Selective Magnetic Nanoheating: Combining Iron Oxide Nanoparticles for Multi-Hot-Spot Induction and Sequential Regulation.

The contactless heating capacity of magnetic nanoparticles (MNPs) has been exploited in fields such as hyperthermia cancer therapy, catalysis, and enzymatic thermal regulation. Herein, we propose an advanced technology to generate multiple local temperatures in a single-pot reactor by exploiting the unique nanoheating features of iron oxide MNPs exposed to alternating magnetic fields (AMFs). The heating power of the MNPs depends on their magnetic features but also on the intensity and frequency conditions of the AMF. Using a mixture of diluted colloids of MNPs we were able to generate a multi-hot-spot reactor in which each population of MNPs can be selectively activated by adjusting the AMF conditions. The maximum temperature reached at the surface of each MNP was registered using independent fluorescent thermometers that mimic the molecular link between enzymes and MNPs. This technology paves the path for the implementation of a selective regulation of multienzymatic reactions.

Unveiling the Dynamical Assembly of Magnetic Nanocrystal Zig-Zag Chains via In Situ TEM Imaging in Liquid.

The controlled assembly of colloidal magnetic nanocrystals is key to many applications such as nanoelectronics, storage memory devices, and nanomedicine. Here, the motion and ordering of ferrimagnetic nanocubes in water via liquid-cell transmission electron microscopy is directly imaged in situ. Through the experimental analysis, combined with molecular dynamics simulations and theoretical considerations, it is shown that the presence of highly competitive interactions leads to the formation of stable monomers and dimers, acting as nuclei, followed by a dynamic growth of zig-zag chain-like assemblies. It is demonstrated that such arrays can be explained by first, a maximization of short-range electrostatic interactions, which at a later stage become surpassed by magnetic forces acting through the easy magnetic axes of the nanocubes, causing their tilted orientation within the arrays. Moreover, in the confined volume of liquid in the experiments, interactions of the nanocube surfaces with the cell membranes, when irradiated at relatively low electron dose, slow down the kinetics of their self-assembly, facilitating the identification of different stages in the process. The study provides crucial insights for the formation of unconventional linear arrays made of ferrimagnetic nanocubes that are essential for their further exploitation in, for example, magnetic hyperthermia, magneto-transport devices, and nanotheranostic tools.

Anisotropic magnetic nanoparticles for biomedicine: bridging frequency separated AC-field controlled domains of actuation.

Magnetic nanoparticles (MNPs) constitute promising nanomedicine tools based on the possibility of obtaining different actuations (for example, heating or mechanical response) triggered by safe remote stimuli. Particularly, the possibility of performing different tasks using the same entity constitutes a main research target towards optimizing the treatment. But such a goal represents, in general, a very difficult step because the requisites for achieving efficient responses for separate actuations are often disparate - if not completely incompatible. An example of this is the response of MNPs to external AC fields, which could in principle be exploited for either magneto-mechanical actuation (MMA) at low frequencies (tens of Hz); or heat release at high frequency (0.1-1 MHz range) for magnetic fluid hyperthermia (MFH). The problem is that efficient MMA involves large torque, the required material parameters for which are detrimental to high heating, thus hindering the possibility of effective alternation between both responses. To overcome such apparent incompatibility, we propose a simple approach based on the use of anisotropic MNPs. The key idea is that the AC-frequency change must be concurrent with a field-amplitude variation able to promote - or impede - the reversal over the shape-determined anisotropy energy barrier. This way it is possible to switch the particle response between an efficient (magnetically dissipationless) rotation regime at low-f, for MMA, and a "frozen" (non-rotatable) high-energy-dissipation regime at high-f, for MFH. Furthermore, we show that such an alternation can also be achieved within the same high-f MFH regime. We use combined Brownian dynamics and micromagnetic simulations, based on real experimental samples, to show how such a field threshold can be tuned to working conditions with hexagonal-disk shape anisotropy.

Towards improved magnetic fluid hyperthermia: major-loops to diminish variations in local heating.

In the context of using magnetic nanoparticles for heat-mediated applications, the need of an accurate knowledge of the local (at the nanoparticle level) heat generation in addition to the usually studied global counterpart has been recently highlighted. Such a need requires accurate knowledge of the links among the intrinsic particle properties, system characteristics and experimental conditions. In this work we have investigated the role of the particles' anisotropy polydispersity in relation to the amplitude (Hmax) of the AC magnetic field using a Monte Carlo technique. Our results indicate that it is better to use particles with large anisotropy for enhancing global heating, whereas for achieving homogeneous local heating it is better to use lower anisotropy particles. The latter ensures that most of the system undergoes major-loop hysteresis conditions, which is the key-point. This is equivalent to say that low-anisotropy particles (i.e. with less heating capability) may be better for accurate heat-mediated applications, which goes against some research trends in the literature that seek for large anisotropy (and hence heating) values.

Distinguishing between heating power and hyperthermic cell-treatment efficacy in magnetic fluid hyperthermia.

In the magnetic fluid hyperthermia (MFH) research field, it is usually assumed that achieving a uniform temperature enhancement (ΔT) of the entire tumour is a key-point for treatment. However, various experimental works reported successful cell apoptosis via MFH without a noticeable ΔT of the system. A possible explanation of the success of these negligible-ΔT experiments is that a local ΔT restricted to the particle nanoenvironment (i.e. with no significant effect on the global temperature T) could be enough to trigger cell death. Shedding light on such a possibility requires accurate knowledge of heat dissipation at the local level in relation to the usually investigated global (average) one. Since size polydispersity is inherent to all synthesis techniques and the heat released is proportional to the particle size, heat dissipation spots with different performances - and thus different effects on the cells - will likely exist in every sample. In this work we aim for a double objective: (1) to emphasize the necessity to distinguish between the total dissipated heat and hyperthermia effectiveness, and (2) to suggest a theoretical approach on how to select, for a given size polydispersity, a more adequate average size so that most of the particles dissipate within a desired heating power range. The results are reported in terms of Fe3O4 nanoparticles as a representative example.

The role of size polydispersity in magnetic fluid hyperthermia: average vs. local infra/over-heating effects.

An efficient and safe hyperthermia cancer treatment requires the accurate control of the heating performance of magnetic nanoparticles, which is directly related to their size. However, in any particle system the existence of some size polydispersity is experimentally unavoidable, which results in a different local heating output and consequently a different hyperthermia performance depending on the size of each particle. With the aim to shed some light on this significant issue, we have used a Monte Carlo technique to study the role of size polydispersity in heat dissipation at both the local (single particle) and global (macroscopic average) levels. We have systematically varied size polydispersity, temperature and interparticle dipolar interaction conditions, and evaluated local heating as a function of these parameters. Our results provide a simple guide on how to choose, for a given polydispersity degree, the more adequate average particle size so that the local variation in the released heat is kept within some limits that correspond to safety boundaries for the average-system hyperthermia performance. All together we believe that our results may help in the design of more effective magnetic hyperthermia applications.

Understanding magnetic hyperthermia performance within the "Brezovich criterion": beyond the uniaxial anisotropy description.

Careful determination of the heating performance of magnetic nanoparticles under AC fields is critical for magnetic hyperthermia applications. However, most interpretations of experimental data are based on the uniaxial anisotropy approximation, which in the first instance can be correlated with the particle aspect ratio. This is to say, the intrinsic magnetocrystalline anisotropy is discarded, under the assumption that the shape contribution dominates. We show in this work that such a premise, generally valid for large field amplitudes, does not hold for describing hyperthermia experiments carried out under small field values. Specifically, given its relevance for in vivo applications, we focus our analysis on the so-called "Brezovich criterion", H·f = 4.85 × 108 A m-1 s-1. By means of a computational model, we show that the intrinsic magnetocrystalline anisotropy plays a critical role in defining the heat output, determining also the role of the shape and aspect ratio of the particles on the SLP. Our results indicate that even small deviations from spherical shape have an important impact on optimizing the heating performance. The influence of interparticle interactions on the dissipated heat is also evaluated. Our results call, therefore, for an improvement in the theoretical models used to interpret magnetic hyperthermia performance.

Correction: Beyond Newton's law of cooling in evaluating magnetic hyperthermia performance: a device-independent procedure.

[This corrects the article DOI: 10.1039/D4NA00383G.].

Beyond Newton's law of cooling in evaluating magnetic hyperthermia performance: a device-independent procedure.

Accurate knowledge of the heating performance of magnetic nanoparticles (MNPs) under AC magnetic fields is critical for the development of hyperthermia-mediated applications. Usually reported in terms of the specific loss power (SLP) obtained from the temperature variation (ΔT) vs. time (t) curve, such an estimate is subjected to a huge uncertainty. Thus, very different SLP values are reported for the same particles when measured on different equipment/in different laboratories. This lack of control clearly hampers the further development of nanoparticle-mediated heat-triggered technologies. Here, we report a device-independent approach to calculate the SLP value of a suspension of magnetic nanoparticles: the SLP is obtained from the analysis of the peak at the AC magnetic field on/off switch of the ΔT(time) curve. The measurement procedure, which itself constitutes a change of paradigm within the field, is based on the heat diffusion equation, which is still valid when the assumptions of Newton's law of cooling are not applicable, as (i) it corresponds to the ideal scenario in which the temperature profiles of the system during heating and cooling are the same; and (ii) it diminishes the role of coexistence of various heat dissipation channels. Such an approach is supported by theoretical and computational calculations to increase the reliability and reproducibility of SLP determination. Furthermore, the new methodological approach is experimentally confirmed, by magnetic hyperthermia experiments performed using 3 different devices located in 3 different laboratories. Furthermore, the application of this peak analysis method (PAM) to a rapid succession of stimulus on/off switches which results in a zigzag-like ΔT(t), which we term the zigzag protocol, allows evaluation of possible variations of the SLP values with time or temperature.

Nanoparticle Size Threshold for Magnetic Agglomeration and Associated Hyperthermia Performance.

The likelihood of magnetic nanoparticles to agglomerate is usually estimated through the ratio between magnetic dipole-dipole and thermal energies, thus neglecting the fact that, depending on the magnitude of the magnetic anisotropy constant (K), the particle moment may fluctuate internally and thus undermine the agglomeration process. Based on the comparison between the involved timescales, we study in this work how the threshold size for magnetic agglomeration (daggl) varies depending on the K value. Our results suggest that small variations in K-due to, e.g., shape contribution, might shift daggl by a few nm. A comparison with the usual superparamagnetism estimation is provided, as well as with the energy competition approach. In addition, based on the key role of the anisotropy in the hyperthermia performance, we also analyse the associated heating capability, as non-agglomerated particles would be of high interest for the application.

Simulating the Self-Assembly and Hysteresis Loops of Ferromagnetic Nanoparticles with Sticking of Ligands.

The agglomeration of ferromagnetic nanoparticles in a fluid is studied using nanoparticle-level Langevin dynamics simulations. The simulations have interdigitation and bridging between ligand coatings included using a computationally-cheap, phenomenological sticking parameter c. The interactions between ligand coatings are shown in this preliminary study to be important in determining the shapes of agglomerates that form. A critical size for the sticking parameter is estimated analytically and via the simulations and indicates where particle agglomerates transition from well-ordered (c is small) to disordered (c is large) shapes. Results are also presented for the hysteresis loops (magnetization versus applied field) for these particle systems in an oscillating magnetic field appropriate for hyperthermia applications. The results show that the clumping of particles has a significant effect on their macroscopic properties, with important consequences on applications. In particular, the work done by an oscillating field on the system has a nonmonotonic dependence on c.

Mapping the Magnetic Coupling of Self-Assembled Fe3O4 Nanocubes by Electron Holography.

The nanoscale magnetic configuration of self-assembled groups of magnetite 40 nm cubic nanoparticles has been investigated by means of electron holography in the transmission electron microscope (TEM). The arrangement of the cubes in the form of chains driven by the alignment of their dipoles of single nanocubes is assessed by the measured in-plane magnetic induction maps, in good agreement with theoretical calculations.

Cancer therapy with iron oxide nanoparticles: Agents of thermal and immune therapies.

Significant research and preclinical investment in cancer nanomedicine has produced several products, which have improved cancer care. Nevertheless, there exists a perception that cancer nanomedicine 'has not lived up to its promise' because the number of approved products and their clinical performance are modest. Many of these analyses do not consider the long clinical history and many clinical products developed from iron oxide nanoparticles. Iron oxide nanoparticles have enjoyed clinical use for about nine decades demonstrating safety, and considerable clinical utility and versatility. FDA-approved applications of iron oxide nanoparticles include cancer diagnosis, cancer hyperthermia therapy, and iron deficiency anemia. For cancer nanomedicine, this wealth of clinical experience is invaluable to provide key lessons and highlight pitfalls in the pursuit of nanotechnology-based cancer therapeutics. We review the clinical experience with systemic liposomal drug delivery and parenteral therapy of iron deficiency anemia (IDA) with iron oxide nanoparticles. We note that the clinical success of injectable iron exploits the inherent interaction between nanoparticles and the (innate) immune system, which designers of liposomal drug delivery seek to avoid. Magnetic fluid hyperthermia, a cancer therapy that harnesses magnetic hysteresis heating is approved for treating humans only with iron oxide nanoparticles. Despite its successful demonstration to enhance overall survival in clinical trials, this nanotechnology-based thermal medicine struggles to establish a clinical presence. We review the physical and biological attributes of this approach, and suggest reasons for barriers to its acceptance. Finally, despite the extensive clinical experience with iron oxide nanoparticles new and exciting research points to surprising immune-modulating potential. Recent data demonstrate the interactions between immune cells and iron oxide nanoparticles can induce anti-tumor immune responses. These present new and exciting opportunities to explore additional applications with this venerable technology. Clinical applications of iron oxide nanoparticles present poignant case studies of the opportunities, complexities, and challenges in cancer nanomedicine. They also illustrate the need for revised paradigms and multidisciplinary approaches to develop and translate nanomedicines into clinical cancer care.

An extraordinary chiral exchange-bias phenomenon: engineering the sign of the bias field in orthogonal bilayers by a magnetically switchable response mechanism.

Isothermal tuning of both the magnitude and the sign of the bias field has been achieved by exploiting a new phenomenon in a system consisting of two orthogonally coupled films: SmCo5 (out-of-plane anisotropy)-CoFeB (in-plane anisotropy). This has been achieved by using the large dipolar magnetic field of the SmCo5 layer resulting in the pinning of one of the branches of the hysteresis loop (either the ascending or the descending branch) at a fixed field value while the second one is modulated along the field axis by varying the orientation of an externally applied magnetic field. This means the possibility of controlling the sign of the bias field in a manner not reported to date. Moreover, modulation of the bias field strength is possible by varying the thickness of a spacer between the SmCo5 and CoFeB layers. This study shows that the observed phenomena find their origin in the competition between the artificially induced anisotropies in both layers, resulting in a reversible chiral bias effect that allows the selection of the initial sign of the bias field by switching (upwards/downwards) the magnetization in the SmCo5 film.

Exploiting Unique Alignment of Cobalt Ferrite Nanoparticles, Mild Hyperthermia, and Controlled Intrinsic Cobalt Toxicity for Cancer Therapy.

Nanoparticle-based magnetic hyperthermia is a well-known thermal therapy platform studied to treat solid tumors, but its use for monotherapy is limited due to incomplete tumor eradication at hyperthermia temperature (45 °C). It is often combined with chemotherapy for obtaining a more effective therapeutic outcome. Cubic-shaped cobalt ferrite nanoparticles (Co-Fe NCs) serve as magnetic hyperthermia agents and as a cytotoxic agent due to the known cobalt ion toxicity, allowing the achievement of both heat and cytotoxic effects from a single platform. In addition to this advantage, Co-Fe NCs have the unique ability to form growing chains under an alternating magnetic field (AMF). This unique chain formation, along with the mild hyperthermia and intrinsic cobalt toxicity, leads to complete tumor regression and improved overall survival in an in vivo murine xenograft model, all under clinically approved AMF conditions. Numerical calculations identify magnetic anisotropy as the main Co-Fe NCs' feature to generate such chain formations. This novel combination therapy can improve the effects of magnetic hyperthermia, inaugurating investigation of mechanical behaviors of nanoparticles under AMF, as a new avenue for cancer therapy.

The Intracellular Number of Magnetic Nanoparticles Modulates the Apoptotic Death Pathway after Magnetic Hyperthermia Treatment.

Magnetic hyperthermia is a cancer treatment based on the exposure of magnetic nanoparticles to an alternating magnetic field in order to generate local heat. In this work, 3D cell culture models were prepared to observe the effect that a different number of internalized particles had on the mechanisms of cell death triggered upon the magnetic hyperthermia treatment. Macrophages were selected by their high capacity to uptake nanoparticles. Intracellular nanoparticle concentrations up to 7.5 pg Fe/cell were measured both by elemental analysis and magnetic characterization techniques. Cell viability after the magnetic hyperthermia treatment was decreased to <25% for intracellular iron contents above 1 pg per cell. Theoretical calculations of the intracellular thermal effects that occurred during the alternating magnetic field application indicated a very low increase in the global cell temperature. Different apoptotic routes were triggered depending on the number of internalized particles. At low intracellular magnetic nanoparticle amounts (below 1 pg Fe/cell), the intrinsic route was the main mechanism to induce apoptosis, as observed by the high Bax/Bcl-2 mRNA ratio and low caspase-8 activity. In contrast, at higher concentrations of internalized magnetic nanoparticles (1-7.5 pg Fe/cell), the extrinsic route was observed through the increased activity of caspase-8. Nevertheless, both mechanisms may coexist at intermediate iron concentrations. Knowledge on the different mechanisms of cell death triggered after the magnetic hyperthermia treatment is fundamental to understand the biological events activated by this procedure and their role in its effectiveness.

Asymmetric Assembling of Iron Oxide Nanocubes for Improving Magnetic Hyperthermia Performance.

Magnetic hyperthermia (MH) based on magnetic nanoparticles (MNPs) is a promising adjuvant therapy for cancer treatment. Particle clustering leading to complex magnetic interactions affects the heat generated by MNPs during MH. The heat efficiencies, theoretically predicted, are still poorly understood because of a lack of control of the fabrication of such clusters with defined geometries and thus their functionality. This study aims to correlate the heating efficiency under MH of individually coated iron oxide nanocubes (IONCs) versus soft colloidal nanoclusters made of small groupings of nanocubes arranged in different geometries. The controlled clustering of alkyl-stabilized IONCs is achieved here during the water transfer procedure by tuning the fraction of the amphiphilic copolymer, poly(styrene-co-maleic anhydride) cumene-terminated, to the nanoparticle surface. It is found that increasing the polymer-to-nanoparticle surface ratio leads to the formation of increasingly large nanoclusters with defined geometries. When compared to the individual nanocubes, we show here that controlled grouping of nanoparticles-so-called "dimers" and "trimers" composed of two and three nanocubes, respectively-increases specific absorption rate (SAR) values, while conversely, forming centrosymmetric clusters having more than four nanocubes leads to lower SAR values. Magnetization measurements and Monte Carlo-based simulations support the observed SAR trend and reveal the importance of the dipolar interaction effect and its dependence on the details of the particle arrangements within the different clusters.

In-situ particles reorientation during magnetic hyperthermia application: Shape matters twice.

Promising advances in nanomedicine such as magnetic hyperthermia rely on a precise control of the nanoparticle performance in the cellular environment. This constitutes a huge research challenge due to difficulties for achieving a remote control within the human body. Here we report on the significant double role of the shape of ellipsoidal magnetic nanoparticles (nanorods) subjected to an external AC magnetic field: first, the heat release is increased due to the additional shape anisotropy; second, the rods dynamically reorientate in the orthogonal direction to the AC field direction. Importantly, the heating performance and the directional orientation occur in synergy and can be easily controlled by changing the AC field treatment duration, thus opening the pathway to combined hyperthermic/mechanical nanoactuators for biomedicine. Preliminary studies demonstrate the high accumulation of nanorods into HeLa cells whereas viability analysis supports their low toxicity and the absence of apoptotic or necrotic cell death after 24 or 48 h of incubation.

Learning from nature to improve the heat generation of iron-oxide nanoparticles for magnetic hyperthermia applications.

The performance of magnetic nanoparticles is intimately entwined with their structure, mean size and magnetic anisotropy. Besides, ensembles offer a unique way of engineering the magnetic response by modifying the strength of the dipolar interactions between particles. Here we report on an experimental and theoretical analysis of magnetic hyperthermia, a rapidly developing technique in medical research and oncology. Experimentally, we demonstrate that single-domain cubic iron oxide particles resembling bacterial magnetosomes have superior magnetic heating efficiency compared to spherical particles of similar sizes. Monte Carlo simulations at the atomic level corroborate the larger anisotropy of the cubic particles in comparison with the spherical ones, thus evidencing the beneficial role of surface anisotropy in the improved heating power. Moreover we establish a quantitative link between the particle assembling, the interactions and the heating properties. This knowledge opens new perspectives for improved hyperthermia, an alternative to conventional cancer therapies.