Au Nanoparticles for Nanomedical

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Multimodal Hybrid FePt/SiO/Au Nanoparticles for Nanomedical Applications: Combining Photothermal Stimulation and Manipulation With an External Magnetic Field Nina Kostevsek, Kristina Žužek Rožman, Muhammad Shahid Arshad, Matjaž Spreitzer, Spomenka Kobe, and Saso Sturm J. Phys. Chem. C, Just Accepted Manuscript • DOI: 10.1021/acs.jpcc.5b03725 • Publication Date (Web): 23 Jun 2015 Downloaded from http://pubs.acs.org on June 25, 2015

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The Journal of Physical Chemistry

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Multimodal Hybrid FePt/SiO2/Au Nanoparticles for Nanomedical Applications: Combining Photothermal Stimulation and Manipulation With an External Magnetic Field

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Nina Kostevšek,ab Kristina Žužek Rožman,ab* Muhammad Shahid Arshad ab , Matjaž Spreitzer,c Spomenka Kobe,ab Sašo Šturmab a

Department for nanostructured materials, Jožef Stefan Institute, Jamova 39, Ljubljana, Slovenia Jožef Stefan International Postgraduate School, Jamova 39, Ljubljana, Slovenia c Department for advanced materials, Jožef Stefan Institute, Jamova 39, Ljubljana, Slovenia *The corresponding author. b

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required in order to combat the disease. In this investigation we have produced an innovative material based on FePt/SiO 2 /Au hybrid nanoparticles that exhibit a combination of photothermal and magnetic properties as a basis for a local hypothermia treatment. The magnetic cores of FePt exhibit the superparamagnetic properties necessary for biomedical purposes, while the gold nano-shells absorb light in the near-infrared range, because of their semicontinuous nature and the nanoparticle clustering, as predicted by our modelling. The as-prepared hybrid FePt/SiO 2 /Au nanoparticles were irradiated with a low-energy laser (λ=808 nm) in a water suspension, which resulted in a photo-thermal effect and a temperature increase of 10 °C during the 10 minutes of irradiation. Furthermore, the results of experiments performed on a suspension of hybrid nanoparticles in a flow of water confirmed that they can be magnetically manipulated and retained at a targeted location under realistic dynamic conditions. This dual magnetic and optical effect makes the FePt/SiO 2 /Au hybrid nanoparticles excellent candidates for photothermal cancer treatments, with the added bonus of being able to magnetically extract the particles after their use.

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Introduction

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Combining magnetically and optically active components in a single nanostructure represents a novel approach to creating multifunctional nanoparticles (NPs) that allow treatment, retention and manipulation in a controllable manner. The basic idea has its roots in the treatment of cancer based on local hyperthermia, i.e., employing a localized temperature increase to selectively overheat and therefore kill the cancerous cells, while preserving the surrounding healthy tissues intact.1-3 Research involving this technique is increasingly focused on the use of magnetically or optically active NPs. For example, it has been shown that local hyperthermia, such as the photothermal ablation of cancer cells, can be achieved with plasmonically active Au NPs.1 Here, a surface plasmon resonance (SPR) (also referred as the Mie resonance) gives rise to a sharp and intense absorption band in the UVVIS region, observed when Au NPs are exposed to light.4 The oscillating electromagnetic field of the light induces a collective, coherent, resonant oscillation of the free electrons (i.e., the conduction-band electrons) at the surfaces of the Au NPs.5 The absorbed photon energy is rapidly converted into heat by going through a process of internal relaxation of the electrons via electron-electron scattering and electron-phonon coupling, resulting in the dissipation of heat into the environment.4 This phenomenon allows the successful use of Au NPs in photothermal therapy for the selective ablation of targeted cells, where laser excitation is used as the source of the light. In order to use Au NPs most effectively for photothermal therapy, the absorption peak needs to be shifted either to the region of the first biological window in the near-infrared region (NIR) at around 800 nm or the second biological window at around 1750 nm, where the penetration of light into the tissue is at a maximum.6 As such, Au NPs were fabricated in the form of rods or shells, which enabled relatively simple positioning of the absorption peak by changing the dimensions and morphology of the appropriate nanostructures.1 Recent reports show that nanoparticles can be photothermally activated, not only in the first, but also in the second, biological window.7 Au NPs are widely used in biomedical applications because of their biocompatibility, stability, and the ease with which their surfaces can be

Abstract Despite the increasing number of successful treatments for cancer, new forms of therapy are urgently

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subsequently functionalized, for example, by the conjugation of biomarkers to Au NPs for targeting tumour cells.8 The major drawback of Au NPs in targeted drug-delivery systems is their inability to be manipulated by external sources, which limits their transport and extraction capabilities. Recently emerging, novel treatment routes, referred to as multifunctional systems, demand an expansion from single-component NPs to multi-component, hybrid nanostructures, thereby minimizing the drug doses necessary for the therapy and the resulting toxicity effects on the surrounding healthy tissues. Until now, it is mainly superparamagnetic nanoparticles (mostly comprising Fe3O4-SPIO) that have been studied for use in (hyper)thermia-based therapy,9, 10 since they are able to comprise several entities in a single system, such us the potential to be used as contrast agents in magnetic resonance imaging (MRI)10-12 and the ability to be manipulated by an applied external magnetic field.13 When used for targeted drug delivery,15 the NPs’ retention at the targeted site14, 15 and their extraction from the biological environment16 lead to reduced effects on healthy tissues, and a lower toxicological impact. However, despite their advantages and the widespread use of iron-oxide NPs, they have been shown to have some weaknesses with regards to their rapid clearance by macrophages that hinder their trans-endothelia passage and tissue penetration.17 Here, FePt-based alloys with a face-centred cubic (fcc) crystal structure represent an alternative, since they possess a three-times-higher bulk saturation magnetization18 (about 1140 emu/cm3) when compared to iron oxides.10 In addition to their promising properties for magnetic manipulation, it was shown that FePt NPs capped with tetramethylammonium hydroxide (TMAOH) have a higher T2-shortening effect than superparamagnetic iron oxide NPs,11 indicating that fcc FePt NPs could be superior contrast agents for MRI. Chen et al.17 reported that fcc FePt and silica-coated fcc FePt NPs both showed a superior capability for MRI contrast enhancement in comparison with commercial Feridex (iron oxide NPs coated with dextran). A limited number of cytotoxicity studies have been performed on FePt-based NPs12, suggesting that coatings of this alloy with biocompatible materials like silica or gold are a good solution to reducing the possible cytotoxicity. Although biocompatibility can be assured by using the above-mentioned procedures, particles present in the body will always represent some level of health risk. As a result, there is a strong belief in the nanomedicine community that there should be some means to extract the nanosized carriers from the targeted site after the treatment.19 It is believed that the optimum size for nanoparticles involved in biomedical applications ranges from 20 nm to 100 nm. Nanoparticles in that optimum size range are thought to be easily internalized by the cells.20 In addition, the choice of SiO2 as the material for the intermediate layer is beneficial, because of its biocompatibility, the possibility for subsequent functionalization and the easy regulation of the coating process.21, 22 It was shown that native and surface functionalized SiO2 nanoparticles are not biodegradable.23 On the other hand, the combined effect of the thickness of the SiO2 shell and the surface structure of the Au plays a vital role in controlling the position and the broadening of the SPR peak.24 As predicted by the Mie theory,25 at a constant core-shell ratio, by increasing the thickness of the Au shell, the SPR peak shifts towards shorter wavelengths. Although the Mie theory is only valid when complete Au shells are formed, the first estimate predicts that the optimum core-shell ratio to achieve the SPR peak at wavelengths longer than 700 nm is at least 4.5,25 which is in good agreement with experimental observations.24 Therefore, controlling the size of the SiO2 intermediate layer between the FePt core and the Au shell is of vital importance if we want to achieve a suitable size for biomedical applications and, at the same time, to shift the SPR peak into the range of the NIR spectrum (i.e., the biological window). At this point it should be pointed out that in more complex systems, experimental results can differ from the theoretical predictions, for example, when Au shells are not entirely complete26 or the nanoparticles undergo agglomeration during their synthesis27. In this study we present a comprehensive experimental set-up for the fabrication and characterization of hybrid core-shell FePt/SiO2/Au NPs (hereinafter referred to as “hybrid NPs”) enabling their magnetic extraction from the targeted site, while their strong wavelength-specific optical absorption and expelled heat is used to produce photothermally induced cell death,2 as shown schematically in Figure 1.

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Fig. 1 Schematic representation of multimodal hybrid NP functionalities for nanomedical applications by combining photothermal stimulation and manipulation with an external magnetic field


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The results of this study confirmed the NPs’ strong photothermal response in the NIR biological window, which is demonstrated by the pronounced temperature increase (∆T=10°C) during the 10 minutes of irradiation of a water suspension containing NPs (0.05 mg/mL) with low-energy laser light (irradiance of around 1 W/cm2, λ=810 nm). Additionally, it was confirmed that these hybrid NPs can be efficiently extracted using a permanent magnet during the liquid flow (150 µL/s), resulting in a 20% reduction in the initial NP concentration in a solution during a 15minute cycle. Until now, magnetically and optically active hybrid nanosystems were prepared on the basis of SPIO/Au core-shell NPs with a superparamagnetic response and a significant absorbance in the NIR region of the light;28 however, the promising properties of FePt led us to design a novel hybrid nanosystem based on FePt/SiO2/Au NPs with properties designed for use in photothermal therapies. Polycrystalline FePt-Au tadpole-, dumbbell-, bead- and necklace-like heterostructures were prepared by growing Au NPs on FePt nanorods,29 but with the aim to explore their catalytic activity. In the present study, the hybrid NPs based on superparamagnetic FePt NPs were proven to have the ability to be retained at targeted locations and then subsequently eliminated in realistic dynamic conditions. The SiO2 shell ensured an improved biocompatibility and the right core-to-Au-shell ratio for shifting the light absorption peak to the NIR “biological window”. The peak broadness into the IR region was modelled and proven by hybrid nanoparticle clustering. The suspension of hybrid NPs showed a promising photothermal effect when irradiated with low-energy laser (λ=808 nm) light. As such, the synthesised hybrid NPs demonstrate all the required properties for biomedical applications in photothermal cancer therapies.

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Materials and methods

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Characterization methods

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The samples were characterized using a transmission electron microscope (Jeol JEM-2010F) equipped with a STEM unit, energy-dispersive X-ray spectroscopy (EDXS) and electron-energy-loss spectroscopy (EELS). Powder X-ray diffractograms was measured using a Siemens D5000 diffractometer with a Cu–Kα source (λ = 1.5406 Å). Magnetic measurements were performed with a vibrating-sample magnetometer (VSM MicroSense model FCM 10) at room temperature. The UV-VIS spectroscopy was performed using a PerkinElmer Lambda 950 spectrometer. The photothermal experiments were performed by using a continuous-wave laser source with a wavelength of 800 to 820 nm and power of 0.9 W (HighLight FAP 100, Coherent, Inc., USA).

Formation of 5-nm superparamagnetic FePt core NPs At room temperature 0.5 mM of platinum acetylacetonate Pt(acac)2 (Merck) and 1 mM of iron acetylacetonate Fe(acac)3 (>99.9% Sigma-Aldrich) were added to a round-bottom flask containing 20 mL of benzyl ether (>98%, Merck) and a mixture of surfactants (2 mM) oleic acid (>99%, Sigma-Aldrich) and (2 mM) oleylamine (70%, Sigma-Aldrich). The mixture was heated using a hemispherical heating mantle (model WiseTherm WHM 12112 from Witeg Labortechnik GmbH) connected to a temperature controller (J-KEM, model 310) with a J-type Teflon thermocouple. In the first step the mixture was heated to 200°C for 30 minutes, and in the second step to 280°C for 30 minutes, before being cooled to room temperature. The heating rate in both steps was 5°C/min. The black product was precipitated by adding absolute ethanol and separated by centrifugation and re-dispersed in hexane.

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Formation of the SiO2 shell

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Formation of Au surface layer

15 mg of as-prepared FePt nanoparticles (concentration of suspension in hexane: 10 mg/mL) were added to a mixture of 170 mL of cyclohexane (>99.9%, Fisher Chemical) and 8 mL of Igepal CO-520 (Polyoxyethylene (5) nonylphenylether, Sigma-Aldrich). The best results were obtained when 1 mL of 25% ammonia solution (Merck) and 0.2 mL of TEOS (tetraethyl orthosilicate, 99.9%, Alfa Aesar) were added drop-wise and the whole mixture was vigorously stirring at room temperature. After the solution was stirred at room temperature for a specific period of time (6–72 h), methanol was added to collect the particles. The obtained suspension was then centrifuged in hexane and re-dispersed in ethanol. In order to obtain positively charged SiO2, which enables the deposition of anionic gold species in the next step, FePt/SiO2 nanoparticles were functionalized with APTES (3-aminopropyltriethoxysilane, >98%, Merck). To the suspension of FePt/SiO2 nanoparticles, 5 mL of 12-mM APTES solution (water:ethanol=1:3) was added. The reaction mixture was stirred at 80°C for 3h before cooling to room temperature. The excess of APTES was removed with five cycles of centrifugation (7500rpm/20min) and re-dispersion in water. The successful functionalization with APTES can be monitored by measuring the change in the zeta-potential (ZetaPALS, Brookhaven Instruments Corporation, USA) on the surface of FePt/SiO2 nanoparticles in the water.



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The gold shells were prepared by the two-step seeding and deposition of gold on the SiO2 surface. First, to adjust the pH value to 7, 0.1-M NaOH was added to 4 mL of 6.35-mM HAuCl4x3H2O (>99.9%, Alfa Aesar) in a water solution. The amine functionalized surface of the silica was seeded with Au(OH)3 by mixing FePt/SiO2 nanoparticles with a gold solution and stirred at 70°C for 5 minutes. The colour change from yellow to brown indicates the attachment of the Au(OH)3 to the SiO2 surface. The product was then centrifuged (950rpm/30min) and washed several times and finally dispersed in distilled water. The gold shell is finally formed by reducing the additional gold on the gold-seeded SiO2 surface. 50 mL of the gold solution with the pH=10.2 contained 30 mg of K2CO3 (>99%, Sigma-Aldrich) and 7 mg of HAuCl4x3H2O. To the mixture of gold solution and gold-seeded FePt/SiO2 core/shell nanoparticles 3 mL of ice-cold 6.6-mM NaBH4 (>99%, Fluka) was added. The reaction mixture was cooled to 0°C to slow down the reaction. An almost immediate colour change from colourless to blue indicated the formation of the Au shells. The Au-shell coverage was controlled by the amount of the gold solution, i.e., 65 mL and 50 mL for a formation of a complete (f~0.98) and semi-continuous Au shell (f≈0.8), respectively.

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Calculated efficiency of the absorption of hybrid FePt/SiO2/Au nanoparticles For hybrid nanoparticles, the efficiency of the absorption, Qabs, was calculated on the basis of the Aden and Kerker theory for coated spheres30 using computer software (MieLab) developed by O. P. Rodriguez et al.31 Software is based on improved recursive algorithm by Yang32 and freely available for download here.33 The input parameters for the code were the values of the thickness and refractive indices of each layer in hybrid nanoparticles. For gold, the values of the complex dielectric function at different wavelengths were used from Johnson and Christy.34 The embedded media for hybrid nanoparticles was considered to be water with a refractive index of 1.33+0i. The calculations were performed in the wavelength range from 300 to 1300 nm. Magnetic extraction in dynamic conditions The fluid flow was simulated by using a peristaltic pump (Ismatec Reglo), which was connected with tubes (diameter=0.5 mm) to the spectrophotometer containing a flow cuvette. Two tubes with a length of 25 cm were used to connect the peristaltic pump, the spectrophotometer and a chamber with a magnet to a closed circuit. Both tubes were connected together outside the spectrophotometer with a slightly broadened connector (1 cm), which served as a chamber to collect the hybrid NPs with a magnet. The chamber was broad enough to prevent possible tube blocking due to the collection of NPs during the experiment. A commercial Nd–Fe–B permanent magnet (µ0H=0.3 T measured right on the top of the magnet) with a disc shape (radius = 1 cm, height = 1cm) was placed next to the chamber to attract the hybrid NPs during their flow. Simultaneously, the absorption spectra were measured every 2 minutes. The normalized concentration changes in the water suspension were obtained by integrating the total spectrum intensity of the individual spectra acquired during the time series.

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Results and discussion

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Synthesis and characterization The synthesis route for the hybrid NPs involved three sequential steps, starting with the synthesis of the superparamagnetic, 5-nm, FePt-core NPs, followed by the formation of a thick, SiO2 shell, which was subsequently decorated with a surface layer of Au. The three-step synthesis route for the hybrid NPs is shown schematically in Figure 2. In short, the superparamagnetic, 5-nm, FePt nanoparticles were synthesized using a modified polyol method in an argon atmosphere, as reported by Sun's group.35 In the next step, the as-prepared FePt NPs were covered with SiO2 shells via the water-in-oil microemulsion method36 and the growth of the SiO2 shells was followed by collecting samples at different times (6–72 h) and examining them with a TEM.

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Figure 2. Schematic presentation of the three steps in the synthesis of the hybrid FePt/SiO2/Au nanoparticles

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In order to obtain positively charged SiO2, which makes it possible to deposit the anionic gold species in the next step, the FePt/SiO2 nanoparticles were functionalized with APTES (3-aminopropyltriethoxysilane), which is covalently bonded to the particle surface.37 It is important to mention that without the proper SiO2 surface modification, no Au NPs could bind to the SiO2 surface in the subsequent synthesis step. The successful


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functionalization with APTES was monitored by measuring the change in the zeta-potential on the surface of the FePt/SiO2 nanoparticles in the water. From the zeta-potential measurements shown in Figure 3 it is clear that the silica surface before the APTES functionalization is negatively charged at a pH higher than 2 (Figure 3, black curve), which is in accordance with the literature.38 This is due to the presence of -OH groups on the surface. A positive surface charge indicates the successful attachment of the aminopropylsilane groups to the particle surface (Figure 3, red curve). From the obtained results it can be concluded that the optimum pH range for attaching the APTES-functionalized FePt/SiO2 nanoparticles to the gold seeds is between pH 3 and 7, where the surface charge has the highest positive value and so the largest coverage with gold seeds can be achieved.

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Figure 3. Zeta-potential measurements of the untreated FePt/SiO2 nanoparticles and the APTES functionalized FePt/SiO2 nanoparticles in water

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The gold shells were prepared using a similar procedure to that reported by Kah et al.21 The amine-functionalized surface of the silica was seeded with gold seeds (small Au NPs 1–3 nm in size). The gold shell is finally formed by reducing the additional gold on the gold-seeded SiO2 surface. The NPs obtained during each synthesis step were examined using a variety of characterization techniques. A representative TEM image of the as-prepared FePt NPs is shown in Figure 4a. To estimate the average size of the FePt NPs, 20 individual NPs were measured from this image, shown in the right-hand-side inset in Figure 4a. The calculated diameter of the nanoparticles was dTEM=4.5±0.5 nm, with a very narrow size distribution. The analysis of the corresponding SAED pattern, shown in the left-hand-side inset in Figure 4a, is in accordance with the fcc crystal structure of the FePt phase.39

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Figure 4. a) TEM image of as-synthesized FePt nanoparticles, with the corresponding HRTEM image and SAED patterns shown as insets, and b) the corresponding XRD spectrum

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A representative TEM image of the FePt/SiO2 core-shell nanoparticles, which were the result of the formation of the SiO2 shell, is shown in Figure 5a. By examining larger areas of the TEM samples it was possible to conclude that all the FePt nanoparticles were successfully coated with the SiO2 shell. To follow the growth evolution of the SiO2 shell with time (Figure 5b), the obtained products were extracted after different reaction times (6–72 h) and examined with the TEM. The measured diameter of the FePt/SiO2 NPs as a function of time is shown in Figure 5b. This result shows that the growth of the SiO2 shell is fast, i.e., ~3 nm/h during the first 5 hours of the reaction.



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Longer reaction times resulted in linear growth with an approximate growth rate of ~0.2 nm/h for the SiO2 shell. The relative standard deviation of the average size of the FePt/SiO2 core-shell NPs measured from 50 particles was around 6 %, which indicates a narrow size distribution. The obtained results confirm that the size of the SiO2 shell can be fine-tuned by changing the synthesis time, as long as all the other parameters are kept constant.

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Figure 5. a) TEM image of SiO2-coated FePt nanoparticles, b) graph indicating the size of the FePt/SiO2 NPs as a function of the synthesis time

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The successfully gold-seeded FePt/SiO2 NPs are shown in Figure 6a. The gold seeds are uniformly distributed over the surface of the SiO2 shell. The size of such gold particles ranged from 1 nm to 3 nm. The gold seeds were used in the final step of the synthesis to serve as the nucleation sites for the growth of the gold nano-shells, as shown in Figure 6b. The estimated thickness of the gold attached to the SiO2 surface is up to 10 nm. Besides individually coated NPs, detailed TEM investigation revealed a partial agglomeration, where a cluster of few (from two to five) NPs was covered with gold. The UV-VIS absorption spectra acquired from the gold-seeded FePt/SiO2 NPs (grey line) and the hybrid core-shell NPs (black line) are shown in Figure 6c. A suspension of gold-seeded FePt/SiO2 NPs with the size of the gold seeds being 1–3 nm, exhibited a very weak SPR peak at a wavelength λ=520 nm, which is in accordance with previous observations.40 This means that for nanoparticles that are smaller than 5 nm the plasmon oscillation is strongly damped, resulting in a broad and low-intensity absorption curve, which effectively disappears for NPs less than about 2 nm in diameter, because the electron density in the conduction band becomes very small.40 In the case of the hybrid core-shell NPs the broad SPR peak saturates at λ=680 nm and remains nearly constant over the entire NIR spectrum region. This is a desirable effect, allowing us to select different laser-excitation sources from 600 nm up to 850 nm, depending on the required application in the area of photothermal cancer treatment.

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Figure 6. TEM images of FePt-SiO 2 NPs with a) gold-seeds, b) Au-shells and c) corresponding UV-VIS spectra of water suspensions containing gold-seeded FePt/SiO 2 NPs and hybrid FePt/SiO2 NPs with a Au shell

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The observed broadening of the SPR peak can be attributed to the several interconnected morphological characteristics of the hybrid core-shell NPs, resulting from the fabrication route. In other words, the coverage of the SiO2 surface with the gold might not be entirely perfect, for example, the thickness of the Au nano-shell may vary in size slightly41 and the hybrid NPs can be partially clustered. Peña-Rodríguez and Pal26 simulated the optical response of the Au nano-shells at different stages of their formation, ranging from a discrete, isolated Au nanoparticle on the SiO2 core to the formation of a complete SiO2-core with a Au shell. The strongest red shift and the largest broadening of the SPR peak were found to occur for incomplete coverage by the Au shell, i.e., a filling fraction of f=0.8. The red-shift and the broadening of the SPR peak were explained by the presence of irregular and intense local fields (known as hot spots42) that are created over the incomplete Au shell. Under the action of these local fields, the position of the SPR showed a red shift up to 50% higher than that for a complete nanoshell.

It was shown recently that gold NPs forming dimers or clusters exhibit a significant red-shift compared to individual gold NPs41 In this study the clusters were, as a first approximation, considered to be a single, large, uniform


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nanoparticle, for which the SPR modes can be theoretically predicted by using the computer software (Mielab31) for a single-standing multi-layered nanoparticle. The obtained theoretical values of the SPR modes were in good agreement with the experimental data, with some modifications, which were attributed to the irregular shapes of the individual particles within the cluster. In order to theoretically assess the correlation between the agglomeration and the corresponding SPR absorption peak value, the series of calculations were performed by assuming several nanoparticle morphologies. These calculations were performed for a series of diameters D=35–125nm, corresponding to the observed sizes of the clusters. For each series of nanoparticle diameters the thickness of the gold shell was assumed to be 10 nm. The results of calculations, shown in Figure 7, clearly show the effect of the cluster size from the significant red-shifting of the SPR absorption peak deep into the NIR spectrum region. It can be speculated that when the distribution of the cluster sizes is not uniform, the resulting UV-VIS spectrum will reflect the averaged signal of a nearly uniform intensity over the whole NIR spectrum region, with the maximum peak positioned at around 700 nm, which is in a good agreement with the experimental data (magenta curve in Figure 7).

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Figure 7. Simulated UV-Vis spectra for Au shells with different core sizes (35 – 125 nm) and comparison with experimental UV-Vis spectrum measured for hybrid NPs in water.

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Photothermal properties Figure 8a shows the experimental set-up that was used to determine the photothermal effect in a water suspension containing the hybrid NPs. The wavelength of the laser light was fixed at 810 nm. Continuous-wave diode light was focused on a cuvette using an optical lens with a spot size of about 8 mm. The temperature of the suspension was measured with a J-type Teflon thermocouple that was immersed in the quartz cuvette and connected to a computer to collect the data in real time. A representative graph of the temperature difference, i.e., the temperature increase, for pure water and the water suspension of hybrid NPs (0.05 mg/mL), which were irradiated with a laser that has an output power of 0.9 W for approximately 10 minutes, is shown in Figure 8b. In the case of the pure water the temperature increase was negligible (black curve, Figure 8b). In contrast, the temperature increase after 600 s of the water suspension containing the NPs was around 10 °C, indicating a photothermal effect (red curve, Figure 8b). The observed heating rate for the suspension of hybrid NPs in the experiment was approximately 1°C/min, which is slow enough to heat tissue in a controllable manner, but efficient enough to raise the temperature above the hyperthermia level. The heat capacity of water (4.2 kJ/kgK) is similar to the heat capacity of human tissue (3.8 kJ/kgK); therefore, it can serve as a good approximation.43 Hyperthermia is considered as a non-invasive, anticancer approach for the selective destruction of abnormal cells in which biological tissues are exposed to temperatures higher than normal body temperature (41–47 °C).2 The heating rate can be controlled by varying the power of the laser and by increasing the concentration of the photothermally active NPs in the water suspension up to a certain threshold concentration. Ji et al.28 observed that the temperature difference increased with an increased concentration of photothermally active NPs, but only up to a certain concentration of NPs. Unfortunately, the authors did not provide an explanation for this threshold behaviour.



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Figure 8. a) Experimental set-up for measuring the photothermal effect and b) graph of the temperature increase for pure water and a water suspension of hybrid NPs (0.05 mg/mL), irradiated by laser light with an output power of 0.9 W for approximately 10 minutes

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Magnetic properties and magnetic manipulation The magnetic properties of the FePt and the hybrid NPs water suspension were measured with a vibrating-sample magnetometer (VSM) at room temperature (298 K) and are presented in Figure 9. In both cases it was confirmed that the NPs are superparamagnetic, which is a general requirement for nanomedical applications. The obtained saturation magnetization value for the FePt NPs (Ms = 6 emu/g) is comparable with the reported values in the literature for a similar size of FePt NPs.12, 44 Saturation magnetization Ms of the hybrid NPs is ten times lower in comparison with the initial FePt suspension, which is due to the dilution of the magnetic phase in the sample (the Ms is given by the mass of the sample). In comparison to bulk fcc FePt, superparamagnetic fcc FePt NPs exhibit a lower Ms (75 emu/g)10 due to the magnetically “dead” surface layer resulting from the oxygen bonds of the surfactant polar end-group (oleic acid/oleylamine) with Fe.45 Since the initial size of our FePt NPs was 4.5±0.5 nm, there is still plenty of room for further improvement by increasing their size and their magnetic moment,44 while keeping their superparamagnetic nature (the Dc for fcc FePt nanoparticles was reported to be 17±2 nm).44, 46-48

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Figure 9. Magnetic properties of FePt and FePt/SiO2/Au NPs suspension

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In order to test the final hybrid NPs in a more realistic situation, an experiment was devised (Figure 10a) to study their magnetic manipulation in a water-suspension flow using a permanent magnet. The blood flow rate in the capillaries of the human body is approximately 0.05 cm/s;49 however, in our experiment a faster flow rate (0.15 cm/s) was selected in order to show that the NPs could be manipulated in harsh conditions. A commercial Nd–Fe–B permanent magnet (µ0H=0.3 T measured right on the top of the magnet) was placed next to the chamber to attract the hybrid NPs during their flow. The resulting graph indicating the normalized concentration drop of the hybrid NPs in the water suspension as a function of time is shown in Figure 10b. The obtained results demonstrate that these hybrid NPs can be efficiently extracted from a water suspension using a permanent magnet during a watersuspension flow, reducing the initial NPs concentration in the solution by 20% in just 15 minutes. For the successful manipulation of the hybrid NPs (hp) the magnetic force on the magnetic NPs (p) must exceed the fluidic drag force.13 The hydrodynamic drag force (Fd) can be calculated using Stokes' law for drag on a sphere: Fd = − 6ηrhp (vp − vf), with the parameters: η - medium viscosity, rhp - diameter of hybrid NP, vp - velocity of the particle, and vf - velocity of the media. This definition is valid in a laminar flow with a Reynolds number smaller than 1. The minimum magnetic force (Fm) needed to manipulate a particle must exceed the hydrodynamic drag force of the NPs under the dynamic flowing conditions. The magnetic force Fm on a small particle due to an external magnetic flux B can be assumed to be equal to the force experienced by a point-like magnetic dipole. This magnetic


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force is defined by: = ( ⋅ ). If we equalize both equations for the drug and the magnetic force, the required magnetic field gradient can be calculated. For the present case of hybrid NPs in a water-suspension flow with the parameters: η(H2O25°C) = 8.9x10-5 Pas, rhp = 20 nm, vp = 0 cm/s, vf = 0.15 cm/s, the calculated magnetic field gradient equals 29 T/m, which can be easily achieved with commercially available permanent magnets. We have shown that hybrid NPs can be successfully manipulated in dynamic conditions with external magnetic fields. This fits well with the literature, which reports that for most of the magnetite-based NPs, the magnetic flux densities at the target site must be of the order of 0.2 T, with field gradients of approximately 8 T/m for femoral arteries and greater than 100 T/m for the cartoid arteries,50 which are comparable with our results. Since the magnetic flux decreases exponentially with the distance, it is hard to achieve sufficient magnetic forces for a controlled manipulation using magnets externally if we want to target internal organs. But there is a possibility that magnetic implants could be located in the vicinity of the target using minimally invasive surgery.15 Thus, a strong enough local magnetic field can be created to overcome the hydrodynamic forces in the blood stream.14 As an example, gold-coated Nd–Fe–B magnets were already inserted into the kidneys of New Zealand rabbits and were proven to more effective at attracting the nanoparticles than externally positioned magnets.15

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Figure 10. a) Schematic representation of the experimental set-up for studying the manipulation of hybrid NPs in a water suspension with the use of an applied external field, and b) the resulting graph indicating the normalized concentration drop of hybrid NPs in the water suspension as a function of time

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Conclusions

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We have demonstrated that by fabricating a magnetic FePt core, embedded in a dielectric SiO2, and covered with an optically active Au shell, hybrid FePt/SiO2/Au NPs with combined magnetic and optical properties can be produced. The fabricated hybrid FePt/SiO2/Au NPs exhibited sufficient magnetization to be guided and separated in dynamic flow conditions. The red shift and the absorption peak broadening over the large NIR biological window region was achieved via partial Au-shell filling and via the clustering of the hybrid FePt/SiO2/Au NPs exhibiting complex SPR modes. Photothermal experiments where laser light of λ=808 nm was used to induce the heating a water suspension of hybrid FePt/SiO2/Au NPs showed a very promising photo-thermal effect, i.e., the temperature of the suspension was found to increase by 10 °C in 10 min, which sufficient to induce photothermia. Additionally, the hybrid FePt/SiO2/Au NPs were successfully retained at the targeted location by using a commercial permanent magnet (µ0H= 0.3T). It should be made clear that the dynamic conditions included liquid flow rates of 0.15 cm/s, which exceeds the average velocity of blood in the body by 3 times. The developed hybrid FePt/SiO2/Au NPs show great potential for the successful implementation of such multifunctional hybrid inorganic NPs in future nanomedicine applications, since their magnetic properties allow them to be manipulated by an applied external field, while their strong wavelength-specific optical absorption and the expelled heat make them suitable for photothermally induced cancer therapies.

Author information Corresponding Author *E-mail:[email protected].

Acknowledgements This work was supported by the Slovenian Research Agency (ARRS), project J2-6760.

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Schematic representation of multimodal hybrid NP functionalities for nanomedical applications by combining photothermal stimulation and manipulation with an external magnetic field 650x500mm (72 x 72 DPI)

ACS Paragon Plus Environment

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Schematic presentation of the three steps in the synthesis of the hybrid FePt/SiO2/Au nanoparticles 49x13mm (300 x 300 DPI)



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Zeta-potential measurements of the untreated FePt/SiO2 nanoparticles and the APTES functionalized FePt/SiO2 nanoparticles in water 74x51mm (300 x 300 DPI)


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a) TEM image of as-synthesized FePt nanoparticles, with the corresponding HRTEM image and SAED patterns shown as insets, and b) the corresponding XRD spectrum 80x80mm (300 x 300 DPI)



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a) TEM image of SiO2-coated FePt nanoparticles, b) graph indicating the size of the FePt/SiO2 NPs as a function of the synthesis time 268x101mm (300 x 300 DPI)


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TEM images of FePt-SiO2 NPs with a) gold-seeds, b) Au-shells and c) corresponding UV-VIS spectra of water suspensions containing gold-seeded FePt/SiO2 NPs and hybrid FePt/SiO2 NPs with a Au shell 99x58mm (300 x 300 DPI)



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Simulated UV-Vis spectra for Au shells with different core sizes (35 – 125 nm) and comparison with experimental UV-Vis spectrum measured for hybrid NPs in water 288x201mm (300 x 300 DPI)


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a) Experimental set-up for measuring the photothermal effect and b) graph of the temperature increase for pure water and a water suspension of hybrid NPs (0.05 mg/mL), irradiated by laser light with an output power of 0.9 W for approximately 10 minutes 294x120mm (300 x 300 DPI)



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Magnetic properties of FePt and FePt/SiO2/Au NPs suspension 55x38mm (300 x 300 DPI)


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a) Schematic representation of the experimental set-up for studying the manipulation of hybrid NPs in a water suspension with the use of an applied external field, and b) the resulting graph indicating the normalized concentration drop of hybrid NPs in the water suspension as a function of time 56x20mm (300 x 300 DPI)



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Table of Contents Graphic 52x17mm (300 x 300 DPI)


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Au Nanoparticles for Nanomedical

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