoacids

In vitro and in vivo

[163, 164]

Ag/Au core-shell

DTTC

In vitro and in vivo

[100]

a

SERS reporters: 3-aminothiophenol [3ATP], 2-naphthalenethiol [2NT], Rhodamine 6G [Rh6G], Prussian blue [PB], malachite green isothio-cyanate [MGIC], 4-mercaptobenzoic acid [4MBA], p-aminothiophenol [pATP], p-nitrothiophenol [PNTP], 4-(methylsulfanyl) thiophenol [4MSTP], 3,30 diethylthiatricarbocyamine iodide [DTTC], 4-pyridinethiol [4PDT], 1-dodecanethiolate (1-DDT), crystal violet [CV], Nile blue [NB], aluminum 1,8,15,22tetrakis(phenylthio)-29H,31H-phthalocyanine chloride [Al-PPC], IR-792 perchlorate [IR-792], 3,30 -diethylthiadicarbocyanine iodide [DTDC], 3,30 diethylthiacarbocyanine iodide [DTC], indocyanine green [ICG], single wall carbon nanotube [SWNT]; graphene oxide [GO], carbon nanotube ring [CNTR], black phosphorus [BP].

temperature was reached when the nanocages, whose plasmonic band was at 790 nm, where irradiated with a laser at 785 nm. That same year, the group of Bhatia [151] carried out an in vivo research using gold NRs functionalized with different Raman reporters. After injecting the functionalized AuNRs, they were able to detect Raman spectra of the reporters selectively, without showing overlapping, indicating the possibility of multiplex diagnosis. Besides, analyzing the thermographic maps obtained while irradiating the injection zone, they could state that the hyperthermia abilities of the nanoparticles reached temperatures around 70°C. Another interesting approach was the one proposed by Luo et al. [157] using AuNRs

functionalized with a pH-sensitive Raman reporter 4-mercaptobenzoic acid (4-MBA) that allowed the ultrasensitive monitoring of the pH of the media in cells during the PTT treatment. Lu et al. [89] developed gold nanopopcorn functionalized with aptamers and antibodies against prostate-specific membrane antigen (PSMA), highly expressed in human prostate cancer cell line (LNCaP), and a Raman reporter, Rh6G. In the presence of target cells, the functionalized nanopopcorn got attached to PSMA on the membrane and aggregated, leading to a really high intensity of the Raman signals. The presence of both targeting ligands increased the sensibility of the system, which was able to

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4. NOBLE METAL-BASED PLASMONIC NANOPARTICLES FOR SERS IMAGING AND PHOTOTHERMAL THERAPY

detect down to 50 cells. Besides, these nanopopcorn allowed the analysis of cell death induced by PTT, and it was possible to establish a relationship between the cell viability and the Raman signals (the higher the cell damage, the lower the aggregation of the nanoparticles on the surface and the disappearance of the Raman signals). Gold nanopopcorn attached to singlewall carbon nanotubes (SWCNTs) were also used by Beqa et al. [154]. They used the G and D bands of these SWCNTs as Raman reporters to detect down to 10 cells/mL. This approach also resulted very attractive for PTT as the effect of the irradiated gold nanopopcorn was enhanced by the heat generation attributed to the carbon nanotubes. The same strategy was later on used by Wang et al. [161] when coating the nanotubes with either gold or silver to study the enhancement of the Raman signals induced by both noble metals subsequently functionalized with PEG and FA for active targeting of KB cells. The photothermal properties of the SWCNT-Au-PEG-FA were also tested in vitro proving to kill selectively the targeted cells in a very efficient way. A novel strategy was developed by Chen et al. [152] to monitor the intracellular temperature in real time. They enhanced the spatial resolution of infrared thermal imaging while carrying out PTT, by using thermosensitive indocyanine green (ICG) attached to gold nanostars. In 2013, Jung et al. [145] showed that spherical gold nanoparticles (AuNPs) could also be used for theragnostics as their aggregation in acidic media in target cells was enough to generate hot spots, that increased the SERS efficiency and induced a red-shift of the plasmonic band for the NIR PTT. To that aim, the AuNPs were functionalized with a pH-sensitive “smart” ligand {4-[2-(6,8-dimercaptooctanamido)ethylamino]-3-methyl-4-oxobut-2-enoic acid} and a Raman reporter (MBA). This system shows a high sensitivity and makes possible to obtain a Raman mapping of the target cells and to be used in PTT. Aioub et al. [142] also used 29-

nm spherical AuNPs functionalized with PEG, RGD motif, and a nuclear localization sequence (NLS) for studying the changes experienced by HSC-3 cells when irradiated. As heat was generated, the proteins in the nucleus denaturated, which could be monitored by the changes induced in the SERS spectra (i.e., the disappearance of the disulfide band which meant the rupture of disulfide bonds, the shift of the band attributed to the amide III vibration of the β-sheet conformation, and the enhancement of the bands corresponding to phenylalanine moieties and attributed to their in plane CdH bend, ring breathing, and in-plane CdH stretching). Boca-Farcau et al. [124] proved that silver nanoprisms could also be used in vitro when coated with chitosan. This polymer improves the biocompatibility and minimizes the cytotoxic effects of the nanoprisms. By functionalizing them with pATP and FA, they developed a selective and multifunctional system toward NIH:OVCAR-3 cancer cells that showed SERS signals once the nanoparticles had been internalized, and induces their death even at concentrations as low as 2.75 μg mL1 (Fig. 4.6). Bimetallic Au/Ag core shell nanostructures functionalized with Rh6G and an aptamer as targeting probe were also used by Wu et al. [162] for both the selective SERS detection of A549 cells (they were able to detect 10 A549 cells/ mL out of seven cell lines) and the efficient cell death induction (almost 100% of cell death in 60 min using 0.20 W cm2). Last but not least, in 2015, Gao et al. [98] reported the use of multilayered nanoparticles referred to as “nanomatryoshkas” with the Raman reporter MBA embedded in a silica coating. They showed the great potential of these nanomaterials as nanoheaters and their stability overtime when tested through six cycles of irradiation. Finally, the in vivo results revealed how the Raman reporter could be detected by SERS (only at the tumor site) and the temperature in the zone could reach up to 60°C as showed by a thermal imaging camera.

A. PRINCIPLES OF HYPERTHERMIA

101

4.7 CONCLUSION

pATP

ed rget uptak Ta

Folic acid

e

ex

= 800

nm

PTT SER

S le = x 532 n m

Intensity [a.u.]

l

800 1200 1600

3000 3500

Raman shift [cm–1]

FIG. 4.6 Scheme reported by Boca-Farcau et al. of silver nanoprisms labeled with p-aminothiophenol (pATP) used for both PTT and SERS. Reprinted with permission from S. Boca-Farcau, M. Potara, T. Simon, A. Juhem, P. Baldeck, S. Astilean, Folic acidconjugated, SERS-labeled silver nanotriangles for multimodal detection and targeted photothermal treatment on human ovarian cancer cells, Mol. Pharm. 11 (2014) 391–399. doi:https://doi.org/10.1021/mp400300m (web archive link). Copyright 2014 American Chemical Society.

4.7 CONCLUSION In summary, both SERS and PTT are very promising techniques for diagnostics and therapy, respectively, and their combined use is a hot topic that has proven to be a very potent theragnostics tool. On one side, SERS provides very specific information and a high sensitivity due to the great enhancement of Raman signals, which can reach 10 orders of magnitude. It has been mostly employed in the development of lab biosensors or on art analysis, but it has recently shown a great potential for both in vitro and in vivo applications. What’s more, the improvements reported in the synthesis methods of different types of anisotropic noble metal nanoparticles, has had a great impact in the development of SERS nanotags in the NIR region due to high enhancement factors combined with very good reproducibility in comparison with traditional SERS studies based on the aggregation of gold and silver nanospheres. On the other side, heat can be generated in localized areas when noble metal nanoparticles are irradiated with an appropriate resonant wavelength. PTT takes this principle to a truly

selective increase of the temperature in the surroundings of these nanostructures in order to promote, for example, the thermoablation of tumoral cells without harming the healthy ones. The combination of these two techniques represents a great step in the development of efficient theragnostics systems. In the last few years, these new noble metal nanosystems have shown their potential for early diagnosis (e.g., detecting down to 10 cancer cells per mL), for ultrasensitive real time monitoring (e.g., detecting changes in the intracellular temperature or pH over PTT treatment) as well as for a selective cell death induction (e.g., selectively killing cancer cells at low irradiation power density without destructing healthy cells nor the surrounding normal tissue). Therefore, one unique system can be used for both aims and offers a great promise in nanomedicine, as their reduced size and the possibility of introducing a wide range of ligands on their surface coating could provide a better access to target areas and less side effects, increasing the life quality of the patients. There are still many aspects that need to be addressed before using these systems for in vivo applications, especially when referring

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4. NOBLE METAL-BASED PLASMONIC NANOPARTICLES FOR SERS IMAGING AND PHOTOTHERMAL THERAPY

to SERS tags, as it is a quite new field for this type of applications. As with many other nanosystems applied to medicine, one of the current challenges is to evaluate their long-term biocompatibility and how easy is to excrete these nanostructures after therapy. In addition, all these studies have shown the use of SERS reporters in diagnostics, but a second challenge remains in reducing the number of these reporters and trying to go for a real label-free technique. There is an opportunity to develop SERS tags where the noble metal nanoparticles enhance the Raman signals of some of the specific target molecules or biomarkers present in the system with good sensitivity and reproducibility. Nevertheless, as all the reports compiled in this chapter indicate, SERS and PTT have a wide and successful road ahead.

[10]

[11]

[12]

[13] [14]

[15]

[16]

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[17]

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