Multiplying Magnetic Hyperthermia Response by Nanoparticle

Article pubs.acs.org/JPCC

Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling David Serantes,*,† Konstantinos Simeonidis,‡ Makis Angelakeris,§ Oksana Chubykalo-Fesenko,† Marzia Marciello,† María del Puerto Morales,† Daniel Baldomir,∥ and Carlos Martinez-Boubeta*,⊥ †

Instituto de Ciencia de Materiales de Madrid, CSIC, Cantoblanco, ES-28049 Madrid, Spain Department of Mechanical Engineering, School of Engineering, University of Thessaly, 38334 Volos, Greece § Department of Physics, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece ∥ Instituto de Investigacións Tecnolóxicas, and Departamento de Física Aplicada, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain ⊥ Departament d’Electrònica and IN2UB, Universitat de Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain ‡

S Supporting Information *

ABSTRACT: The oriented attachment of magnetic nanoparticles is recognized as an important pathway in the magnetic-hyperthermia cancer treatment roadmap, thus, understanding the physical origin of their enhanced heating properties is a crucial task for the development of optimized application schemes. Here, we present a detailed theoretical analysis of the hysteresis losses in dipolar-coupled magnetic nanoparticle assemblies as a function of both the geometry and length of the array, and of the orientation of the particles’ magnetic anisotropy. Our results suggest that the chain-like arrangement biomimicking magnetotactic bacteria has the superior heating performance, increasing more than 5 times in comparison with the randomly distributed system when aligned with the magnetic field. The size of the chains and the anisotropy of the particles can be correlated with the applied magnetic field in order to have optimum conditions for heat dissipation. Our experimental calorimetrical measurements performed in aqueous and agar gel suspensions of 44 nm magnetite nanoparticles at different densities, and oriented in a magnetic field, unambiguously demonstrate the important role of chain alignment on the heating efficiency. In low agar viscosity, similar to those of common biological media, the initial orientation of the chains plays a minor role in the enhanced heating capacity while at high agar viscosity, chains aligned along the applied magnetic field show the maximum heating. This knowledge opens new perspectives for improved handling of magnetic hyperthermia agents, an alternative to conventional cancer therapies.

1. INTRODUCTION Synergy means that a collaborative work will produce an overall better result than if each unit within the group were working toward the same goal individually. Rowing is one good example of collaboration, where an eight-person crew arranged in a line has higher efficiency per propulsive power and higher average speed than rowing individually. Similarly, in our paper we will describe how the assembling of nanoparticles in a row (chain) increases the heating output in hyperthermia protocols. In general, understanding the hysteresis losses (HL) and the underlying physics is of utmost importance for the engineering and development of magnetic nanostructures in modern technology, with applications in magnetic recording, electric machinery, and biomedicine, to name a few examples. There is a strong interconnection between HL and the energy associated with the magnetic dipole−dipole interaction, particularly at the nanoscale. Many results for dense nanoparticle systems have shown that dipolar interactions do not only affect the susceptibility,1 but also the blocking temperature transition,2 the motion of particles in solution,3 etc. Thus, understanding how dipolar interactions modify the collective magnetic behavior is a big challenge from both the experimental and © 2014 American Chemical Society

theoretical point of view. In particular, dipolar interactions could lead, for instance, to optimized designs for nanoparticle vectors used in magnetic resonance imaging (MRI).4,5 Similarly, hyperthermia-based cancer therapy could also benefit from correlations between particles. Recent experimental investigations have shown that the specific absorption rate (SAR), i.e., the heat dissipated from the magnetic nanoparticles, may vary by orders of magnitude, depending on the strength and frequency of the applied alternating current (AC) magnetic field but also on the material’s nature and nanoparticle concentration.6−9 Theoretical comprehension till now has been complicated, since there are several superposing effects influencing SAR, which may not clearly be distinguished in experiments. Besides particle size, also intrinsic magnetic propertiesin particular, anisotropy of the particleshould be considered. A further important issue is clustering of particles leading to complex magnetic interactions, with controversial results reported in the Received: October 30, 2013 Revised: February 11, 2014 Published: February 12, 2014 5927

dx.doi.org/10.1021/jp410717m | J. Phys. Chem. C 2014, 118, 5927−5934

The Journal of Physical Chemistry C

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terms of the anisotropy energy barrier of the particles, t = kBT/ 2KV = 0.001, guaranteeing that our results are applied to all nanoparticles fulfilling the above conditions. This condition of the particles being in the blocked state ensures that the SAR value is proportional to the area of a single M(H) curve by the usual relation SAR = HL*f. In order to investigate the influence of the magnetic dipolar coupling between nanoparticles, we studied series of chains with N particles. The random distribution of the anisotropy easy axis of each particle within a cone around the chain axis was chosen in order to account for deviations in the positions of the crystals from the chain axis, thus resembling the results obtained by electron holography on magnetosomes.19 For the other geometrical arrangements, the direction of the anisotropy easy axes of the particles was distributed at random. The results are obtained by averaging over 100 different configurations of easy-axes orientations for each considered case. Synthesis and Assemble Process. Monodisperse nanoparticles of 44 nm were produced using a previously described precipitation method.26 In particular, FeSO4 concentration was 0.037 M, the base concentration was 0.077 M, and the oxidant concentration 0.1 M, keeping the excess of hydroxyl ions concentration in the reaction media constant at 0.001 M (as calculated by applying the following equation: [OH−]excess = [NaOH] − 2[FeSO4]). The nanoparticles were dispersed in agar, whose viscosity was varied by changing the concentration between 0.1 and 2%, and subjected to a magnetic field (applied parallel, perpendicular, or at 45°) during the cooling process. First, nanocrystals were dispersed in water in a sonication bath at 70 °C, and hot agar solution was added, keeping sonication for 15 min and a final concentration of 4 mg of nanoparticles/ mL. The hot suspension was then subjected to an external magnetic field during 30 min and stored up at 4 °C. Semisolid agar media contain a 1.5% concentration, which is used to grow and select isolated colonies, while lower concentrations (around 0.4%) are used for motility studies. Characterization. Nanoparticles were characterized by transmission (200 keV JEOL-2000FXII) and scanning electron microscopy (FEI Nova NanoSEM 230). Quasi-static magnetic characterization was carried out in a commercial vibrating sample magnetometer (VSM). AC magnetic hyperthermia experiments were performed using a 1.2 kW Ambrell Easyheat 0112 and a converted 4.5 kW commercial inductive heater. While frequency was kept constant at 205 kHz and 765 kHz, the amplitude of the applied magnetic field was tuned from 150 up to 300 Oe. Temperature was monitored by using a GaAsbased fiber optic probe immersed in a test tube containing 1 mL of solution. The heating capability (SAR), usually reported in watts per gram of magnetic material, was estimated by subtracting the solvent (water) background signal and the heat losses to the environment, as described previously.18

literature. Here we focus on some ingenious designs widely met in nature to exploit their enhanced magnetic properties. Employing computational modeling based on the Monte Carlo framework, we investigate the influence of dipolar interactions on the hysteresis loops in magnetic nanosized assemblies, e.g., chain-like morphologies as in the case of biogenic magnetosomes. Recently, Alphandéry and co-workers reported the use of magnetosomes in magnetically triggered heat therapy.10 They found that chains of these magnetic organelles isolated from magnetotactic bacteria were more effective than synthetic nanoparticles at killing cultured tumor cells and shrinking tumors in vivo. Also worth mentioning here is the introduction of iron-chelating agents to the bacterial growth medium demonstrated to increase the magnetosome size and chain length resulting in improved heating properties.11 In a previous work,12 we observed that dipolar interactions significantly affect the magnetic susceptibility and hysteresis losses in disordered nanoparticle systems, demonstrating that a considerable effect in specific heating power can be obtained. Specifically for a chain-like arrangement, we also anticipated that the achievable hysteresis area increases with the chain length, indicating a promising way for hyperthermia enhancement.13 Here, we report our first effort to implement the strategy proposed in ref 13. It will be shown that the directional dependence of dipolar interactions in arrays of nanoparticles resembling magnetotactic bacteria can result in substantially enhanced hysteresis loss. Their superior heating performance strongly depends both on the distribution of the particles’ anisotropy axes with respect to the chain longitudinal direction, and on the relative orientation of the AC field with respect to the chain. On the other hand, further reduction of hysteresis losses occurs in the case of particles with different aggregation geometries such as rings or squares. Remarkably, our experimental data using magnetite nanoparticles dispersed in a different media suggest that, for biological-like viscosity conditions, the initial relative orientation between chains and AC field is of minor importance for the enhanced heating performance. Our results may have important implications for clinical applications, especially considering that the enclosing of single nanoparticles by cell membranes may result in long linear aggregates as recently suggested by theory.14

2. THEORETICAL AND EXPERIMENTAL METHODS Computational Details. In order to estimate the heating power of the system, we used the Monte Carlo method with the standard Metropolis algorithm. The physical model employed for our numerical simulations considers a system of single-domain magnetic particles with no volume distribution and with an effective uniaxial magnetic anisotropy. The energy model is the same as in refs 8 and 12, so that the energy of each particle has three main sources: anisotropy, Zeeman, and dipolar interactions. Simulations were performed at a temperature below the blocking temperature of the system, thus ensuring that the main dissipation mechanism is via the hysteresis-losses (i.e., field activated), and no size-dependence of the particle properties is considered.15 The contribution for heat generation from magnetic losses is evaluated by the area of the hysteresis loop. The number of Monte Carlo steps for the field-variation ratio was optimized in order to reproduce Stoner−Wohlfarth features at very low temperature for the noninteracting particle ensemble (HC ≈ 0.48HA and MR ≈ 0.5MS). Please note that the temperature was introduced in

3. RESULTS AND DISCUSSION We start this investigation by considering hysteresis M(H) cycles of an ensemble of noninteracting chains formed by N particles each. Please note that we have previously demonstrated that the interactions among parallel neighboring chains would be of second-order effects.19 In order to make the calculations more realistic, we consider a random angular distribution of the anisotropy easy axis within the angle α that defines a cone around the longitudinal direction of the chain as illustrated in the inset of Figure 1. Further, unless explicitly specified, the magnetic field is applied parallel to the 5928



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Figure 1. Representative hysteresis M(H) normalized loops corresponding to different lengths (N) of a chain of magnetic nanoparticles with uniaxial easy anisotropy axes distributed within a cone of angle α = 20°. The black line corresponds to the case of randomly distributed noninteracting particles, also with the easy axes distributed at random. The inset illustrates the distribution of the axes within the cone of angle α, for the N = 4 chain.

longitudinal axes, under the assumption that any misaligned chain would be driven by the magnetic torque toward the field direction. We simulate the evolution of the magnetization (M) versus applied magnetic field (H), i.e., hysteresis cycles of such chains as a function of both N and α parameters. The calculation of hysteresis losses is similar to standard experimental practices (see Computational Details section). The M and H data are normalized by the saturation magnetization (MS), and anisotropy field (HA = 2K/MS, K being the anisotropy, assumed of uniaxial type for the sake of simplicity), respectively. The scheme of this chain and the corresponding hysteresis cycles are illustrated in Figure 1 for the representative cases of different lengths of chains consisting of N = 2, 4, 8, 12 nanoparticles. As shown in Figure 1 within these values, the simulations show that stronger dipolar interactions (i.e., bigger value of number of particles N) result in steeper M−H slopes (larger susceptibility) and larger coercivities, as has been previously observed in other magnetic systems.20 Although these features seem to saturate for larger chain lengths (N > 8), even the smallest chain length case of N = 2 still remains clearly distinguishable from the case of randomly distributed noninteracting particles, also included for comparison in Figure 1. In real induction heating devices, as the frequency increases, there is a limitation in the maximum value of the magnetic field Hmax that can be applied, due to the technical difficulty of producing high fields over large volumes (as human bodies) at high frequencies. As a result, the magnetic systems at high frequency are likely to be subjected to nonsaturating magnetic fields and will therefore be cycled around minor hysteresis loops. Figure 2 provides a valuable estimation for the necessary field amplitude H to generate non-negligible SAR values as defined by the material specific anisotropy field HA, for a fixed cone angle of α= 20°. The role of the chain length (N) on hysteresis loop features is illustrated in Figure 2a,b, for the extreme cases of N = 2 and 12, respectively. The hysteresis area increases on increasing the chain length, and strongly depends on Hmax. In Figure 2c, the field dependence of the hysteresis losses (normalized values HL/2K) is explored in more detail for several chain lengths. A sharp rise of the HL from an essentially zero value, to a field-independent regime is observed. Concomitantly, that rapid saturation of the HL value versus Hmax/HA indicates that the heating efficiency threshold for HL optimization may be sought by maximizing the ratio HL/Hmax.

Figure 2. Panels (a) and (b) illustrate the dependence of the hysteresis curves on the maximum applied field, Hmax, for two different chains of length N = 2 and N = 12, respectively, and α = 20°. For some of the loops, the vertical displacement reflects that the magnetization of certain nanoparticles is anchored due to the intrachain coupling. Main panel (c) shows the dependence HL vs Hmax for different chain lengths, for the same α = 20° case. Inset in (c) illustrates the optimal conditions for hyperthermia applications, as inferred by plotting HL/ (2K·Hmax) versus Hmax.

These optimum values of field and hysteresis losses, HmaxOPT and HLOPT respectively, are the X−Y coordinates in the inset of Figure 2c, where the local maximum in the HL/2K versus Hmax/HA curve indicates the best performance based on HL heating. From the application point of view, it will be necessary to correlate both the optimizing field and the corresponding optimized hysteresis losses as a function of the system characteristics (namely MS, K, N, and α). It is well known that the magnetic dipolar interaction favors the longitudinal alignment of the magnetocrystalline easy axes during the chain formation. For example, Dunin-Borkowski et al.16 have shown by electron holography of magnetotactic bacteria that single particles are aligned with magnetic easy [111] axes parallel to the chain axis. The magnetic field lines bend in some of the magnetite crystals to minimize their magnetostatic energy, whereas in others their direction differs slightly from that of the chain axis. In our case, the conical distribution centered on the chain axis and having a half angle α has been considered in order to account for deviations in the anisotropy direction of the crystals. In Figure 3 we depict the optimal conditions for magnetic-hyperthermia applications, i.e., HLOPT and HmaxOPT as a function of α and of the chain length N. Two effects with opposite optimizing tendencies are observed. The hysteresis area, shown in Figure 3a, increases with the number of particles (and approaches saturation for N > 8) being maximum for collinear easy axes (α = 0°), although this ideal collinear-axes condition is difficult to fulfill in real systems. At the same time, the HL is found to decrease for misaligned anisotropy axes. 5929



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Figure 3. Dependence on the chain length, for different values of α, of (a) the optimal hysteresis losses, HLOPT; and (b) the field value that optimizes that area, HmaxOPT. Both optimizing values are normalized, by 2K and HA, respectively. In (c) the dependence of HLOPT on HmaxOPT is summarized, for different values of N and α. Different symbols denote different cone angle distributions, while numbers as data labels denote the corresponding chain lengths.

Similar trends are observed also for HmaxOPT, as shown in Figure 3b. The correlation of optimum conditions derived from the maxima of curves of the type shown in Figure 3a,b, is plotted in Figure 3c as a function of the applied field amplitude. Remarkably, most of the data seem to collapse along a linear region of constant proportionality between HLOPT and HmaxOPT. The smaller the field amplitudes available for therapy are, the larger is the chain size (N) that should be chosen for achieving a sufficient heating effect. This linear region widens for misaligned easy axes (increasing α). Figure 3c provides an essential guide for choosing the optimum operational conditions for hyperthermia in terms of the available field amplitude regimes. Up to this point, we have explored the effect of magnetic chain length on the hysteresis area. The magnetic energy of the chain is dominated by the anisotropic dipole−dipole interactions, which keep the magnetization parallel to the chain axis and result in an enhanced effective anisotropy of the particles (higher the more collinear their easy axes are, i.e., smaller α). However, experimental preparation of perfectly straight chains meets certain constraints.21 Although they have been widely reported in the literature, some bending and misalignment can hardly be avoided. On the other hand, computations and experiment have shown that due to the low bending energy cost, once a straight chain becomes slightly bent, it easily transforms into a ring.22 Additionally, welldefined nanoscale flux-closure polygons have been fabricated on hydrophilic surfaces.23 Furthermore, because anisotropic nanoparticles exhibit shape-dependent physical and chemical properties, the self-assembly of these nanoparticles can lead to a variety of other structures, although the knowledge about the detailed issues controlling the assembly of magnetic nanoparticles is still rather immature.24 In particular, clustering of magnetic nanocrystals inside liposomes significantly improve their MRI contrast properties.25 Similarly, the influence of

particle clustering on the hyperthermal efficiency has been investigated by Eggemann et al.26 and Hyeon’s group.27 Consequently, to have a better comprehension of the dissipating mechanisms in hyperthermia therapy, we will focus now on the evolution of the hysteresis area of different assemblies (nanoparticle ring and closely packed hexagon and cube clusters) as displayed in Figure 4a. For a sufficient number of particles (N = 8), it is observed that dipolar interactions diminish the hysteresis area in all casescompared to the noninteracting case (black continuous curve)except for the chain array. These issues are better illustrated in Figure 4b, where the importance of the applied field (normalized to HA) is underlined for the assorted configurations: for fields Hmax < 0.5HA (roughly HC in the noninteracting case), assembling is beneficial due to the dominant role of the coercivity reduction, whereas for larger fields the nanoparticles assembling is detrimental for the hyperthermia, with the exception for the chain case where again remarkable area increase can be achieved. Zooming into any of those areas reveals that a 3D cluster (example, the “cube” in Figure 4) will exhibit reduced heating compared to the string, except for the case of nanomagnets with anisotropy axes practically along the chain axis (α = 20°) where the saturation takes place above HA. Comparison with experiments should provide further insights and validate the physics underlying the present model. For our proof-of-concept, the heating capacity of magnetite nanoparticles dispersed in agar and forming different assembles has been studied. Monodisperse nanoparticles about 44 in diameter were produced using a previously described precipitation method.17 The nanoparticles were dispersed in agar at different concentrations and subjected to a perpendicular, 45 degrees, or parallel magnetic field during the cooling process. Agarose-gel (namely Agar) a typical polysaccharide which, due to its natural origin, low cost and high degree of biocompatibility, is specifically used as a culture medium of 5930



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motion, rotation, and interaction until they find a minimal energy configuration. In the absence of external magnetic field, SEM images show that particles in the agar matrix arrange in irregular clusters (control sample in Figure 6). When a magnetic field (0.12 T) is applied during the agar cooling, nanoparticles form elongated structures whose length is inversely proportional to agar concentration since solution viscosity hampers particles from following external magnetic field (Figure 5). First, we discuss results for a group of samples. The samples covered a variety of agar concentrations cooled at different field orientations. At low agar concentrations, the resulting nanoparticle aqueous solutions exhibit strong heating capabilities (Figure 6). On increasing the AC applied field, the SAR for the

Figure 4. (a) M(H) hysteresis curves corresponding to different spatial arrangements (bidimensional chain, hexagonal lattice, and ring; 3D cube) of the same amount of particles, N = 8, and for the easy anisotropy axes randomly distributed into a cone of angle α = 90°. The black line stands for the case of noninteracting particles; (b) shows the HL vs Hmax data corresponding to the cases displayed in (a), plus an additional case: the same N = 8 particles chain, with α = 20°.

bacteria and other cells for diagnostic or laboratory experiments purposes. Previous studies have shown that both the size (and shape) of particles and the media viscosity affect the kinetics of aggregate formation and thus can be used to achieve different arrangements.28 In our case, agar is employed as (i) a phantom system mimicking biological-media viscosity (via varying concentration from 0.1 till 3 wt % agar concentration on a 4 mg/mL magnetite dispersion) simulating an in vivo environment, and at the same time as (ii) a segregant-assisting background, which favors the simultaneously formation of chains but attenuates dipolar interactions between adjacent chains. It is envisaged that the particles undergo continuous

Figure 6. Experimental hyperthermia power of the chain arrangements at different agar concentrations, measured at 765 kHz (top panel) and 205 kHz (bottom panel). The control data are shown for comparison. In both panels, inset shows the corresponding hyperthermia power of the 0.1% agar concentration at different applied AC fields.

Figure 5. SEM micrographs of MNPs at 0.5% and 2.0% agar concentrations orientated in a magnetic field, and control sample without applied field. Scale bar length is 10 μm. 5931



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The decrease of the aspect ratio for those structures at high agar concentration, observed experimentally, accounts for the lower SAR also predicted by the simulations. Worth of mention, results obtained for a given sample undergoing rotation, with AC field applied parallel and perpendicular to the original chains, mimics the aforementioned results for the series of samples (see Supporting Information for further details). Qualitatively, the calculations are in agreement with our experimental findings, supporting the feasibility of our simulations. In addition, we note our results are also in qualitative agreement with previous reports on the role of dipolar interactions in nanoparticles.29 It is shown that interparticle interactions have a nontrivial effect on the energy loss per cycle, leading to either decrease or increase of the energy loss depending on the intrinsic properties.30 Consistently, for ultrasmall superparamagnetic particles, Eggemann et al.26 found no measurable heating in well dispersed samples, while for clusters of similar particles at comparable concentration, much larger SAR values were measured. The primary mechanism in their case seems to be an enhancement of the energy barrier due to interactions, sufficient to displace the particles from superparamagnetism (no hysteresis) into the ferromagnetic-like state (blocked state), and as a consequence, bringing in hysteresis losses. The presence of other coupling effects, like for example exchange correlations,31 would also modify the observations reported here.

nanoparticles assembled into chains approaches 1.5 kW/g for a 0.1 wt % agar concentration under a 300 Oe amplitude and 765 kHz frequency (50 W/g for 205 kHz). Control samples, jellified in absence of magnetic field, show SAR values of around 460 W/g (and 16 W/g, respectively). For the 765 kHz measurement, SAR values increases 4-fold when the field rises from 200 up to 300 Oe in both cases (chains and control) (see inset in Figure 6a), indicating the fact that the solution viscosity affects the chain formation and eventually the heating response. This trend is in agreement with the simulations showed in Figure 4. The overall lower SAR values for the 205 kHz measurements can be ascribed to the effect of magnetic relaxation due to slower time scale. Surprisingly, maximum SAR was found in aligned samples at low agar density, even in the case of AC field applied perpendicular to the chains axes, i.e., perpendicular to the shape anisotropy. Concomitantly, an increase on the viscosity (agar >0.5%) results in a decrease on the SAR, which reaches values similar to the control samples. In order to confirm these observations, the SAR was also measured by applying the AC field parallel to the chains direction. Results depicted in Figure 7a confirm the elevated SAR values even at denser agar

4. CONCLUSIONS In short, inspired by the excellent heating properties of bacterial magnetosomes, we have focused on understanding the heating trends after the chain formation in the case of magnetite nanoparticles of similar morphology. Specifically, we investigated the role of magnetic dipolar interactions in determining the hysteresis properties and energy losses of several examples of linear, circular, flat and tridimensional assemblies, therefore exploring their potential for hyperthermia applications. Importantly, the assembly’s properties are strongly dependent on easy-axes orientation (always accounting for the intrinsic magnetic profile of the nanoparticle, as well as the applied field conditions), and its study can be undertaken by means of Monte Carlo simulations. Our simulations predict that the area of hysteresis loop increases (and therefore the SAR) with the length of the chain. This behavior can be easily interpreted in terms of the enhanced effective anisotropy of the particles arising from their preferential orientation along the chain due to the dipolar coupling, which may lead to SAR values several times larger than the intrinsic SAR of an isolated particle. This finding is in remarkably good agreement with the results observed for magnetosomes by Alphandéry et al.11 On the one hand, disorientation of the assembly would lead to a considerable decrease in the hysteresis loop area and to drastic effect on magnetically triggered heating. Example of the later is the decrease of the heating efficiency of separate biogenic nanoparticles compared with those of magnetosomes arranged in a chain.10 On the other hand, our results show that the longer the chain, the greater the SAR.11 Although, worthy to mention, an attenuating SAR growth rate with chain length may be anticipated based on the cubic dependence of the dipolar coupling strength on the inverse distance between particles, producing the effect that after some length (namely around 8 particles in a row according to our calculations) further chain

Figure 7. (a) Experimental hyperthermia power of the 0.5% and 1% agar cases measured at 765 kHz and 300 Oe maximum AC field, applied at different orientations with respect to the chains long axis (0°, 45°, and 90°; schematically illustrated in the top panel). (b) Simulated angle-dependence of the hysteresis losses for different chain lengths. Dotted line represents the hysteresis losses of a randomly distributed noninteracting system.

concentrations. For nanoparticles assembled into chains at 45°, the situation is intermediate. The origin of this behavior is unclear but may be related to the fact that low agar concentrations (0.1−0.25%) partially allow for chains rotation toward the AC field direction. Simulations of the heating-power dependence on the relative orientation between the AC field direction and chain, support our interpretation (see Figure 7b). 5932



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Author Contributions

growth no longer results in noticeable heating-performance gain. The theoretical considerations presented here are evidenced in proof-of-concept experiments for the case of magnetite particles but are in fact general. Not only do these observations indicate an attractive means for tailoring the magnetic heating capabilities based on existing materials by just reorienting them in chain formations, but the proposed model also contributes to the understanding of phenomena that typically occur in any ferrofluid. For instance, the scaffolding of magnetic particles into quasi-linear aggregates decorating Tobacco mosaic virus nanotubes has been shown to give rise to a dramatic enhancement of the magnetoviscosity, which is also a measure for the dissipation of energy in the fluid.32 Similarly, Müller et al.33 observed very different SAR values in the case of particles gelled with or without applying a magnetic field. Although no interpretation was provided by the authors, we attribute the increase of SAR in the samples textured by a large magnetic field to the formation of chains or columns. Our results show that the assembling of nanoparticles into chains with a uniaxial anisotropy is the way to reach the maximum possible SAR with a given magnetic material, in agreement with the conclusions recently pointed by Mehdaoui et al.34 While commonly available iron oxide ferrofluids show SAR values about 100 W/g, in a few special cases experimental values in excess of 500 W/g,25 values up to about 1 kW/g were found for magnetosomes. Our work shows that anisotropic interactions of magnetic nanoparticles can be used to produce chain-like mesoscopic architectures with superior heating capabilities of around 2 kW per Fe gram (1.5 kW/g nanoparticle). Remarkably, the heating properties seem to not be very sensitive to the initial chain direction with respect to the AC field in low viscosity media, which is important for in vivo applications. We summarize that these chain-like tailored nanoparticle assemblies will allow effective hyperthermia protocols at much lower pharmaceutical doses and shorter handling time compared to isolated nanoparticles, thus preventing side-effects and discomfort to the already stressed patient. Finally, we anticipate that our results would have an impact on the understanding of phenomena related to magnetic nanoparticles in biomedical applications. For instance, chain structures may pave the way for overcoming obstacles for the clinical use of hyperthermia inside an MRI setup.35

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D.S. and C.M.B. conceived and designed the research; K.S., M.A., M.M., and M.P.M. performed the experiments; and D.S. carried out simulations with the assistance of O.C.-F. and D.B. D.S., K.S., and C.M.B. co-wrote the paper. All authors discussed the results and commented on the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS C.M.B. was supported by the Spanish Government under the ’Ramón y Cajal’ Fellowship program. K.S. thanks the Action “Supporting Postdoctoral Researchers” of Operational Program “Education and Lifelong Learning”, co-financed by the European Social Fund (ESF) and the Greek State (GSRT). We also thank the Centro de Supercomputación de Galicia (CESGA) for the computational facilities. The work of D.S. and O.C.-F. has been supported by the EU project NNP3-SL-2012281043 (FEMTOSPIN) and the Spanish Ministry of Science and Innovation under the Grant FIS2010-20979-C02-02. M.P.M.’s work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (MAT2011-23641) and the European Union (EU-FP7MULTIFUN project, ref. 246479). D.B. acknowledges the Spanish Ministry of Economy and Competitiveness for project MAT2009-08165.

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ASSOCIATED CONTENT

* Supporting Information S

TEM image of the dry particles, size distribution, X-ray difractogram, and magnetization measurements. SEM images of the particles at different agar concentrations and cooled under a magnetic field (0.12 T). Elemental analysis for C, Fe, and O. Dependence on agar-concentration of SAR values at different field amplitudes, and for different initial configurations. Table comparing different SAR values as a function of relative alignment between field and chain, and schematic illustration of the experimental setup. Simulated hysteresis curves at different orientation between chains and field. This information is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

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NOTE ADDED IN PROOF During the review process for this paper, two related articles appeared, one that studies the influence of particle chain formation on the heating properties,36 and one that describes how many-body interactions drive the formation of chains and membranes,37 as the ones depicted in our Figure 5. Regarding the paper by Branquinho et al.36, they showed that, in general, nanoparticle chain formation decreases the hyperthermia efficiency. Again, we note that linear response theory has its limitations and improved models are needed to better describe the physical phenomena of magnetic colloids exposed to magnetic fields. Finally, we surmise that the directed assembly of nanoparticle building blocks by means of silica encapsulation,38 or DNA linkers,39 can help translate the fundamental nanomaterial design principles discussed here into clinically relevant nanomedicine solutions.

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Multiplying Magnetic Hyperthermia Response by Nanoparticle

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