Nonspecific eddy current heating in magnetic field hyperthermia

In this Perspective article, we explore the definition and use of clinical tolerability metrics associated with nonspecific eddy current heating in magnetic field hyperthermia (MFH). We revisit the origins of the “Brezovich criterion,” Hof ≤ 485 MA m−1s−1, as it is applied to axial time-varying magnetic fields H (t) = Ho sin(2πft) and the human torso. We then consider alternative metrics, including the “maximal specific absorption rate” (SARmax) of eddy-current-induced power absorbed per unit mass of tissue. With reference to previously published clinical data and the results of two volunteer studies in our laboratory, we show that the SARmax metric is both suitable and reliable. We also show how it may be extracted from in silico finite element models to cope with confounding effects such as anatomical hot spots and non-axial-field geometries. We note a parallel with a standardized metric, the “local SAR” used in magnetic resonance imaging (MRI). We suggest that the limits established in clinical MRI (that the local SAR, averaged over 10 g of tissue and 6 min of treatment, should not exceed 20 mW g−1 in the torso or head, and 40 mW g−1 in the limbs) might be regarded as a good starting point for the design of MFH interventions. We conclude with the recommendation that the SARmax metric is adopted for future use in the development of clinically safe and tolerable MFH equipment

Triple-Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tumours In Vivo

Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic superparamagnetic iron oxide nanoparticles, are formulated and used to magnetically target solid tumours after intravenous administration in tumour-bearing mice. The engineered magnetic polymeric nanocapsules m-NCs are ~200 nm in size with negative Zeta potential and shown to be spherical in shape. The loading efficiency of superparamagnetic iron oxide nanoparticles in the m-NC was ~100%. Up to ~3- and ~2.2-fold increase in tumour uptake at 1 and 24 h was achieved, when a static magnetic field was applied to the tumour for 1 hour. m-NCs, with multiple imaging probes (e.g. indocyanine green, superparamagnetic iron oxide nanoparticles and indium-111), were capable of triple-modal imaging (fluorescence/magnetic resonance/nuclear imaging) in vivo. Using triple-modal imaging is to overcome the intrinsic limitations of single modality imaging and provides complementary information on the spatial distribution of the nanocarrier within the tumour. The significant findings of this study could open up new research perspectives in using novel magnetically-responsive nanomaterials in magnetic-drug targeting combined with multi-modal imaging

On the ‘centre of gravity’ method for measuring the composition of magnetite/maghemite mixtures, or the stoichiometry of magnetite-maghemite solid solutions, via 57Fe Mössbauer spectroscopy

We evaluate the application of 57Fe Mössbauer spectroscopy to the determination of the composition of magnetite (Fe3O4)/maghemite (?-Fe2O3) mixtures and the stoichiometry of magnetite-maghemite solid solutions. In particular, we consider a recently proposed model-independent method which does not rely on a priori assumptions regarding the nature of the sample, other than that it is free of other Fe-containing phases. In it a single parameter, ?RT-the 'centre of gravity', or area weighted mean isomer shift at room temperature, T = 295 ± 5 K - is extracted by curve-fitting a sample's Mössbauer spectrum, and is correlated to the sample's composition or stoichiometry. We present data on high-purity magnetite and maghemite powders, and mixtures thereof, as well as comparison literature data from nanoparticulate mixtures and solid solutions, to show that a linear correlation exists between ?RT and the numerical proportion of Fe atoms in the magnetite environment: ? = Femagnetite/Fetotal = (?RT - ?o)/m, where ?o= 0.3206 ± 0.0022 mm s-1 and m = 0.2135 ± 0.0076 mm s-1. We also present equations to relate ? to the weight percentage w of magnetite in mixed phases, and the magnetite stoichiometry x = Fe2+/Fe3+ in solid solutions. The analytical method is generally applicable, but is most accurate when the absorption profiles are sharp; in some samples this may require spectra to be recorded at reduced temperatures. We consider such cases and provide equations to relate ?(T) to the corresponding ? value.This work was supported by the European Union Seventh Framework Programme through the NanoMag project ‘Nanometrology standardisation methods for magnetic nanoparticles’, under grant agreement no. 60444

Safety Implications of High-Field MRI: Actuation of Endogenous Magnetic Iron Oxides in the Human Body

Background: Magnetic Resonance Imaging scanners have become ubiquitous in hospitals and high-field systems (greater than 3 Tesla) are becoming increasingly common. In light of recent European Union moves to limit high-field exposure for those working with MRI scanners, we have evaluated the potential for detrimental cellular effects via nanomagnetic actuation of endogenous iron oxides in the body.Methodology: Theoretical models and experimental data on the composition and magnetic properties of endogenous iron oxides in human tissue were used to analyze the forces on iron oxide particles.Principal Finding and Conclusions: Results show that, even at 9.4 Tesla, forces on these particles are unlikely to disrupt normal cellular function via nanomagnetic actuation

Prenormative verification and validation of a protocol for measuring magnetite–maghemite ratios in magnetic nanoparticles

An important step in establishing any new metrological method is a prenormative interlaboratory study, designed to verify and validate the method against its stated aims. Here, the 57Fe Mössbauer spectrometric ‘centre of gravity’ (COG) method was tested as a means of quantifying the magnetite/maghemite (Fe3O4/γ-Fe2O3) composition ratio in biphasic magnetic nanoparticles. The study involved seven laboratories across Europe and North and South America, and six samples—a verification set of three microcrystalline mixtures of known composition, and a validation set of three nanoparticle samples of unknown composition. The spectra were analysed by each participant using in-house fitting packages, and ex post facto by a single operator using an independent package. Repeatability analysis was performed using Mandel’s h statistic and modified Youden plots. It is shown that almost all (83/84) of the Mandel h statistic values fall within the 0.5% significance level, with the one exception being borderline. Youden-based pairwise analysis indicates the dominance of random uncertainties; and in almost all cases the data analysis phase is only a minor contributor to the overall measurement uncertainty. It is concluded that the COG method is a robust and promising candidate for its intended purpose

Magnetic drug targeting: Preclinical in vivo studies, mathematical modeling, and extrapolation to humans

A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev–Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5–8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting

Real-time tracking of delayed-onset cellular apoptosis induced by intracellular magnetic hyperthermia

Aim: To assess cell death pathways in response to magnetic hyperthermia. Materials & methods: Human melanoma cells were loaded with citric acid-coated iron-oxide nanoparticles, and subjected to a time-varying magnetic field. Pathways were monitored in vitro in suspensions and in situ in monolayers using fluorophores to report on early-stage apoptosis and late-stage apoptosis and/ or necrosis. Results: Delayed-onset effects were observed, with a rate and extent proportional to the thermal-load-per-cell. At moderate loads, membranal internal-to-external lipid exchange preceded rupture and death by a few hours (the timeline varying cell-to-cell), without any measurable change in the local environment temperature. Conclusion: Our observations support the proposition that intracellular heating may be a viable, controllable and nonaggressive in vivo treatment for human pathological conditions

Challenges and Recommendations for Magnetic Hyperthermia Characterization Measurements

The localized heating of magnetic nanoparticles (MNPs) via the application of time-varying magnetic fields – a process known as magnetic field hyperthermia (MFH) – can greatly enhance existing options for cancer treatment; but for broad clinical uptake its optimization, reproducibility and safety must be comprehensively proven. As part of this effort, the quantification of MNP heating – characterized by the specific loss power (SLP), measured in W/g, or by the intrinsic loss power (ILP), in nHm2/kg – is frequently reported. However, in SLP/ILP measurements to date, the apparatus, the analysis techniques and the field conditions used by different researchers have varied greatly, leading to questions as to the reproducibility of the measurements. To address this, we report here on an interlaboratory study (across N = 21 European sites) of calorimetry measurements that constitutes a snapshot of the current state-of-the-art within the MFH community. The data show that although there is very good intralaboratory repeatability, the overall interlaboratory measurement accuracy is poor, with the consolidated ILP data having standard deviations on the mean of ca. ± 30% to ± 40%. There is a strong systematic component to the uncertainties, and a clear rank correlation between the measuring laboratory and the ILP. Both of these are indications of a current lack of normalization in this field. A number of possible sources of systematic uncertainties are identified, and means determined to alleviate or minimize them. However, no single dominant factor was identified, and significant work remains to ascertain and remove the remaining uncertainty sources. We conclude that the study reveals a current lack of harmonization in MFH characterization of MNPs, and highlights the growing need for standardized, quantitative characterization techniques for this emerging medical technology.Multifunctional Nanoparticles for Magnetic Hyperthermia and Indirect Radiation Therap