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Superparamagnetic iron oxide nanodiscs for hyperthermia therapy: Does size matter?
Journal of Alloys and Compounds 714 (2017) 709e714
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Journal of Alloys and Compounds journal homepage: http://www.elsevier.com/locate/jalcom
Superparamagnetic iron oxide nanodiscs for hyperthermia therapy: Does size matter? Z. Nemati a, S.M. Salili b, c, J. Alonso a, d, **, A. Ataie c, R. Das a, M.H. Phan a, H. Srikanth a, * a
Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA Chemical Physics Interdisciplinary Program & Liquid Crystal Institute, Kent State University, Kent, OH, 44242, USA c School of Metallurgy and Materials Engineering, University of Tehran, Tehran, Iran d gico de Vizcaya, Derio, 48940, Spain BCMaterials Edificio No. 500, Parque Tecnolo b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 February 2017 Received in revised form 17 April 2017 Accepted 19 April 2017 Available online 20 April 2017
For the final realization of magnetic nanoparticles (MNPs) mediated hyperthermia as a viable clinical therapy for cancer treatment, it is necessary to devise novel approaches in order to improve the heating efficiency or Specific Loss Parameter (SLP) of these MNPs. Recently, it has been shown that magnetic nanodiscs with enhanced shape anisotropy, diameters around 200 nm (25 nm thick), and vortex magnetic domain structure exhibit very high SLP values. Despite their high heating efficiency, biomedical applications of these nanodiscs could not be hassle-free due to their relatively big size. Therefore, in this work, we have studied how the heating efficiency of the nanodiscs changes upon size reduction (~12 nm diameter and ~3 nm thickness). In addition, we have compared these results with those obtained for more typically studied spherical nanoparticles of similar volume. Transmission Electron microscopy, Atomic Force Microscopy and X-ray Diffraction confirm the disc shape of our MNPs and that they are mostly composed of iron oxide (Fe3O4 or g-Fe2O3) phase. Magnetometry indicates that the nanodiscs do not exhibit a vortex magnetic domain structure, but still present a superparamagnetic-like behavior, with zero magnetization in the absence of field at room temperature (ideal for biomedical applications) and enhanced effective anisotropy as compared to the spherical nanoparticles. Finally, calorimetric methods based magnetic hyperthermia experiments indicate that the SLP values for these small nanodiscs are much lower than those reported for the bigger disc-shaped nanoparticles, but these superparamagnetic nanodiscs act as better heating mediators than the spherical nanoparticles of similar volume. © 2017 Elsevier B.V. All rights reserved.
Keywords: Iron oxide nanodiscs Magnetic hyperthermia Effective anisotropy
1. Introduction Magnetic nanoparticles (MNPs) mediated hyperthermia is one of the most promising techniques for cancer treatment [1e3]. This technique essentially comprises the following steps: injecting MNPs into the human body, delivering them to the tumor area, and once the MNPs are disseminated inside the tumor, an external AC magnetic field is applied, and the nanoparticles transform the electromagnetic radiation into heat [4]. The generated heat rises the temperature in the tumor area and, in this way, damages or
* Corresponding author. Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA. ** Corresponding author. Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA. E-mail addresses: [email protected] (J. Alonso), [email protected] (H. Srikanth). http://dx.doi.org/10.1016/j.jallcom.2017.04.211 0925-8388/© 2017 Elsevier B.V. All rights reserved.
even kills and eradicates cancerous cells with minimally affecting the healthy ones, because healthy cells present a better resistance to high temperature than cancer cells [5,6]. In this way, the patient can receive a localized and highly efficient cancer therapy, without suffering from the collateral damage associated with other more commonly employed treatments, such as chemotherapy or radiotherapy. Despite the many promising aspects of this therapy, the current status of the clinical application of magnetic hyperthermia therapy is still very preliminary [3]. Only in a few places in the world, including Germany, Japan, and China, clinical trials have been carried out [7]. For example, ferrite core-based magnetic nanoparticles are being used for clinical cancer treatment (MagForce Nanotechnologies AG, Berlin, Germany) with a magnetic field strength of up to 225 Oe at 100 kHz, in combination with radiotherapy [8]. The results indicate an increase in the median survival time of the patients, but unfortunately no full recovery has been achieved yet.
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There are several limitations that negatively affect the efficiency of the magnetic hyperthermia treatment and therefore hinder its clinical realization [9]. These include problems in the delivery of the nanoparticles to the tumor area, restrictions in the maximum field and frequency that can be applied within the safety limits, low performance of the nanoparticles once inside the tumor, etc. [10]. In particular, the limitations related to the low heating efficiency of the commonly employed iron oxide (Fe3O4 or g-Fe2O3) nanoparticles have received great attention in the last few years. Superparamagnetic iron oxide nanoparticles (SPIONs) were initially considered as the ideal MNPs for a wide range of biomedical applications, including magnetic hyperthermia, due to the excellent biocompatibility of the material and the small tendency to agglomeration, thanks to their superparamagnetic nature [11,12]. However, results have shown that these MNPs present a rather limited heating efficiency or Specific Loss Power (SLP), as it is denominated in the context of magnetic hyperthermia [13,14]. The SLP of the MNPs is directly related to their hysteresis losses [15], and therefore to their AC hysteresis loop area: the bigger the area under a certain applied AC field, the better the heating efficiency. Therefore, despite their good biocompatible characteristics, SPIONs generally present relatively low saturation magnetization (MS) and coercivity (HC), which diminish their heating efficiency, and therefore, deter their applicability. Different strategies have been proposed in order to overcome this limitation [16]. These include changing the magnetic material by other with higher MS (Fe, FeCo, …) [17,18]; tuning the size of the nanoparticles in order to optimize the hysteresis losses [19]; increasing the coercivity (anisotropy) of the nanoparticles through exchange coupling or doping [17,18,20e22] or changing the morphology (aspect ratio, shape) of the MNPs [23,24]. In this way, different shapes of MNPs other than the typical spheres have been proposed in order to tune their anisotropy and improve their heating efficiency: cubes, octopods, octahedral, cube-octahedral [23,25,26,46,47]. In this regard, disc shaped magnetic particles have attracted much attention in biomedicine [27e29,48]. Thanks to their large surface area, they can attach several bio-substances at once; their disc shape also increases their effective anisotropy; and at bigger sizes, they develop a vortex magnetic domain structure that ensures null magnetization in absence of magnetic field, reducing the problem of particle agglomeration [24,27]. As an example, it has been reported that bio-functionalized magnetic-vortex microdiscs (60-nm-thick, 1-mm-diameter 20:80% iron-nickel (perm-alloy discs) can oscillate in the presence of an alternating magnetic field, destroying the cancerous cells directly by mechanical force [31]. Despite this growing interest, in the field of magnetic hyperthermia for cancer treatment there have been only a few articles on the heating properties of magnetic nanodiscs. Recently Yang et al. [30] have reported that Fe3O4 nanodiscs (225 nm diameter; 26 nm thickness) exhibit much better hyperthermia performance than isotropic nanoparticles (SLPmax ¼ 4400 W/g at 600 Oe and 488 kHz), attributed to the parallel alignment of nanodiscs with respect to the AC field. Previously, Ma et al. [32] had reported that their nanodiscs (150e200 nm diameter; 10e15 nm thickness) presented a SLP value of 253 W/g (12 Oe and 180 kHz), higher than those typically reported for spherical MNPs. Despite these remarkable results, the average size of the nanodiscs that have been investigated is much bigger than that of MNPs typically used in hyperthermia therapy (5e100 nm) [33]. Their large size could restrict their capacity for being internalized by cancerous cells, decrease their average lifetime in blood and lead to potential negative agglomeration effects [34]. Therefore, in this work, we have synthesized smaller iron oxide nanodiscs (~12 nm diameter, ~3 nm thickness) and compared their
heating properties with those of the much bigger nanodiscs reported in the literature [28] and with spherical MNPs of similar volume synthesized by us. The results indicate that the reduction in the size of the nanodiscs deters their heating efficiency but still, the heating results obtained are better than those measured for the spherical MNPs of similar volume. Our study indicates that in order to continue with the development of nanodiscs for magnetic hyperthermia, the size needs to be carefully tuned in order to improve their “in-vivo” properties (kinetics, internalization, dissemination, agglomeration …) while still obtaining a significant heating efficiency. 2. Experimental methods For this study, we have prepared one sample composed of disc shaped MNPs and one sample formed by spherical MNPs. Iron oxide (Fe3O4 or g-Fe2O3) disc-shaped MNPs were synthesized via the soft template-assisted synthesis [35,36] in a binary system of H2O/Cetyltrimethylammonium bromide (CTAB), 77/23 g at room temperature. This mixture forms a hexagonal lyotropic liquid crystalline phase. Fe(acac)3 in H2O/CTAB goes through a cascade of reduction-hydrolysis reactions in the presence of aqueous NaBH4. Fe(OH)x, where x is 1, 2 and 3 are formed as intermediately until Magnetite (Fe3O4) is formed via nucleation reactions of Fe(OH)2 and Fe(OH) [37]. In a 3-neck round bottom flask, Fe(acac)3 (2 mmol) was dissolved in a mixture of 77 g of degassed DI water and 23 g of CTAB. 10 mmol of NaBH4 was then mixed with 3 mL of degassed DI water and added to the above mixture. The vessel was under constant flow of nitrogen as well as vigorous mechanical stirring (500 rpm) at room temperature. The reaction resulted in two products, the froth and the gel after 5 h, and the disc shaped MNPs were retrieved from the formed gel. In order to isolate the particles from the surfactant, the gel was washed several times with 50 C water and centrifuged at 5000 rpm and was eventually dried out. On the other hand, we also produced iron oxide spherical MNPs by using non-hydrolytic thermal decomposition. Details of the synthesis route have been given previously (see Ref. [38]). Briefly, a three neck flask was charged with 1,2 hexadecane diol, Benzyl ether (98%), Oleylamine (70%), Oleic acid (90%), and Iron (III) acetylacetonate, which was used as the precursor. The mixture was stirred magnetically under a flow of nitrogen gas for 2 h at 200 C. Temperature was raised subsequently to 300 C for 1 h. After reflux the sample was cooled down to room temperature. Finally, the spherical MNPs were coated with tetramethylammonium hydroxide (TMAH) to make them water dispersible. A Bruker AXS D8 X-ray diffractometer (Cu -Ka radiation, 0.15418 nm) was used to analyze the crystalline structure of the disc and spherical shaped MNPs, and an FEI Morgagni 268 transmission electron microscope (TEM), operating at 60 kV, was used to obtain information about their size distribution and morphology. Both Xray diffraction and selected area electron diffraction were utilized to further investigate the sample's crystalline structure. The thickness of the nanodiscs was determined by using Atomic Force Microscopy (AFM) in tapping mode (DSP Classic model, Nanotec). Magnetic measurements were carried out using a Physical Property Measurement System (PPMS) from Quantum Design, with a vibrating sample magnetometer (VSM) option. The zero-fieldcooling/field-cooling (ZFC/FC) curves were measured between 5 and 350 K, with an applied field of 50 Oe, while the hysteresis loops were measured at room temperature, 300 K, applying fields up to 50 kOe. Magnetic hyperthermia measurements were carried out using calorimetric methods, with a 4.2-kW Ambrell Easyheat Li3542 system. A suspension of 1 mg/ml of nanoparticles in water was used for measurements and the AC magnetic field was tuned from 0 to 800 Oe, at a constant frequency of 310 kHz.
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3. Results and discussion 3.1. Structural properties TEM images for the sample composed of spherical MNPs can be seen in Fig. 1 (a). In addition, a TEM image of the disc-shaped MNPs is presented in Fig. 1 (b). As one can see, the discs present mostly a circular surface, with a relatively wide size distribution, being the estimated average diameter around 11.5 ± 2.7 nm (see the inset to Fig. 1 (b)), and the circularity around 0.90 ± 0.08 nm (circularity ¼ (4p Area/Perimeter2, ranges from 0 (infinitely elongated polygon) to 1 (perfect circle)). The thickness for these nanodiscs has been estimated via AFM, as depicted in Fig. 1 (c) and (f). AFM is an ideal tool to measure thickness of nanostructures, allowing us to reach perpendicular resolutions below 1 nm. However, the lateral resolution is not very good, due to the effect of the curvature radius of the tip [39], and this limits the capacity to laterally resolve individual discs unless they are well separated. This can be observed in Fig. 1 (f), in which the measured diameter is much bigger than the ones obtained by TEM, suggesting that the image corresponds to a few nanodiscs next to each other. The thicknesses of disc-shaped samples has been estimated to vary between 2.5 and 3 nm. Therefore, the average volume calculated for these nanodiscs is ~340 nm3. The spherical nanoparticles are more uniform than the discs, with an average volume of ~270 nm3, and therefore they are more or less comparable to our nanodiscs (~20% difference in volume). The comparison between these samples will be useful to determine if the heating properties of the nanoparticles are improved by modifying the shape of the MNPs, from spheres to discs. The selected area electron diffraction (SAED) shows the characteristic ring pattern of the crystal Fe3O4 or g-Fe2O3 (Fig. 1 (d)). In order to further analyze the crystalline structure of our samples, we have also performed XRD. As indicated in Fig. 1 (e), the obtained patterns for disc and spherical shaped nanoparticles present similar characteristics, with several well defined diffraction peaks. The position and relative intensities of all the XRD peaks match well with those of an inverse spinel structure, either
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magnetite or maghemite (America Mineralogy Crystal Structure Database AMCSD 0000945). No other iron oxide phase (such as wüstite, FeO) has been detected by XRD within the resolution of the used instrument. 3.2. Magnetic properties The magnetic response of these samples has been characterized both as a function of the temperature (ZFC/FC curves) and as a function of the field (M - H loops), as depicted in Fig. 2. The ZFC/FC curve for the spherical MNPs is typical of small superparamagnetic nanoparticles, with a maximum at the ZFC around 55 K, corresponding to the blocking temperature, TB, of the nanoparticles and a FC curve that continuously increases with decreasing temperature [40,41]. However, the ZFC/FC curve for the nanodiscs is very different from the one obtained for the spherical nanoparticles. The ZFC/FC curve for the nanodiscs exhibits a much broader maximum displaced towards higher temperatures for the ZFC curve and strong irreversibility between the ZFC and FC branches until high temperatures. This behavior could be related, on one hand, to the wider size distribution of the nanodiscs, which could explain the broadening of the ZFC curves, and on the other hand, to an increase in the effective anisotropy: since the blocking temperature is essentially proportional to the product of the effective anisotropy of the nanoparticles, K, by their volume, V, the difference in TB between the spherical and disc shaped samples, despite having a similar volume, could be related to an increase of K for the nanodiscs. This increase in the effective anisotropy can be associated with the shape (shape anisotropy) and the increase in surface area (surface anisotropy) of the nanodiscs [42] as has been reported elsewhere [43]. The increase in the effective anisotropy is in principle favorable for the heating of the MNPs during the magnetic hyperthermia experiments, since it tends to give rise to an increased hysteresis loop area, and therefore, enhanced hysteresis losses, as has been reported in the literature [16]. On the other hand, the M - H loops at room temperature (Fig. 2 (b)) exhibit zero coercivity and remanence, and the shape of the
Fig. 1. TEM images for (a) spherical MNPs, and (b) nanodiscs (in the inset, we present the size distribution). (c) AFM image obtained for the nanodiscs. A profile (blue line) has been measured across the nanodiscs, as represented in (f). (d) Selected area electron diffraction (SAED) of the disc shaped sample. (e) XRD patterns for samples nanospheres and nanodiscs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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Fig. 2. (a) ZFC (solid)/FC (dashed) curves measured at 50 Oe and (b) M - H loops obtained at room temperature for the spherical and disc shaped nanoparticles. The fitting of the M H loops to Equation (1) is also included. In the inset, a zoom-in of the M - H loops in the low field region is presented.
curves is again similar to that typically observed in systems of nanoparticles with superparamagnetic-like behavior [40]. This is especially important for biomedical applications of the nanoparticles, since the absence of magnetization in zero field diminishes the tendency of the MNPs to agglomerate due to magnetic interactions and ensures the colloidal stability of the ferrofluids. In addition, it can be observed that the M - H loops for the nanodiscs do not exhibit the characteristic shape obtained in vortex domain structures, i.e. zero coercivity and remanence, but nonzero hysteresis loop area [29]. This can be easily understood considering that the size of our nanodiscs is too small to give rise to multidomains as required for the vortex domain structure. The superparamagnetic behavior of these spherical and disc shaped MNPs has been further confirmed by the fitting the M - H hysteresis loops using the
following expression [40]:
MðHÞ ¼ MS
Z∞ mH f ðVÞdV þ cH L kB T
(1)
0
where V is the volume of the nanoparticles, f(V) corresponds with a Log-Normal size distribution, c is the paramagnetic susceptibility of the surface spins, and L(x) ¼ cotanh(x)-1/x. As can be seen, the fittings obtained for both samples are pretty good: the estimated magnetic volumes for the nanospheres and the nanodiscs are ~210 and ~290 nm3, which are around 20e25% smaller than the physical volumes estimated by TEM (270 and 340 nm3, respectively), as expected due to the high contribution of surface spin disorder for
Fig. 3. Heating curves measured for (a) spherical and (b) disc-shaped MNPs at 0e800 Oe and 310 kHz. (c) Comparison of the SLP values obtained for spheres and for the nanodiscs (discs). We have also included the SLP results for bigger nanodiscs (discs D > 20 nm), for comparison's sake.
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such small MNPs that effectively reduces the apparent size determined by magnetic measurements. Nevertheless, there are some appreciable differences in the shape of the curves, as can be seen in the inset to Fig. 2 (b): for the nanodiscs, the approach to saturation is faster, being the M - H loops slightly more rectangular, while the approach to saturation for the spherical samples is slower. This again suggests an increased anisotropy for the nanodiscs. In order to confirm this, we have roughly estimated the effective anisotropy using the law of approach to saturation [44]:
. M ¼ Ms 1 b H2
(2)
where MS is the saturation magnetization and b is correlated with the effect of the anisotropy. In the case of uniaxial magnetic crystals the fitting parameter b can be used to obtain an estimation of the anisotropy:
K ¼ m0 Ms ð15b=4Þ1=2
(3) 5
The estimated anisotropy values are 8.5 10 erg/cc for the spherical MNPs and 10.1 105 erg/cc for the disc shaped nanoparticles, corroborating the increase in effective anisotropy for the nanodiscs. This increase in the effective anisotropy also agrees with the increase in the blocking temperature observed in the ZFC/FC curves. In fact, the obtained K value for the spherical MNPs compares well with that estimated from the blocking temperature of the ZFC curve (K~6.6 105 erg/cc). Unfortunately, the broadening of the ZFC curve for the nanodiscs doesn't allow us to obtain an estimation of the blocking temperature (and the effective anisotropy) to compare with, but, as explained before, it is supposed to be higher.
3.3. Magnetic hyperthermia Once the magnetic behavior of the nanodiscs and spheres has been analyzed, we have measured their heating capacity, and compared the results with those of the bigger nanodiscs reported recently in the literature [30,32], as we commented in the Introduction. In order to estimate the heating efficiency of the nanoparticles, we have used the standard hyperthermia calorimetric experiments. In these experiments, a vial with the sample is placed into a coil connected to a power generator, which allows us to control the amplitude of the AC field inside the coil. While the field is applied, a fiber optic temperature sensor inserted into the vial with the solution records the increase in temperature, and from the initial slope of these Temperature vs time curves, one can obtain the SLP values:
ms DT SLP ¼ Cp mn Dt
(4)
where Cp is the specific heat capacity of the medium, ms is the mass of the solvent, and mn is the mass of the nanoparticles. The heating curves measured for the 2 samples have been obtained with applied AC magnetic fields at 300 kHz between 0 and 800 Oe. In Fig. 3 (a) and (b), we present the results for the spherical and disc shaped MNPs, respectively. As can be observed, the heating rates are relatively slow, even for the maximum field applied, 800 Oe. This can also be seen in Fig. 3 (c), where the heating efficiency or SLP values for the two samples are directly compared. As observed, the nanodiscs present SLP values that are appreciably higher than those exhibited by the spherical MNPs of similar volume, especially at low fields. To further confirm the improved heating efficiency of the nanodiscs, we have also compared the SLP values for bigger spherical (~1400 nm3) and disc shaped (~1200 nm3) MNPs and
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again observed an appreciably increased heating efficiency for the nanodiscs: the nanodiscs present a maximum SLP of 125 W/g vs the 90 W/g of the spheres (see Fig. 3 (c)). This clearly confirms that the disc-shaped MNPs exhibit advantages over the spherical ones for hyperthermia treatment. However, the SLP values we have obtained here are much smaller than those reported by Yang et al. [8], and Ma et al. [9] for their bigger nanodiscs. This indicates that size reduction of the nanodiscs appreciably hinders their heating capacity, despite the potential improvement of other important “invivo” characteristics such as the circulation life time in the blood or the MNPs disaggregation. A possible explanation for this deterioration of the heating properties of the nanodiscs with decreasing size can be related to the loss of the vortex magnetic domain structure, as commented in the Introduction, which has been reported to increase the hysteresis loop area and therefore, the hysteresis losses of this kind of nanostructures [29,45]. In addition, the magnetic properties also deteriorate with decreasing size of the MNPs: the maximum MS we obtain for our nanodiscs is around 60 emu/g while Yang et al. report a value of 84 emu/g for their samples, which is closer to the bulk value of magnetite (92 emu/g). Moreover, this could also affect the capacity of the MNPs to align in the direction of the field, which has been shown to be very important in order to improve the heating efficiency of this kind of anisotropic nanostructures [24,26]. Nevertheless, our hyperthermia measurements have shown that the heating efficiency of these small nanodiscs is still better than that of spherical MNPs of similar volume, and therefore, these superparamagnetic nanodiscs are still interesting for magnetic hyperthermia treatment. 4. Conclusions We have attempted to shed light on the change in heating efficiency of small superparamagnetic nanoparticles when their shape is changed from spherical to disc -shaped. It has been observed that the heating efficiency of these nanodiscs improves especially in the low field region, in comparison to their spherical counterparts. As the size of these nanodiscs decreases, their heating efficiency also tends to decrease. In this way, the obtained SLP values are much smaller than those recently reported for the bigger nanodiscs. Therefore, the size of these nanodiscs should be carefully tuned in order to enhance their heating properties while conserving the “in-vivo” advantages associated with small superparamagnetic nanoparticles. Acknowledgements Research at USF was supported by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering under Award No. DE-FG02-07ER46438 (Synthesis and magnetic studies) and by the Bizkaia Talent Program, Basque Country (Hyperthermia measurements). Javier Alonso acknowledges the financial support provided through a postdoctoral fellowship from Basque Government. We would like to thank Dr. Carolina Redondo (Physical Chemistry Dept., UPV/EHU) for the use of the Atomic Force Microscope. References [1] D. Ortega Ponce, Q. Pankhurst, Magnetic hyperthermia, in: P. O'Brien (Ed.), Nanoscience, Royal Society of Chemistry, 2012, pp. 60e88. http://discovery. ucl.ac.uk/1386519/. [2] C. Binns, Magnetic nanoparticle hyperthermia treatment of tumours, in: B. Aktas¸, F. Mikailzade (Eds.), Nanostructured Mater. Magnetoelectron, Springer Berlin Heidelberg, Berlin, Heidelberg, 2013, pp. 197e215, http:// dx.doi.org/10.1007/978-3-642-34958-4.
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Journal of Alloys and Compounds journal homepage: http://www.elsevier.com/locate/jalcom
Superparamagnetic iron oxide nanodiscs for hyperthermia therapy: Does size matter? Z. Nemati a, S.M. Salili b, c, J. Alonso a, d, **, A. Ataie c, R. Das a, M.H. Phan a, H. Srikanth a, * a
Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA Chemical Physics Interdisciplinary Program & Liquid Crystal Institute, Kent State University, Kent, OH, 44242, USA c School of Metallurgy and Materials Engineering, University of Tehran, Tehran, Iran d gico de Vizcaya, Derio, 48940, Spain BCMaterials Edificio No. 500, Parque Tecnolo b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 February 2017 Received in revised form 17 April 2017 Accepted 19 April 2017 Available online 20 April 2017
For the final realization of magnetic nanoparticles (MNPs) mediated hyperthermia as a viable clinical therapy for cancer treatment, it is necessary to devise novel approaches in order to improve the heating efficiency or Specific Loss Parameter (SLP) of these MNPs. Recently, it has been shown that magnetic nanodiscs with enhanced shape anisotropy, diameters around 200 nm (25 nm thick), and vortex magnetic domain structure exhibit very high SLP values. Despite their high heating efficiency, biomedical applications of these nanodiscs could not be hassle-free due to their relatively big size. Therefore, in this work, we have studied how the heating efficiency of the nanodiscs changes upon size reduction (~12 nm diameter and ~3 nm thickness). In addition, we have compared these results with those obtained for more typically studied spherical nanoparticles of similar volume. Transmission Electron microscopy, Atomic Force Microscopy and X-ray Diffraction confirm the disc shape of our MNPs and that they are mostly composed of iron oxide (Fe3O4 or g-Fe2O3) phase. Magnetometry indicates that the nanodiscs do not exhibit a vortex magnetic domain structure, but still present a superparamagnetic-like behavior, with zero magnetization in the absence of field at room temperature (ideal for biomedical applications) and enhanced effective anisotropy as compared to the spherical nanoparticles. Finally, calorimetric methods based magnetic hyperthermia experiments indicate that the SLP values for these small nanodiscs are much lower than those reported for the bigger disc-shaped nanoparticles, but these superparamagnetic nanodiscs act as better heating mediators than the spherical nanoparticles of similar volume. © 2017 Elsevier B.V. All rights reserved.
Keywords: Iron oxide nanodiscs Magnetic hyperthermia Effective anisotropy
1. Introduction Magnetic nanoparticles (MNPs) mediated hyperthermia is one of the most promising techniques for cancer treatment [1e3]. This technique essentially comprises the following steps: injecting MNPs into the human body, delivering them to the tumor area, and once the MNPs are disseminated inside the tumor, an external AC magnetic field is applied, and the nanoparticles transform the electromagnetic radiation into heat [4]. The generated heat rises the temperature in the tumor area and, in this way, damages or
* Corresponding author. Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA. ** Corresponding author. Materials Institute and Department of Physics, University of South Florida, Tampa, FL, 33620, USA. E-mail addresses: [email protected] (J. Alonso), [email protected] (H. Srikanth). http://dx.doi.org/10.1016/j.jallcom.2017.04.211 0925-8388/© 2017 Elsevier B.V. All rights reserved.
even kills and eradicates cancerous cells with minimally affecting the healthy ones, because healthy cells present a better resistance to high temperature than cancer cells [5,6]. In this way, the patient can receive a localized and highly efficient cancer therapy, without suffering from the collateral damage associated with other more commonly employed treatments, such as chemotherapy or radiotherapy. Despite the many promising aspects of this therapy, the current status of the clinical application of magnetic hyperthermia therapy is still very preliminary [3]. Only in a few places in the world, including Germany, Japan, and China, clinical trials have been carried out [7]. For example, ferrite core-based magnetic nanoparticles are being used for clinical cancer treatment (MagForce Nanotechnologies AG, Berlin, Germany) with a magnetic field strength of up to 225 Oe at 100 kHz, in combination with radiotherapy [8]. The results indicate an increase in the median survival time of the patients, but unfortunately no full recovery has been achieved yet.
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There are several limitations that negatively affect the efficiency of the magnetic hyperthermia treatment and therefore hinder its clinical realization [9]. These include problems in the delivery of the nanoparticles to the tumor area, restrictions in the maximum field and frequency that can be applied within the safety limits, low performance of the nanoparticles once inside the tumor, etc. [10]. In particular, the limitations related to the low heating efficiency of the commonly employed iron oxide (Fe3O4 or g-Fe2O3) nanoparticles have received great attention in the last few years. Superparamagnetic iron oxide nanoparticles (SPIONs) were initially considered as the ideal MNPs for a wide range of biomedical applications, including magnetic hyperthermia, due to the excellent biocompatibility of the material and the small tendency to agglomeration, thanks to their superparamagnetic nature [11,12]. However, results have shown that these MNPs present a rather limited heating efficiency or Specific Loss Power (SLP), as it is denominated in the context of magnetic hyperthermia [13,14]. The SLP of the MNPs is directly related to their hysteresis losses [15], and therefore to their AC hysteresis loop area: the bigger the area under a certain applied AC field, the better the heating efficiency. Therefore, despite their good biocompatible characteristics, SPIONs generally present relatively low saturation magnetization (MS) and coercivity (HC), which diminish their heating efficiency, and therefore, deter their applicability. Different strategies have been proposed in order to overcome this limitation [16]. These include changing the magnetic material by other with higher MS (Fe, FeCo, …) [17,18]; tuning the size of the nanoparticles in order to optimize the hysteresis losses [19]; increasing the coercivity (anisotropy) of the nanoparticles through exchange coupling or doping [17,18,20e22] or changing the morphology (aspect ratio, shape) of the MNPs [23,24]. In this way, different shapes of MNPs other than the typical spheres have been proposed in order to tune their anisotropy and improve their heating efficiency: cubes, octopods, octahedral, cube-octahedral [23,25,26,46,47]. In this regard, disc shaped magnetic particles have attracted much attention in biomedicine [27e29,48]. Thanks to their large surface area, they can attach several bio-substances at once; their disc shape also increases their effective anisotropy; and at bigger sizes, they develop a vortex magnetic domain structure that ensures null magnetization in absence of magnetic field, reducing the problem of particle agglomeration [24,27]. As an example, it has been reported that bio-functionalized magnetic-vortex microdiscs (60-nm-thick, 1-mm-diameter 20:80% iron-nickel (perm-alloy discs) can oscillate in the presence of an alternating magnetic field, destroying the cancerous cells directly by mechanical force [31]. Despite this growing interest, in the field of magnetic hyperthermia for cancer treatment there have been only a few articles on the heating properties of magnetic nanodiscs. Recently Yang et al. [30] have reported that Fe3O4 nanodiscs (225 nm diameter; 26 nm thickness) exhibit much better hyperthermia performance than isotropic nanoparticles (SLPmax ¼ 4400 W/g at 600 Oe and 488 kHz), attributed to the parallel alignment of nanodiscs with respect to the AC field. Previously, Ma et al. [32] had reported that their nanodiscs (150e200 nm diameter; 10e15 nm thickness) presented a SLP value of 253 W/g (12 Oe and 180 kHz), higher than those typically reported for spherical MNPs. Despite these remarkable results, the average size of the nanodiscs that have been investigated is much bigger than that of MNPs typically used in hyperthermia therapy (5e100 nm) [33]. Their large size could restrict their capacity for being internalized by cancerous cells, decrease their average lifetime in blood and lead to potential negative agglomeration effects [34]. Therefore, in this work, we have synthesized smaller iron oxide nanodiscs (~12 nm diameter, ~3 nm thickness) and compared their
heating properties with those of the much bigger nanodiscs reported in the literature [28] and with spherical MNPs of similar volume synthesized by us. The results indicate that the reduction in the size of the nanodiscs deters their heating efficiency but still, the heating results obtained are better than those measured for the spherical MNPs of similar volume. Our study indicates that in order to continue with the development of nanodiscs for magnetic hyperthermia, the size needs to be carefully tuned in order to improve their “in-vivo” properties (kinetics, internalization, dissemination, agglomeration …) while still obtaining a significant heating efficiency. 2. Experimental methods For this study, we have prepared one sample composed of disc shaped MNPs and one sample formed by spherical MNPs. Iron oxide (Fe3O4 or g-Fe2O3) disc-shaped MNPs were synthesized via the soft template-assisted synthesis [35,36] in a binary system of H2O/Cetyltrimethylammonium bromide (CTAB), 77/23 g at room temperature. This mixture forms a hexagonal lyotropic liquid crystalline phase. Fe(acac)3 in H2O/CTAB goes through a cascade of reduction-hydrolysis reactions in the presence of aqueous NaBH4. Fe(OH)x, where x is 1, 2 and 3 are formed as intermediately until Magnetite (Fe3O4) is formed via nucleation reactions of Fe(OH)2 and Fe(OH) [37]. In a 3-neck round bottom flask, Fe(acac)3 (2 mmol) was dissolved in a mixture of 77 g of degassed DI water and 23 g of CTAB. 10 mmol of NaBH4 was then mixed with 3 mL of degassed DI water and added to the above mixture. The vessel was under constant flow of nitrogen as well as vigorous mechanical stirring (500 rpm) at room temperature. The reaction resulted in two products, the froth and the gel after 5 h, and the disc shaped MNPs were retrieved from the formed gel. In order to isolate the particles from the surfactant, the gel was washed several times with 50 C water and centrifuged at 5000 rpm and was eventually dried out. On the other hand, we also produced iron oxide spherical MNPs by using non-hydrolytic thermal decomposition. Details of the synthesis route have been given previously (see Ref. [38]). Briefly, a three neck flask was charged with 1,2 hexadecane diol, Benzyl ether (98%), Oleylamine (70%), Oleic acid (90%), and Iron (III) acetylacetonate, which was used as the precursor. The mixture was stirred magnetically under a flow of nitrogen gas for 2 h at 200 C. Temperature was raised subsequently to 300 C for 1 h. After reflux the sample was cooled down to room temperature. Finally, the spherical MNPs were coated with tetramethylammonium hydroxide (TMAH) to make them water dispersible. A Bruker AXS D8 X-ray diffractometer (Cu -Ka radiation, 0.15418 nm) was used to analyze the crystalline structure of the disc and spherical shaped MNPs, and an FEI Morgagni 268 transmission electron microscope (TEM), operating at 60 kV, was used to obtain information about their size distribution and morphology. Both Xray diffraction and selected area electron diffraction were utilized to further investigate the sample's crystalline structure. The thickness of the nanodiscs was determined by using Atomic Force Microscopy (AFM) in tapping mode (DSP Classic model, Nanotec). Magnetic measurements were carried out using a Physical Property Measurement System (PPMS) from Quantum Design, with a vibrating sample magnetometer (VSM) option. The zero-fieldcooling/field-cooling (ZFC/FC) curves were measured between 5 and 350 K, with an applied field of 50 Oe, while the hysteresis loops were measured at room temperature, 300 K, applying fields up to 50 kOe. Magnetic hyperthermia measurements were carried out using calorimetric methods, with a 4.2-kW Ambrell Easyheat Li3542 system. A suspension of 1 mg/ml of nanoparticles in water was used for measurements and the AC magnetic field was tuned from 0 to 800 Oe, at a constant frequency of 310 kHz.
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3. Results and discussion 3.1. Structural properties TEM images for the sample composed of spherical MNPs can be seen in Fig. 1 (a). In addition, a TEM image of the disc-shaped MNPs is presented in Fig. 1 (b). As one can see, the discs present mostly a circular surface, with a relatively wide size distribution, being the estimated average diameter around 11.5 ± 2.7 nm (see the inset to Fig. 1 (b)), and the circularity around 0.90 ± 0.08 nm (circularity ¼ (4p Area/Perimeter2, ranges from 0 (infinitely elongated polygon) to 1 (perfect circle)). The thickness for these nanodiscs has been estimated via AFM, as depicted in Fig. 1 (c) and (f). AFM is an ideal tool to measure thickness of nanostructures, allowing us to reach perpendicular resolutions below 1 nm. However, the lateral resolution is not very good, due to the effect of the curvature radius of the tip [39], and this limits the capacity to laterally resolve individual discs unless they are well separated. This can be observed in Fig. 1 (f), in which the measured diameter is much bigger than the ones obtained by TEM, suggesting that the image corresponds to a few nanodiscs next to each other. The thicknesses of disc-shaped samples has been estimated to vary between 2.5 and 3 nm. Therefore, the average volume calculated for these nanodiscs is ~340 nm3. The spherical nanoparticles are more uniform than the discs, with an average volume of ~270 nm3, and therefore they are more or less comparable to our nanodiscs (~20% difference in volume). The comparison between these samples will be useful to determine if the heating properties of the nanoparticles are improved by modifying the shape of the MNPs, from spheres to discs. The selected area electron diffraction (SAED) shows the characteristic ring pattern of the crystal Fe3O4 or g-Fe2O3 (Fig. 1 (d)). In order to further analyze the crystalline structure of our samples, we have also performed XRD. As indicated in Fig. 1 (e), the obtained patterns for disc and spherical shaped nanoparticles present similar characteristics, with several well defined diffraction peaks. The position and relative intensities of all the XRD peaks match well with those of an inverse spinel structure, either
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magnetite or maghemite (America Mineralogy Crystal Structure Database AMCSD 0000945). No other iron oxide phase (such as wüstite, FeO) has been detected by XRD within the resolution of the used instrument. 3.2. Magnetic properties The magnetic response of these samples has been characterized both as a function of the temperature (ZFC/FC curves) and as a function of the field (M - H loops), as depicted in Fig. 2. The ZFC/FC curve for the spherical MNPs is typical of small superparamagnetic nanoparticles, with a maximum at the ZFC around 55 K, corresponding to the blocking temperature, TB, of the nanoparticles and a FC curve that continuously increases with decreasing temperature [40,41]. However, the ZFC/FC curve for the nanodiscs is very different from the one obtained for the spherical nanoparticles. The ZFC/FC curve for the nanodiscs exhibits a much broader maximum displaced towards higher temperatures for the ZFC curve and strong irreversibility between the ZFC and FC branches until high temperatures. This behavior could be related, on one hand, to the wider size distribution of the nanodiscs, which could explain the broadening of the ZFC curves, and on the other hand, to an increase in the effective anisotropy: since the blocking temperature is essentially proportional to the product of the effective anisotropy of the nanoparticles, K, by their volume, V, the difference in TB between the spherical and disc shaped samples, despite having a similar volume, could be related to an increase of K for the nanodiscs. This increase in the effective anisotropy can be associated with the shape (shape anisotropy) and the increase in surface area (surface anisotropy) of the nanodiscs [42] as has been reported elsewhere [43]. The increase in the effective anisotropy is in principle favorable for the heating of the MNPs during the magnetic hyperthermia experiments, since it tends to give rise to an increased hysteresis loop area, and therefore, enhanced hysteresis losses, as has been reported in the literature [16]. On the other hand, the M - H loops at room temperature (Fig. 2 (b)) exhibit zero coercivity and remanence, and the shape of the
Fig. 1. TEM images for (a) spherical MNPs, and (b) nanodiscs (in the inset, we present the size distribution). (c) AFM image obtained for the nanodiscs. A profile (blue line) has been measured across the nanodiscs, as represented in (f). (d) Selected area electron diffraction (SAED) of the disc shaped sample. (e) XRD patterns for samples nanospheres and nanodiscs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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Fig. 2. (a) ZFC (solid)/FC (dashed) curves measured at 50 Oe and (b) M - H loops obtained at room temperature for the spherical and disc shaped nanoparticles. The fitting of the M H loops to Equation (1) is also included. In the inset, a zoom-in of the M - H loops in the low field region is presented.
curves is again similar to that typically observed in systems of nanoparticles with superparamagnetic-like behavior [40]. This is especially important for biomedical applications of the nanoparticles, since the absence of magnetization in zero field diminishes the tendency of the MNPs to agglomerate due to magnetic interactions and ensures the colloidal stability of the ferrofluids. In addition, it can be observed that the M - H loops for the nanodiscs do not exhibit the characteristic shape obtained in vortex domain structures, i.e. zero coercivity and remanence, but nonzero hysteresis loop area [29]. This can be easily understood considering that the size of our nanodiscs is too small to give rise to multidomains as required for the vortex domain structure. The superparamagnetic behavior of these spherical and disc shaped MNPs has been further confirmed by the fitting the M - H hysteresis loops using the
following expression [40]:
MðHÞ ¼ MS
Z∞ mH f ðVÞdV þ cH L kB T
(1)
0
where V is the volume of the nanoparticles, f(V) corresponds with a Log-Normal size distribution, c is the paramagnetic susceptibility of the surface spins, and L(x) ¼ cotanh(x)-1/x. As can be seen, the fittings obtained for both samples are pretty good: the estimated magnetic volumes for the nanospheres and the nanodiscs are ~210 and ~290 nm3, which are around 20e25% smaller than the physical volumes estimated by TEM (270 and 340 nm3, respectively), as expected due to the high contribution of surface spin disorder for
Fig. 3. Heating curves measured for (a) spherical and (b) disc-shaped MNPs at 0e800 Oe and 310 kHz. (c) Comparison of the SLP values obtained for spheres and for the nanodiscs (discs). We have also included the SLP results for bigger nanodiscs (discs D > 20 nm), for comparison's sake.
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such small MNPs that effectively reduces the apparent size determined by magnetic measurements. Nevertheless, there are some appreciable differences in the shape of the curves, as can be seen in the inset to Fig. 2 (b): for the nanodiscs, the approach to saturation is faster, being the M - H loops slightly more rectangular, while the approach to saturation for the spherical samples is slower. This again suggests an increased anisotropy for the nanodiscs. In order to confirm this, we have roughly estimated the effective anisotropy using the law of approach to saturation [44]:
. M ¼ Ms 1 b H2
(2)
where MS is the saturation magnetization and b is correlated with the effect of the anisotropy. In the case of uniaxial magnetic crystals the fitting parameter b can be used to obtain an estimation of the anisotropy:
K ¼ m0 Ms ð15b=4Þ1=2
(3) 5
The estimated anisotropy values are 8.5 10 erg/cc for the spherical MNPs and 10.1 105 erg/cc for the disc shaped nanoparticles, corroborating the increase in effective anisotropy for the nanodiscs. This increase in the effective anisotropy also agrees with the increase in the blocking temperature observed in the ZFC/FC curves. In fact, the obtained K value for the spherical MNPs compares well with that estimated from the blocking temperature of the ZFC curve (K~6.6 105 erg/cc). Unfortunately, the broadening of the ZFC curve for the nanodiscs doesn't allow us to obtain an estimation of the blocking temperature (and the effective anisotropy) to compare with, but, as explained before, it is supposed to be higher.
3.3. Magnetic hyperthermia Once the magnetic behavior of the nanodiscs and spheres has been analyzed, we have measured their heating capacity, and compared the results with those of the bigger nanodiscs reported recently in the literature [30,32], as we commented in the Introduction. In order to estimate the heating efficiency of the nanoparticles, we have used the standard hyperthermia calorimetric experiments. In these experiments, a vial with the sample is placed into a coil connected to a power generator, which allows us to control the amplitude of the AC field inside the coil. While the field is applied, a fiber optic temperature sensor inserted into the vial with the solution records the increase in temperature, and from the initial slope of these Temperature vs time curves, one can obtain the SLP values:
ms DT SLP ¼ Cp mn Dt
(4)
where Cp is the specific heat capacity of the medium, ms is the mass of the solvent, and mn is the mass of the nanoparticles. The heating curves measured for the 2 samples have been obtained with applied AC magnetic fields at 300 kHz between 0 and 800 Oe. In Fig. 3 (a) and (b), we present the results for the spherical and disc shaped MNPs, respectively. As can be observed, the heating rates are relatively slow, even for the maximum field applied, 800 Oe. This can also be seen in Fig. 3 (c), where the heating efficiency or SLP values for the two samples are directly compared. As observed, the nanodiscs present SLP values that are appreciably higher than those exhibited by the spherical MNPs of similar volume, especially at low fields. To further confirm the improved heating efficiency of the nanodiscs, we have also compared the SLP values for bigger spherical (~1400 nm3) and disc shaped (~1200 nm3) MNPs and
713
again observed an appreciably increased heating efficiency for the nanodiscs: the nanodiscs present a maximum SLP of 125 W/g vs the 90 W/g of the spheres (see Fig. 3 (c)). This clearly confirms that the disc-shaped MNPs exhibit advantages over the spherical ones for hyperthermia treatment. However, the SLP values we have obtained here are much smaller than those reported by Yang et al. [8], and Ma et al. [9] for their bigger nanodiscs. This indicates that size reduction of the nanodiscs appreciably hinders their heating capacity, despite the potential improvement of other important “invivo” characteristics such as the circulation life time in the blood or the MNPs disaggregation. A possible explanation for this deterioration of the heating properties of the nanodiscs with decreasing size can be related to the loss of the vortex magnetic domain structure, as commented in the Introduction, which has been reported to increase the hysteresis loop area and therefore, the hysteresis losses of this kind of nanostructures [29,45]. In addition, the magnetic properties also deteriorate with decreasing size of the MNPs: the maximum MS we obtain for our nanodiscs is around 60 emu/g while Yang et al. report a value of 84 emu/g for their samples, which is closer to the bulk value of magnetite (92 emu/g). Moreover, this could also affect the capacity of the MNPs to align in the direction of the field, which has been shown to be very important in order to improve the heating efficiency of this kind of anisotropic nanostructures [24,26]. Nevertheless, our hyperthermia measurements have shown that the heating efficiency of these small nanodiscs is still better than that of spherical MNPs of similar volume, and therefore, these superparamagnetic nanodiscs are still interesting for magnetic hyperthermia treatment. 4. Conclusions We have attempted to shed light on the change in heating efficiency of small superparamagnetic nanoparticles when their shape is changed from spherical to disc -shaped. It has been observed that the heating efficiency of these nanodiscs improves especially in the low field region, in comparison to their spherical counterparts. As the size of these nanodiscs decreases, their heating efficiency also tends to decrease. In this way, the obtained SLP values are much smaller than those recently reported for the bigger nanodiscs. Therefore, the size of these nanodiscs should be carefully tuned in order to enhance their heating properties while conserving the “in-vivo” advantages associated with small superparamagnetic nanoparticles. Acknowledgements Research at USF was supported by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering under Award No. DE-FG02-07ER46438 (Synthesis and magnetic studies) and by the Bizkaia Talent Program, Basque Country (Hyperthermia measurements). Javier Alonso acknowledges the financial support provided through a postdoctoral fellowship from Basque Government. We would like to thank Dr. Carolina Redondo (Physical Chemistry Dept., UPV/EHU) for the use of the Atomic Force Microscope. References [1] D. Ortega Ponce, Q. Pankhurst, Magnetic hyperthermia, in: P. O'Brien (Ed.), Nanoscience, Royal Society of Chemistry, 2012, pp. 60e88. http://discovery. ucl.ac.uk/1386519/. [2] C. Binns, Magnetic nanoparticle hyperthermia treatment of tumours, in: B. Aktas¸, F. Mikailzade (Eds.), Nanostructured Mater. Magnetoelectron, Springer Berlin Heidelberg, Berlin, Heidelberg, 2013, pp. 197e215, http:// dx.doi.org/10.1007/978-3-642-34958-4.
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