Maghemite nanoparticles with very high AC-losses for application in RF-magnetic hyperthermia

Maghemite nanoparticles covalently coated with polyethylene glycol are investigated with respect to different loss processes in magnetic AC-fields. Transmission electron microscopy reveals a narrow size distribution which may be well approximated by a normal distribution (mean diameter 15.3 nm and distribution width 4.9 nm). Aqueous ferrofluids were characterised by DC-magnetometry, by measuring susceptibility spectra for a frequency range 20 Hz to 1 MHz and by calorimetric measurements of specific loss power (SLP) at 330 and 410 kHz for field amplitudes up to 11.7 kA/m. Extremely high values of SLP in the order of 600 W/g result for 400 kHz and 11 kA/m. In addition to liquid ferrofluids measurements were performed with suspensions in gel in order to elucidate the role of Brownian relaxation. The measured susceptibility spectra may be well reproduced by a model using a superposition of Néel and Brown loss processes under consideration of the observed narrow normal size distribution. In this way the observed very high specific heating power may be well understood. Results are discussed with respect to further optimisation of SLP for medical as well as technical RF-heating applications.     

Adiabatic vs. non-adiabatic determination of specific absorption rate of ferrofluids

The measurement of temperature variations in adiabatic conditions allows the determination of the specific absorption rate of magnetic nanoparticles and ferrofluids from the correct incremental expression, SAR=(1/m_MNP)C(ΔT/Δt). However, when measurements take place in non-adiabatic conditions, one must approximate this expression by SAR≈Cβ/m_MNP, where β is the initial slope of the temperature vs. time curve during alternating field application. The errors arising from the use of this approximation were estimated through several experiments with different isolating conditions, temperature sensors and sample-sensor contacts. It is concluded that small to appreciable errors can appear, which are difficult to infer or control.     

Parametric investigation of heating due to magnetic fluid hyperthermia in a tumor with blood perfusion

Magnetic fluid hyperthermia (MFH) is a cancer treatment that can selectively elevate the tumor temperature without significantly damaging the surrounding healthy tissue. Optimal MFH design requires a fundamental parametric investigation of the heating of soft materials by magnetic fluids. We model the problem of a spherical tumor and its surrounding healthy tissue that are heated by exciting a homogeneous dispersion of magnetic nanoparticles infused only into the tumor with an external AC magnetic field. The key dimensionless parameters influencing thermotherapy are the Péclet, Fourier, and Joule numbers. Analytical solutions for transient and steady hyperthermia provide correlations between these parameters and the portions of tumor and healthy tissue that are subjected to a threshold temperature beyond which they are damaged. Increasing the ratio of the Fourier and Joule numbers also increases the tumor temperature, but doing so can damage the healthy tissue. Higher magnetic heating is required for larger Péclet numbers due to the larger convection heat loss that occurs through blood perfusion. A comparison of the model predictions with previous experimental data for MFH applied to rabbit tumors shows good agreement. The optimal MFH conditions are identified based on two indices, the fraction I_T of the tumor volume in which the local temperature is above a threshold temperature and the ratio I_N of the damaged normal tissue volume to the tumor tissue volume that also lies above it. The spatial variation in the nanoparticle concentration is also considered. A Gaussian distribution provides efficacy while minimizing the possibility of generating a tumor hot spot. Varying the thermal properties of tumor and normal tissue alters I_Tand I_N but the nature of the temperature distribution remains unchanged.     

Size-dependant heating rates of iron oxide nanoparticles for magnetic fluid hyperthermia

Using the thermal decomposition of organometallics method we have synthesized high-quality, iron oxide nanoparticles of tailorable size up to ∼15 nm and transferred them to a water phase by coating with a biocompatible polymer. The magnetic behavior of these particles was measured and fit to a log-normal distribution using the Chantrell method and their polydispersity was confirmed to be very narrow. By performing calorimetry measurements with these monodisperse particles we have unambiguously demonstrated, for the first time, that at a given frequency, heating rates of superparamagnetic particles are dependent on particle size, in agreement with earlier theoretical predictions.     

Magnetic study of iron-containing carbon nanotubes: Feasibility for magnetic hyperthermia

We present a detailed magnetic study of iron containing carbon nanotubes (Fe-CNT), which highlights their potential for contactless magnetic heating in hyperthermia cancer treatment. Magnetic field dependent AC inductive heating experiments on Fe-CNT dispersions show a substantial temperature increase of Fe-CNT dispersions in applied AC magnetic fields. DC and AC magnetization studies have been done in order to elucidate the heating mechanism. We observe a different magnetic response of Fe-CNT powder compared to Fe-CNT dispersed in aqueous solution, e.g., ferromagnetic Fe-CNT in powder do not show any hysteresis when being dispersed in liquid. Our data indicate the motion of Fe-CNT in liquid in applied magnetic fields.     

X-ray microtomography of field-induced macro-structures in a ferrofluid

X-ray microtomography is used to visualize, in-situ, the three-dimensional nature of the magnetic field induced macro-structures (>1 μm) inside a bulk (∼1 mm diameter) magnetite-particle-mineral oil ferrofluid sample. Columnar structures of ∼10 μm diameter were seen under a 0.35 kG applied magnetic field, while labyrinth type structures ∼4 μm in width were seen at 0.55 kG. The structures have height/width aspect ratios >100. The results show that the magnetite volume fraction is not constant within the structures and on average is considerably less than a random sphere packing model.     

Large specific absorption rates in the magnetic hyperthermia properties of metallic iron nanocubes

We report on the magnetic hyperthermia properties of chemically synthesized ferromagnetic 11 and 16 nm Fe(0) nanoparticles of cubic shape displaying the saturation magnetization of bulk iron. The specific absorption rate measured on 16 nm nanocubes is 1690±160 W/g at 300 kHz and 66 mT. This corresponds to specific losses-per-cycle of 5.6 mJ/g, largely exceeding the ones reported in other systems. A way to quantify the degree of optimization of any system with respect to hyperthermia applications is proposed. Applied here, this method shows that our nanoparticles are not fully optimized, probably due to the strong influence of magnetic interactions on their magnetic response. Once protected from oxidation and further optimized, such nano-objects could constitute efficient magnetic cores for biomedical applications requiring very large heating power.     

Comparison between experimental and predicted specific absorption rate of functionalized iron oxide nanoparticle suspensions

Radio-frequency heated magnetic nanoaparticle suspensions have potential applications in cancer hyperthermia. To optimize these systems for hyperthermia applications it is important to be able to predict how their heat generation or specific absorption rate (SAR) is influenced by various factors, including nanoparticle coating or functionalization and aggregation. However, at present it is unclear how well-existing models predict experimental SAR results. Direct comparisons between predicted and measured SAR are scarce, despite an abundance of works reporting on heat generation rate of various magnetic nanoparticles suspensions. The main objective of this paper is to experimentally assess the validity of current models for SAR and extract information on the effects of coating and aggregation on heat generation rate. In this context, AC susceptibility and magnetization of suspensions of uncoated particles, as well as particles with aminosilane and carboxymethyl-dextran functionalizations, were measured. These properties were then used to predict the heat generation rate in alternating magnetic field starting from first principles, which was then compared to measured SAR. It was found that experimental SAR agrees relatively well with predictions (by a factor of two) when using experimental susceptibility values for the SAR calculation. However, for uncoated and amine-functionalized particles poor agreement (more than an order of magnitude difference) was found when the experimental susceptibility was substituted with predictions based on the Debye model. This apparent discrepancy is attributed to dipolar interactions between nanoparticles within aggregates in these samples, which enhances the imaginary part of the susceptibility and, consequently, the SAR values. The results also suggest that the thermal resistance effect of the coating has little influence on the SAR.     

Synthesis of copper-nickel nanoparticles prepared by mechanical milling for use in magnetic hyperthermia

Mechanical alloying of a mixture of copper and nickel powders has been applied for the preparation of copper-nickel alloy particles in the nanometer range. The particles were designed to be used for controlled magnetic hyperthermia applications. The milling conditions were optimized using the desired alloy composition. Utilizing a ball-to-powder mass ratio of 20, we could obtain a nanocrystalline Cu_27.5Ni_72.5 (at%) alloy with a crystallite size of around 10 nm and a Curie temperature of 45 °C.Thermal demagnetization in the vicinity of the Curie temperature of the nanoparticles was determined by thermomagnetic measurements using an adapted TGA-SDTA apparatus. The size and morphology of the particles were determined by XRD measurements and TEM analyses. The magnetic properties were also examined with a VSM. The magnetic heating effects were measured for the powdered material.     

Preparation of magnetite aqueous dispersion for magnetic fluid hyperthermia

An aqueous magnetic suspension was prepared by dispersing amphiphilic co-polymer-coated monodispersed magnetite nanoparticles synthesized through thermal decomposition of iron acetylacetonate (Fe(acac)₃) in a mixture of oleic acid and oleylamine. The average diameter of narrow-size-distributed magnetite nanoparticles varied between 5 and 12 nm depending on the experimental parameters such as reaction temperature, metal salt concentration and oleic acid/oleylamine ratio. Though the as-synthesized particles were coated with oleate and were dispersible in organic solvent, their surfaces were modified using amphiphilic co-polymers composed of poly(maleic anhydride-alt-1-octadecene) and polyethylene glycol-methyl ether and made dispersible in water. Infrared spectra of the sample indicated the existence of −COOH groups on the surface for further conjugation with biomolecules for targeted cancer therapy.     

Correlation for Nusselt number in pure magnetic convection ferrofluid flow in a square cavity by a numerical investigation

Magnetic convection heat transfer in a two-dimensional square cavity induced by magnetic field gradient is investigated numerically using a semi-implicit finite volume method. The side walls of the cavity are heated with different temperatures, the top and bottom walls are isolated, and a permanent magnet is located near the bottom wall. Thermal buoyancy-induced flow is neglected due to the nongravity condition on the plane of the cavity. Conditions for the different values of non-dimensional variables in a variety of ferrofluid properties and magnetic field parameters are studied. Based on this numerical analysis, a general correlation for the overall Nusselt number on the side walls is introduced for a wide range of effective parameters. Results showed that maximum error produced by use of this correlation is about 6 percent.     

Enhancement of AC-losses of magnetic nanoparticles for heating applications

Aqueous ferrofluids of maghemite nanoparticles coated with carboxydextran were investigated with respect to their specific loss power (SLP) in dependence on frequency and field amplitude of magnetic AC-fields. In order to elucidate the effect of the size distribution on SLP fluid fractions with different mean particle core size were prepared by a magnetic separation procedure from the original ferrofluid. Structural characterisation by means of TEM and XRD as well as reconstruction of core size distributions from magnetisation curves reveals that the narrow size distributions of the fractions cover a range of mean core sizes from about 8 up to 20 nm. Spectra of the complex susceptibility were measured for a frequency range of 20 Hz to 1 MHz. From the imaginary part of the susceptibility the specific loss power is calculated in dependence on frequency. The results are compared with calorimetrical measurements performed in dependence on field amplitude up to 11 kA/m at 410 kHz. A very high specific loss power in the order of 400 W per gram maghemite was found at 410 kHz and 11 kA/m for the fluid fraction having the largest mean core diameter. A deviation from linear response behaviour is found for this sample showing a power law field dependence of the specific loss power SLPH^2.5. In addition to liquid suspensions measurements were performed with particles immobilised in mannitol or gel in order to elucidate the role of Brownian relaxation. The experimentally found dependence of SLP on the mean particle core diameter may be understood in the frame of the Debye dispersion model. Results are discussed with respect to applications of ferrofluids in RF-magnetic hyperthermia.     

Synthesis of Fe3O4 magnetic fluid used for magnetic resonance imaging and hyperthermia

Fe₃O₄ magnetic nanoparticles were prepared by co-precipitation from FeSO₄·7H₂O and FeCl₃·6H₂O aqueous solutions using NaOH as precipitating reagent. The nanoparticles have an average size of 12 nm and exhibit superparamagnetism at room temperature. The nanoparticles were used to prepare a water-based magnetic fluid using oleic acid and Tween 80 as surfactants. The stability and magnetic properties of the magnetic fluid were characterized by Gouy magnetic balance. The experimental results imply that the hydrophilic block of Tween 80 can make the Fe₃O₄ nanoparticles suspending in water stable even after dilution and autoclaving. The magnetic fluid demonstrates excellent stability and fast magneto-temperature response, which can be used both in magnetic resonance imaging and magnetic fluid hyperthermia.     

Magnetic hyperthermia with biphasic gel of La1−xSrxMnO3 and maghemite

Magnetic hyperthermia experiments were carried out using a biphasic gel of La_1−xSr_xMnO₃(LSMO) and γ-Al_0.07 Fe_1.93O₃ with an AC magnetic field of amplitude 88 mT and a frequency of 108 kHz. Specific absorption rate (SAR) increases with the increased ratio of Al-substituted maghemite. The T_max value for the gels prepared by the mixture of LSMO and Al-substituted maghemite can be adjusted to suit therapeutic temperature. The time required to reach optimum temperature decreased with the increased ratio of later. Such biphasic gel could be very useful for magnetic hyperthermia with in vivo control of temperature.     

Heat dissipation mechanism of magnetite nanoparticles in magnetic fluid hyperthermia

The relative contributions of Néel and Brownian relaxations on magnetic heat dissipation were studied by investigating the physical, magnetic and heating characteristics of magnetite nanoparticle suspensions with average diameters of 12.5 and 15.7 nm. Heating characteristics depended on the dispersion states of particles. The specific absorption rates (SAR) dropped by 27% for the 12.5 nm particles to 16.8×10⁻⁹ W g⁻¹ Oe⁻² Hz⁻¹ and by 67% for the 15.7 nm particles to 9.69×10⁻⁹ W g⁻¹ Oe⁻² Hz⁻¹, when the particle rotation was suppressed by dispersing magnetite nanoparticles in hydro-gel.     

In vitro application of Fe/MgO nanoparticles as magnetically mediated hyperthermia agents for cancer treatment

In this work we study the heating efficiency of Fe/MgO magnetic core/biocompatible shell nanoparticles and their in vitro application in magnetic hyperthermia on cancer cells. Different human breast cancer cell lines were used to assess the suitability of nanoparticles for in vivo application. The experiments revealed a very good cytotoxicity profile and significant uptake efficiency together with relatively high specific absorption rates and fast thermal response, features that are crucial for adequate thermal efficiency and minimum duration of treatment.     

Suitability of commercial colloids for magnetic hyperthermia

Commercial nanoparticles supplied by Chemicell, Micromod and Bayer-Schering were characterised with regard to their nanocrystalline diameter, hydrodynamic diameter, total iron content and relative ferrous iron content. Additionally, calorimetric measurements were taken using a 900 kHz AC magnetic field of amplitude 5.66 kA/m. It was found that those samples containing relatively high (>18%) ferrous content generated a substantially smaller (12% on average) intrinsic loss power (ILP) than those samples with a lower ferrous content. Two nominally identical Chemicell samples that differed only in their production date showed significantly different ILPs, attributed to a variation in batch-to-batch crystallite sizes. The highest ILP values in the cohort, ca. 3.1 nHm²/kg, were achieved for particles with hydrodynamic diameters of ca. 70 nm and nanocrystalline diameters of ca. 12 nm. These compare favourably with most samples prepared in academic laboratories, although they are not as high as the ca. 23.4 nHm²/kg reported for naturally occurring bacterial magnetosomes.     

AC susceptibility of magnetic markers in suspension for liquid phase immunoassay

AC susceptibility of magnetic markers in solution was studied for biosensor applications. First, frequency dependence of the susceptibility was measured, and size distribution of the markers was estimated by analyzing the experimental result with the so-called singular value decomposition (SVD) method. The size distribution estimated with the magnetic measurement agreed with that obtained from conventional optical measurement. Next, susceptibility measurement was applied to the liquid-phase immunoassay without bound/free (B/F) separation. We performed the detection of biotin-coated polymer beads in suspension using avidin-coated magnetic markers. Changes of the susceptibility and the size distribution caused by the binding reaction were shown.     

Magnetic Properties of Nanoparticles Useful for SQUID Relaxometry in Biomedical Applications

We use dynamic susceptometry measurements to extract semiempirical temperature-dependent, 255-400 K, magnetic parameters that determine the behavior of single-core nanoparticles useful for SQUID relaxometry in biomedical applications. Volume susceptibility measurements were made in 5 K degree steps at nine frequencies in the 0.1-1000 Hz range, with a 0.2 mT amplitude probe field. The saturation magnetization (M_s) and anisotropy energy density (K) derived from the fitting of theoretical susceptibility to the measurements both increase with decreasing temperature; good agreement between the parameter values derived separately from the real and imaginary components is obtained. Characterization of the Néel relaxation time indicates that the conventional prefactor, 0.1 ns, is an upper limit, strongly correlated with the anisotropy energy density. This prefactor decreases substantially for lower temperatures as K increases. We find, using the values of the parameters determined from the real part of the susceptibility measurements at 300 K, that SQUID relaxometry measurements of relaxation and excitation curves on the same sample are well described.