This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. www.acsanm.org Article Controlling Magnetization Reversal and Hyperthermia Efficiency in Core−Shell Iron−Iron Oxide Magnetic Nanoparticles by Tuning the Interphase Coupling K. Simeonidis, C. Martinez-Boubeta, D. Serantes,* S. Ruta, O. Chubykalo-Fesenko, R. Chantrell, J. Oró-Solé, Ll. Balcells, A. S. Kamzin, R. A. Nazipov, A. Makridis, and M. Angelakeris* Cite This: ACS Appl. Nano Mater. 2020, 3, 4465−4476 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: Magnetic particle hyperthermia, in which colloidal nanostructures are exposed to an alternating magnetic field, is a promising approach to cancer therapy. Unfortunately, the clinical efficacy of hyperthermia has not yet been optimized. Consequently, routes to improve magnetic particle hyperthermia, such as designing hybrid structures comprised of different phase materials, are actively pursued. Here, we demonstrate enhanced hyperthermia efficiency in relatively large spherical Fe/Fe-oxide core−shell nanoparticles through the manipulation of interactions between the core and shell phases. Experimental results on representative samples with diameters in the range 30−80 nm indicate a direct correlation of hysteresis losses to the observed heating with a maximum efficiency of around 0.9 kW/g. The absolute particle size, the core−shell ratio, and the interposition of a thin wüstite interlayer are shown to have powerful effects on the specific absorption rate. By comparing our measurements to micromagnetic calculations, we have unveiled the occurrence of topologically nontrivial magnetization reversal modes under which interparticle interactions become negligible, aggregates formation is minimized and the energy that is converted into heat is increased. This information has been overlooked until date and is in stark contrast to the existing knowledge on homogeneous particles. KEYWORDS: iron, iron oxides, magnetic hyperthermia, core−shell nanoparticles, hybrid nanostructures ■ INTRODUCTION The capability of magnetic nanoparticles to convert radio- Despite rapid progress, the precise way to increase the heating efficacy of magnetic nanoparticle-based therapeutics is unknown.8 This has posed a challenge for theoretical frequency (RF) electromagnetic energy into heat has drawn a modeling. In fact, most of the reported hyperthermia data as strong and growing research interest during the past decade, a function of particle concentration is encompassed by a with examples in the field of catalysis,1 lightweight thermo- universal response.9 On the one hand, manipulation of the field plastic composites for aeronautical and automotive engineer- conditions is the primary source of efficiency control.10,11 ing,2 and numerous biomedical applications.3,4 In particular, Importantly, recent numerical analyses carried out by using 3D biocompatible magnetic nanoparticles have emerged as realistic models of the human body indicated that acceptable promising agents for use in drug delivery5 and selective values for the magnetic field amplitude/frequency product (H· destruction of tumors by hyperthermia.6 Numerous clinical f) may increase up to four times in comparison to the usually and basic studies have shown that temperature stresses can considered safety threshold of ∼5 × 108 A/ms.12 On the other alter tumor endurance in a significant manner. The use of RF hand, factors, such as the nanoparticle features (composition, fields instead of conventional methods allows for minimally size, shape), their geometrical arrangement and volume invasive and real-time control of the temperature, particularly in deep body regions, while preventing damage to healthy Received: February 27, 2020 tissues. At present, many fundamental research studies have Accepted: April 13, 2020 been carried out worldwide and some have entered into Published: April 13, 2020 clinical trials, especially when magnetic hyperthermia is combined with more traditional therapeutic approaches, such as the codelivery of anticancer drugs or radiation therapy.7 © 2020 American Chemical Society https://dx.doi.org/10.1021/acsanm.0c00568 4465 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article Scheme 1. Overview of Core−Shell Nanoparticles Production Methodology, Growth Mechanism, and Function as Magnetic Hyperthermia Agents with Tunable Magnetic Reversal Potential concentration within the dielectric cellular matrix also play an of the nanoparticle unit) hypothesis.17,18 This scenario opens important role.13 And so, in practice, the heat transfer from the way to a superior control of the heating performance, magnetic nanoparticles subjected to an oscillating field is not particularly for in vivo applications, where it is known to only affected by their intrinsic properties but also by the attenuate in comparison to in vitro measurements. surrounding environment. For instance, the thermal con- ductivity of nanofluids is largely dependent on whether the nanoparticles stay dispersed, form large aggregates, or assume a ■ EXPERIMENTAL SECTION Particles’ Preparation. A very simple, fast, green, and cost- percolating linear configuration.14 effective way by using solar vapor phase condensation was used. This Minimizing the dosage of nanoparticles required for an technique allows the preparation of large quantities of nanoparticle effective treatment is another task of high significance. In that dry powders presenting a narrow particle size distribution without respect, ferrite nanoparticles are undoubtedly the most purification steps.19 Families of particles were prepared using almost convenient building blocks for magnetic hyperthermia because all 3d metals and many others, but here, we use iron, which is of their good biocompatibility and stability. But conventional considered to be an essential nutrient for cells that are dividing rapidly, such as in tumors, and also plays a vital role to perform single-phase iron oxide systems, and especially, those with various body functions. Moreover, produced iron nanoparticles are smaller dimensions, where Brown mechanisms for heating are featured with some significant advantages very difficult to be delivered practically disabled during particles immobilization in bio- by wet chemistry methods for nanoparticles preparation: chemical logical environments,15 suffer from low heating efficiency. Any stability over a prolonged period of time without the need for special further improvement of their known performance would handling, low surface charge, and energy resulting in weak aggregation involve precise chemical engineering on the nanoscale.6,16 tendency. Particularly, evaporation of pure Fe powder pressurized in a Here, we present results of an experimental study that directly pellet form, under Ar flow (70 Torr) resulted in 50 nm nanoparticles. relates the structural and magnetic properties of iron-based Under the same pressure, coevaporation of Fe and Fe3O4 mixtures core−shell particles. In particular, it is shown that surrounding produces a similar particle diameter but the thickness of oxide on the surface is anticipated to increase as compared to the shell stabilized a ferromagnetic (FM) iron core with a ferrimagnetic iron oxide after natural oxidation. The decrease in particles diameter (down to shell can tune the specific absorption rate (SAR) to about 35 nm) was achieved by using lower pressure (50 Torr), unprecedented efficiency (Scheme 1). Additional modeling whereas evaporation of a pure Fe3O4 target at 80 Torr enables the demonstrates that different reversal mechanisms are promoted, production of larger nanoparticles (75 nm) with a very low zerovalent depending on the core−shell ratio and absolute particle size. Fe content. The pumping of oxygen is sufficient to provide a More crucial to the synchronized behavior of this multiphase completely oxidized dark-red product (γ-Fe2O3). All samples were material, we find that the presence (or not) of a nonmagnetic stored in a desiccator periodically pumped with nitrogen to succeed interlayer, which changes the interphase coupling and alters the the extension of the time-scale without significant surface oxidation to reversal mechanism, is key to allowing for diminished a many months period. Morphology and Crystal Structure. Structural characterization importance of the detrimental interparticle dipolar interactions. was performed by X-ray diffraction (XRD) using a Rigaku Ultima+ This constitutes a remarkably different approach in comparison powder diffractometer with Cu Kα radiation. Transmission electron with other works dealing with core−shell geometries in which microscopy (TEM) images and selected area electron diffraction the objective was essentially to tune the effective single-particle (SAED) patterns were obtained on a JEOL JEM-1210 operating at properties but still under the giant-spin (i.e., coherent rotation 120 kV. A number of samples were examined in more detail using 4466 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article Table 1. Summary of the Parameters Used for the Simulations MS (emu/cm3) KC (erg/cm3) Aexch (J/m) axis1 axis2 Fe core 1711 4.6 × 105 2.5 × 10−11 (1,0,0) (0,1,0) Fe3O4 shell 477 −1.1 × 105 1.0 × 10−11 FeO spacer 1 0 0 Table 2. Overview of Preparation Conditions, Main Characteristics, and Schematic Illustrations of Studied Samplesa a Single asterisk (*), estimated by geometrical features, compositional analysis, and magnetic properties; double asterisk (**), composition analysis by Mossbauer spectroscopy is indicated into parentheses. high-resolution (HRTEM) and scanning transmission electron compared and validated to the quantified data from the corresponding (STEM) microscopy with a FEI Tecnai G2 F20 microscope operating XRD diagrams using the Rietveld methodology. at 200 kV and equipped with EDAX element analysis system. Samples Magnetism. Magnetic features of fixed nanoparticles powder were were prepared by dispersing the powders in ethanol. A small droplet evaluated by room temperature vibrating sample magnetometer of the suspension was placed on a holey carbon film supported on a (VSM−1.2H/CF/HT Oxford Instruments) in a magnetic field range copper grid. Scanning electron microscopy (SEM) micrographs of ±1 T. Additional minor hysteresis loops, carried out at maximum numerous samples were obtained in a Quanta 200 ESEM FEG FEI fields equal to the calorimetric magnetic hyperthermia measurements microscope. (30 and 60 mT), were also recorded after demagnetizing the samples Mössbauer Spectroscopy. To give more accurate description of to determine the maximum attainable power loss that can be coexisting iron phases, the powders were investigated by 57Fe generated by each system. Quantitative evaluation of DC minor loops Mö ssbauer spectrometry. The spectra were collected at room appears as a very reliable way to get a first estimation of the potential of each sample to provide hysteresis loss heat dissipation in cases temperature in transmission geometry, using a conventional constant where hysteresis represents the dominant magnetic heating acceleration spectrometer operating in triangular wave mode and a 57 mechanism. However, it should not be confused with the actual Co source into rhodium matrix. The speed scale of the Doppler behavior of the magnetic nanoparticles under the high frequency modulator and isomer shift calibration were performed using a 10 μm hyperthermia field. thick α-Fe foil. Mössbauer spectra were fitted using the Mosfit Calorimetric Measurements. The heating efficiency of nano- software, a least-squares iteration program.20 Hyperfine interaction particles dispersions in distilled water was evaluated in two different parameters are denoted as follows: IS for isomer shift (mm/s), QS for devices using a higher frequency (765 kHz) AC magnetic field peak of quadrupolar shift (mm/s), and Heff for magnetic hyperfine field (T). 30 mT and a lower frequency (210 kHz) setup capable of operating in Estimated errors (±5%) originate from the statistical inaccuracy given 30−60 mT field amplitude range. Temperature was monitored by by the fitting program. Results concerning composition were using a GaAs-based fiber optic probe immersed in a test tube 4467 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article containing 1 mL of dispersion. The quantifiable index of heating efficiency, the specific absorption rate or specific loss power, was derived from the slope of the temperature versus time curve in nonadiabatic conditions with detailed modeling of the heat exchange with the surrounding environment.21−23 Despite reduced dipolar interactions in the studied samples, the application of the AC field during the hyperthermia experiment was sufficient to cause a gradual precipitation of the solid within the first 100 s of measurement. After this time, nanoparticles were arranged at the side of the vessel forming a ring next to the induction coil. This effect is unavoidable in any magnetic nanoparticles system; however, recorded heating curves did not seem to be influenced by this inhomogeneity transition and this is probably attributed to the high heat transfer rate from nanoparticles to the whole solution volume. Computational Details. Micromagnetic simulations were carried out using the 3D version of the OOMMF package.24 In the first approximation, all particles were assumed spherical with a single- crystal core. M(H) hysteresis loops were simulated for several core− shell structures varying the Fe3O4 shell thickness-to-Fe core radius, that is, tS/rC ratio. When necessary, a separating FeO interlayer of width tsp was included. In all cases we considered a 1 nm-side cubic cell discretization, that is, below the smaller specific exchange length, lexch1 = 3.7 nm for the iron core and lexch1 = 8.4 nm for the Fe3O4 shell. Field was set collinear to the [100] easy axis of magnetization of iron (as corresponds to physically oriented nanoparticles under applied field in viscous conditions).25 No thermal excitations were considered, Figure 1. Representative TEM image of sample F03 (a) and thus rendering the results applicable only to blocked nanoparticles corresponding selected area electron diffraction pattern (b) showing (reasonable assumption for the large sizes considered26,27). The coexistence of metallic iron (red rings) and magnetite (green ring). micromagnetic parameters are shown in Table 1, with the exchange Focusing on a small particle, HRTEM discloses a fluffy coating layer between core and shell assumed to be 0.175 × 10−11 J/m (i.e., about of magnetite (c). STEM mode imaging and composition profile 10% of the average between the two phases). The easy axes of the derived from energy-dispersive spectroscopy analysis demonstrating shell are randomly oriented. The separating spacer is treated as the iron-rich core (d). paramagnetic-like, with a negligible MS value, that is, easily polarized and with no magnetic exchange or anisotropy contributions. The simulations were performed assuming quasi-static conditions nanoparticles while the surrounding outer shell is probably (reasonable for FM-like behavior, as discussed elsewhere9,28). To related to native oxidation. Another series (F03−05) discard undesired artificial effects of the initial configuration for minor comprises a constant Fe core (25 nm in diameter) coated by loops, the results were checked against the initialization in the random oxide shells with increasing thicknesses from 4 up to 24 nm. By or vortex states. ■ introducing Fe3O4 in the evaporating pellet material, the oxide content gradually increases and becomes the dominant phase RESULTS AND DISCUSSION when the Fe/Fe3O4 ratio in the target reaches 1:1 (sample Structure, Composition, and Magnetism. Composi- F04). However, even in the evaporation of pure Fe3O4, a small tional tuning is a major strategy to tailor magnetic properties. percentage of Fe is still observed as a result of Fe3O4 To this end, we have fabricated a series of complex structures decomposition during the evaporation procedure (sample using solar vapor phase condensation by varying the Fe-to- F05). Finally, a pure oxide sample (F06) stands for comparison Fe3O4 target ratio, the chamber pressure and the oxidizing to the 40 nm metallic nuclei. conditions as defined by pumping gas. Briefly, the evaporation Further insight into the microstructure by using TEM and of Fe under inert conditions preserves the metallic character- elemental mapping provides evidence about the core−shell istics in a core that is lately passivated with a thin oxide shell, distribution of Fe and its oxides, depicted in Figure 1, while simultaneous Fe3O4 decomposition also produces a small representatively, for the smallest overall diameter (sample metallic core but surrounded by a thicker oxide shell. F03). Low-resolution images (Figure 1a) clearly show the Moreover, depending on the composition of the gas stream morphology of the particles and point to the presence of a during synthesis (Ar or air), completely oxidized nanoparticles lower contrast material casing a darker center, but the presence (γ-Fe2O3) may also be produced.22 Table 2 shows a of the core−shell morphology is definitively proven by the compilation of both the preparation conditions and structural high-resolution TEM image of the individual particles. The and morphological results extracted from a compendium of electron diffraction results (Figure 1b), in consistence to XRD, characterization techniques. Figure S1 (see Supporting suggest the coexistence of pure metal and oxide phases. Figure Information) presents SEM images of samples under study. 1c presents a high contrast difference of the core and shell In general, our experimental system is a nanocrystalline regions where the oxide phase is indexed as Fe3O4. Further, magnetic sphere composed of several layers (up to three) of Fe local electron energy loss spectra analysis across the whole and its oxides. The initial structural analysis of obtained particle (Figure 1d) confirms that element distribution nanopowders was performed by XRD diagrams (see Figures S2 corresponds to the iron core/oxide shell morphology. and S3). A first set of samples (F01−02) includes a Fe grain We note that, independently of the median size, the relative size about 40 nm surrounded by variable oxides ∼5 nm distribution width is constant at about 15−20%, a character- thickness. Results suggest that, when a metallic target is istic of our synthesis process.22,29 Indeed, it is obvious that, in evaporated under inert gas flow (sample F01), a large real situations, there are spreads in the volume of particles but percentage of Fe (up to 80% wt.) is preserved in the prepared also the system may contain a number of different phases, each 4468 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article Figure 2. Minor hysteresis loops obtained by cycling with maximum field of 30 (in blue) and 60 (red) mT for samples under study with decreasing Fe content (F01−F06). The gray-shaded region accounts for the corresponding full cycles with 1 T, well above saturation field. with a specific saturation magnetic moment and anisotropy conditions. Moreover, every time that the target was a mixture energy, and, therefore, several relaxation parameters. Mössba- of Fe and Fe3O4 in variable proportions (samples F02, F03, uer spectroscopy measures directly the contribution from F04), the Mössbauer spectrum shows also a broad para- magnetically distinct phases. At room temperature (see Table magnetic central peak, which can be assigned to non- S1 and Figure S4 in the Supporting Information), the observed stoichiometric wüstite (FeO is an antiferromagnet with a intensity ratio 3:2:1 between the sextet lines and the value of Néel temperature around 200 K). It is worth mentioning that the hyperfine magnetic field (∼33 T) indicate that the core of FeO is known to disproportionate into Fe and Fe3O4.32 Giving most of the samples (except F06) is composed of bcc Fe, a model to explain the oxidation process of iron, it seems together with broad oxide components superimposed to the reasonable that this ferrous FeO phase would be placed at the metallic iron. This picture is consistent also with the XRD and core−shell interface, between the pure metallic Fe and the electron microscopy analyses. oxidized outer region.33,34 Obviously, epitaxial strains arise due Within the resolution of the structural analysis, it appears to the accommodation of the crystalline lattices of the oxide that the magnetic state of the nucleus remains unchanged, no and the metal. And probably, this strain favors the nucleation matter the shell. In this regard, the iron oxide phases consist of of the otherwise metastable FeO-like phase. For example, in two components (Fe3O4 and Fe2O3-like). We and others have thin films, the misfit between the iron atoms in the [1̅10] demonstrated that any sample made of nanocrystalline iron- direction of FeO and the [001] direction of iron is oxides is a mixture of several stoichiometries, whereas the small approximately 6%, whereas between FeO and Fe3O4 it is particles are maghemite rich.30 It is well-established that the only 3%. Regarding the oxidation of iron nanoparticles, there is octahedral Fe2+ ions located at the surface of magnetite still little information on the evolution of growth stresses in particles are very sensitive to oxidation,31 thus giving rise to these multiphase regimes. Naturally, a tensile stress is expected this Fe3+ rich layer, more visible in the smaller particles in the Fe3O4 shell opposing the compressive strain on the (sample F03) and those grown under the oxidizing atmosphere core,35 and this stress increases, at the very initial phase, with (sample F06). The corresponding oxide phase (mostly Fe3O4) the thickness of the oxide layer.36 In our case, stress occurrence in the case of pure iron targets (sample F01) is explained by as witnessed by XRD main peak shift attributed to reduction in the inevitable surface passivation after exposure to ambient average lattice parameter is reported in Figure S2. 4469 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article content decreases and oxide percentage is added gradually to the shell. The coercivity first increases, reaches a maximum at a Fe-to-oxide ratio of 2 and then decreases. We highlight that for iron, maximum coercivities because of the magneto-crystalline anisotropy alone are about 40 mT,37 though strain anisotropies may force it up to 60 mT, which is the case reported here. Complete oxidation of nanoparticles (sample F06) results again in weaker magnetic features. Incidentally, room-temperature magnetic properties of core−shell iron/iron oxide nanocrystals with core sizes ranging from ∼5 to 20 nm and constant thickness of the oxide shell about 2 nm were previously investigated by Kaur et al.38 They concluded that dipolar interparticle interactions become stronger with the growth of size. There, the decrease in coercive field Hc from 50 mT to about 5 mT with decreasing particle size was due to thermal effects. This is not the case here, and we surmise that not only interparticle but also intraparticle interactions between the iron core (ferromag- netic) and oxide shells should be considered. So far, we have determined the quasi-static magnetic response in a core−shell iron/iron oxide system. A combined study of microscopy, XRD, and Mössbauer reveals the existence of several oxides in the shell region, with a major contribution from FeO and Fe 3 O 4 . Apart from the compositions, hysteresis loops demonstrate that optimizing material performance requires the change in core−shell size proportion. Thus, it is anticipated that particular ratios of soft Figure 3. Room-temperature dependence of saturation magnetization, to hard phases would lead to enhanced heating response. coercive field and remanence ratio as a function of the Fe/Fe3O4 mass ratio of core−shell magnetic nanoparticles. Horizontal lines in the Hc Magnetic Heating. The efficiency of magnetoheating plot account for maximum fields in minor cycles (30 and 60 mT) and particles is primarily governed by three interrelated parame- hyperthermia measurements. ters: the magnetic anisotropy energy (which depends on several features, for example, the size of the particles via surface effects), the experimental field conditions, and the dosage. Figure 4 indicates that since the amount of generated heat is given by the product of the frequency and the area of the hysteresis loop, SAR is gradually enhanced upon increasing the frequency. Concomitantly, according to the hysteresis losses (see Figure 2), oxide-rich nanoparticles are by far more efficient at lower AC fields (see data at 30 mT) while Fe-rich samples require higher fields to unfold their full response, as also anticipated from the Hc and Mr dependencies shown in Figure 3. On the other hand, the complete oxidation results in similar response to that for typical iron oxides reported in literature.39 Thus, it seems that the change in the two phases ratio can lead to both magnetic hardening and enhanced heating efficiency, provided the proper hyperthermia con- ditions are applied (AC frequency and field amplitude). Indeed, we acknowledge that similar (bi)magnetic iron/iron oxide core−shell nanoparticles (though <15 nm in size) have been already explored for in vivo hyperthermia.40 But Figure 4. Hyperthermia efficiency for fixed frequency (210 kHz) but extraordinary, in our case, sample F05, with oxide shell different field amplitudes and for the same field amplitude (30 mT) thickness tS = 24 nm and Fe core’s radius rC = 15 nm, shows a but different AC field frequency (765 kHz). Particles concentration is remarkable heating efficiency which approaches 0.9 kW/g. On 4 mg/mL. Sample F06 would correspond to infinite shell/core ratio. this, one should remark the puzzling coincidence that the term (tS + rC)/tS is found practically equal to the term tS/rC and Magnetization measurements shown in Figure 2 demon- both very close to the value of φ = 1.618..., which is known as strate different reversal mechanisms depending on the core− the geometric golden ratio. A similar finding has been reported shell ratio and absolute particle size. On the one hand, the for core−shell bimagnetic Fe3O4/CoxZn1−xFe2O4 nanopar- saturation magnetization increases with the percentage of iron ticles.41 However, much more research is required to suggest and reaches 200 Am2/kg for F01, which is close to the pure any association of nanoscale effects with such conception of bulk value. But, as shown in Figure 3, this trend is not reflected symmetry and perfection, which is met in many instances of in monotonic behavior of the Mr/Ms ratio and coercivity as Fe nature, science, and human art. 4470 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article Figure 5. Micromagnetic magnetization configuration at remanence of an example core−shell structure (Dtot = 40 nm; rC = 16 nm, tsp = 4 nm; tS = 8 nm), in this case showing AFM-like coupling between core and shell. The snapshots are taken at regular cross sections of the particle, as illustrated by the sketch shown up, left. For clarity purposes the arrows representing the magnetization are magnified (each arrow corresponds to 8 cubic subunits of 1 nm side each). Magnetic Modeling. The simplest and most generally hysteresis loops. Interestingly, the threshold between employed model of magnetic hyperthermia is the linear regimes, which corresponds to an enhanced loop area, response theory of Rosensweig.42 For a given particle size, this occurs at the transition at which the exchange energy gives a scaling of the heating with f·H2. The measurements contribution is similar to the magnetostatic one. given in Figure 4 clearly do not conform to this scaling. To B Core−shell ratio: For a given Dtot, magnetization explain the behavior of such complex systems one must use a switching evolves from a noncoherent behavior (of model allowing the possibility of nonuniform reversal with the small hysteresis area values) to a fully coherent one capability to introduce the detailed structure of the core−shell (with associated large areas) with increasing the tS/rC combination. In an effort to infer which are the main core− value. Interestingly, the transition occurs around tS/rC = shell features determining the magnetic response (e.g., aspect 1. ratio, total size, etc.) and to correlate those with the heat C Thickness of interlayer spacer: The presence of a PM- release, a theoretical approach based on a micromagnetic like interlayer allows antiferromagnetic-like (AFM), that technique using the OOMMF software package24 was carried is, antiparallel, coupling between the core and the shell out. An illustrative example of the micromagnetic simulations through magnetostatic interactions, being the soft shell is shown in Figure 5. The simulated structure has a Fe core of the dominating phase, that is, switching first and forcing radius rC, a magnetite shell of thickness tS, and a FeO interlayer the core to switch later and also polarizing the FeO. In of width tsp treated as paramagnetic. In some cases, the shell such cases, the hysteresis area may be significantly was considered polycrystalline with random easy axis enlarged. distribution. Considering the relatively large dimensions of D Polycrystalline shell may lead to a complete change in the particles, we have focused on one field-amplitude/ the shape of the loop, from smooth to very abrupt frequency case Hmax = 30 mT and f = 765 kHz for blocked (squared) that would be highly desired for enhancing entities. the heat output.43,44 It is worth noting that, in this case, On the basis of the experimental details reported in Table 2, both Fe and Fe3O4 phases are coupled in parallel some representative examples of computed hysteresis loops are configuration and the magnetization reversal is essen- summarized in Figure 6, illustrating the different roles of the tially coherent. Another important characteristic of the particle size Dtot (panel A), the core−shell tS/rC ratio (B), presence of a polycrystalline shell is that it significantly thickness of the paramagnetic interlayer spacer (C), and influences the dependence of the magnetic response on average size of shell crystallites (D) on the magnetization the direction of field application. Simulations were response. Overall, the results suggest several key roles of these performed on the basis of the average shell crystallite four parameters. size estimated by XRD diagrams for the oxide phases A. Total particle size: For small values of Dtot, the particle given in Table S2. behaves as a large magnetic supermoment with coherent The comparison between experimentally measured and magnetization behavior, while increasing Dtot leads to a theoretically predicted heating performance is shown in Figure noncoherent magnetization reversal and narrower 7. Very good agreement between experiment and theory is 4471 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article Figure 6. Case study of the hysteresis loops for an isolated particle depending on the total particle size (A), core−shell ratio (B), thickness tsp of the paramagnetic interlayer spacer (C), and average size Lcryst of crystallites composing the shell (D). The central sketch depicts the associated core− shell structure. obtained, except in the case of sample F03. Additional summarized in the Supporting Information section S4, indicate modeling (see the Supporting Information section S3) no improvement in the overall experiment-theory comparison demonstrates that there is a crucial difference between sample but, on the contrary, increased divergence in some other F03 and rest: sample F03 is the only one not completely samples. So, we are left with the conclusion that the presumed reversing the magnetization, that is, undergoing minor loop hypotheses stating that interparticle interactions plays a conditionsmay this feature be enough to justify the secondary role does not hold for sample F03, and that the divergence? dipole−dipole coupling changes the field parameters necessary The implications of such minor-loop conditions regarding to achieve the maximum SAR.45 Our assumption is that heating performance can be extremely important (minor loops nonreversing particles (as for example, those whose easy axes correspond to much smaller heating power than the maximum are almost parallel to the field direction) in the minor loop achievable one; not to mention other effects such as e.g. higher condition create a static field on the reversing particles. To test dispersion in local heating performance28). However, the fact this, we next simulated the heating performance of pairs of is that experimentally, the heat dissipated by this sample is not potentially interacting particles from sample F03 at several negligible, but comparable to those of samples F01 and F02 separations and arrangements (see Figure S15). The results and even higher than that of F04. Clearly, there is significant indicate a significant decrease of the heating performance with heat dissipation from sample F03 that is not predicted by the decreasing interparticle distances for special geometrical theoretical model in the minor loop condition (see Figure S8). arrangements. We also show that in these situations the In the major loop conditions, even when a random distribution interparticle distances less than 1.5 times the particles’ of nanoparticles is included, the predicted heat release is diameter can meaningfully explain the measured SAR values. significantly higher than the experimentally measured value, as The reason why this effect of particle−particle interactions illustrated by the gray nonshaded tall column of sample F03 on SAR is only observed in sample F03 stems from the fact within Figure 7 (see Figure S11 and discussion therein). that this is the only sample exhibiting both requirements of To investigate this complex scenario, we have performed coherent reversal and minor loop behavior. various modifications to the model, including the addition of Furthermore, Figure 8 presents magnetic configurations in perpendicular surface anisotropy in the outer layer of the shell three orthogonal planes for three samples F01, F02, and F04, or at the interface, dynamical effects, etc. The results, which have similar sizes. The occurrence of noncoherent 4472 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article coherent magnetization rotation. The occurrence of curling 2D or 3D vortices minimizes magnetostatic energy and diminishes the stray field of nanoparticles. The above curved magnetic structures are topologically nontrivial. Recently, such structures in magnetism have attracted intensive research, given their potential applications to information technology. They have been also exploited by other researchers in the effort to fight cancer. For instance, the magnetic vortex in planar thin-film microdiscs creates an oscillation when a low frequency (tens of Hz) AC magnetic field is applied.46 This movement transmits a mechanical force to the surrounding tissue that may be enough to compromise integrity of the cellular membrane. Additionally, coupling the vortex eigenmode to MHz frequencies may provide a new and efficient means of energy absorption by and emission from magnetic nanoparticles.47 However, from the standpoint of micromagnetism, our study differs completely from those not only because they were based on soft-magnetic permalloy, while our particles comprise a core and shell iron derivatives Figure 7. Comparison between experimentally measured SAR values but also in the considered frequency range. Instead, our case (blue bars) and the theoretical predictions (green bars) obtained resembles the one reported by Liu et al.48 in iron oxide based on the model reported in Figure 6, for noninteracting nanorings, in which magnetization is circumferential to the ring conditions and field characteristics of f = 765 kHz and Hmax= 30 mT. The SAR values are estimated from the area of the loops as SAR without stray fields. Minimization of stray fields is very crucial = f·area. Note that the computed heating efficiency for sample F03 to reduce dipole−dipole interactions and agglomeration of describes the observational studies only if particle−particle dipolar magnetic particles in solution, supporting the argument that coupling is included (marked red column), further explained in the the oxide shell promotes decoupling of the iron nuclei. Such text. hypothesis was verified by establishing the effect of vortex-like intraparticle magnetization structures, FePt/iron oxide core− shell nanoparticles, in lowering of magnetic dipole−dipole interactions and enhancement of stabilization.49 And so, this work adds to the growing body of knowledge showing the complex issue of physical interpretation of interaction effects in magnetic hyperthermia. Finally, it is worth relating our work with the question posed by Z. Nemati et al.,17 are core−shell magnetic nanoparticles promising for hyperthermia? Our answer is not only a clear yes, but furthermore, we emphasize the rich possibilities opened by tuning the core−shell coupling of those structures to tailor specific response. ■ CONCLUSIONS In summary, distribution of iron and its oxides in well-defined core−shell nanoparticles is proven to be a crucial parameter when it comes to optimal magnetic properties in hyperthermia. This stems from the fact that the geometry of a coupled core− shell structure prohibits an existence of spatially homogeneous magnetization in the nanoparticle as whole, and when made of a magnetically softer-harder ferromagnets, for each thickness, there exists a critical radius where curling or more complicated nonhomogeneous structures become promoted. In particular, observations of topologically nontrivial vortex-like structures Figure 8. (A) Cross sections of magnetization configurations at stress the difference between core−shell magnetic construc- remanence for the samples F01, F02, and F04 discussed in Table 2; tions and homogeneous particles. the magnetization arrows correspond to the average over 8-unit cells. Remarkably, in our case, samples with noncoherent reversal The snapshots have been taken along the X, Y, and Z directions (left, surprisingly seem more adequate in generating large SAR center, and right snapshot for each sample, respectively) and always at values because interparticle interactions are negligible in the center of the particle. comparison with the inner magnetization processes, thus, diminishing the possibility of aggregated formation. Combined reversal modes is clearly visible. Particularly, sample F01 experimental and theoretical analysis also revealed a novel demagnetizes through the occurrence of a 2D vortex, the core magnetization process wherein the iron-oxides effectively of which forms a tube, parallel to the easy-axis of Fe that is reduce the coercivity of the ferromagnetic cores by leading closer to the applied field direction. Sample F02 demagnetizes the magnetization process at small magnetic fields, thus, through a 3D vortex-like structure, in which the core is overcoming the main drawbacks of minor loops for stand-alone displaced from the center. Sample F04 presents almost homogeneous nanoparticles for magnetoheating. Overall, we 4473 https://dx.doi.org/10.1021/acsanm.0c00568 ACS Appl. Nano Mater. 2020, 3, 4465−4476 ACS Applied Nano Materials www.acsanm.org Article show the existence of far more options to tune the heating Author Contributions performance in magnetic nanoparticles as was foreseen up to The manuscript was written through contributions of all authors. All authors have given approval to the final version of now. The presented methodology can easily serve as flexible the manuscript. toolbox to support examination of nanoparticles behavior using Notes different sizes, shapes, concentrations, mobilities, aggregation The authors declare no competing financial interest. types, and dispersion media. ■ ASSOCIATED CONTENT ■ ACKNOWLEDGMENTS Financial support of the Royal Society through International * Supporting Information sı Exchanges scheme IE160535 is gratefully acknowledged. This work made use of computational facilities funded by the Small The Supporting Information is available free of charge at items of research equipment at the University of York https://pubs.acs.org/doi/10.1021/acsanm.0c00568. ENERGY (Grant No. EP/K031589/1). We thank the CNRS-PROMES laboratory, UPR 8521, belonging to the Further data on the analysis of particles morphology, the French National Centre for Scientific Research (CNRS) for crystal structure, Mössbauer spectra, raw experimental providing access to its installations, the support of its scientific observations on magnetic properties and hyperthermia and technical staff (N. Boullet, E. Guillot, A. Badziaka), and efficiency and a deep explanation of the finite difference the financial support of the SFERA-III project (Grant simulation method to theoretically derive the main Agreement No 823802). We also acknowledge the Centro core−shell features determining the magnetic response de Supercomputación de Galicia (CESGA) for the computa- and correlate those with the heat release (PDF) tional resources. This research was partially supported by the Conselleriá de Educación Program for Development of a ■ AUTHOR INFORMATION Corresponding Authors Strategic Grouping in Materials (AeMAT) at the Universidade de Santiago de Compostela (Grant No. ED431E2018/08, Xunta de Galicia). D.S. also acknowledges Xunta de Galicia for D. Serantes − Department of Physics, University of York, financial support under the I2C Plan. K.S. acknowledges Heslington, York YO10 5DD, United Kingdom; Applied Physics Stavros Niarchos Foundation for financial support. C.M.B. Department and IIT, Universidade de Santiago de Compostela, would like to thank his wife, Marian, for sustaining him during Compostela 15782, Spain; orcid.org/0000-0002-3860- the many rough draft versions of this paper. 2133; Email: david.serantes@usc.es M. Angelakeris − Department of Physics, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece; orcid.org/0000- ■ REFERENCES (1) Houlding, T. K.; Rebrov, E. V. Application of Alternative Energy 0001-9109-0221; Email: agelaker@auth.gr Forms in Catalytic Reactor Engineering. Green Process. Synth. 2012, DOI: 10.1515/greenps-2011-0502. Authors (2) Beck, M. M.; Lammel, C.; Gleich, B. Improving Heat Generation K. Simeonidis − Department of Physics, Aristotle University of of Magnetic Nanoparticles by Pre-Orientation of Particles in a Static Thessaloniki, Thessaloniki 54124, Greece; Ecorecources P.C., Three Tesla Magnetic Field. J. Magn. Magn. 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