Rudolf Hergt

Magnetic particle hyperthermia: nanoparticle magnetism and materials development for cancer therapy

Loss processes in magnetic nanoparticles are discussed with respect to optimization of the specific loss power (SLP) for application in tumour hyperthermia. Several types of magnetic iron oxide nanoparticles representative for different preparation methods (wet chemical precipitation, grinding, bacterial synthesis, magnetic size fractionation) are the subject of a comparative study of structural and magnetic properties. Since the specific loss power useful for hyperthermia is restricted by serious limitations of the alternating field amplitude and frequency, the effects of the latter are investigated experimentally in detail. The dependence of the SLP on the mean particle size is studied over a broad size range from superparamagnetic up to multidomain particles, and guidelines for achieving large SLP under the constraints valid for the field parameters are derived. Particles with the mean size of 18 nm having a narrow size distribution proved particularly useful. In particular, very high heating power may be delivered by bacterial magnetosomes, the best sample of which showed nearly 1 kW g −1 at 410 kHz and 10 kA m −1 . This value may even be exceeded by metallic magnetic particles, as indicated by measurements on cobalt particles.

Physical limits of hyperthermia using magnetite fine particles

Structural and magnetic properties of fine particles of magnetite are investigated with respect to the application for hyperthermia. Magnetic hysteresis losses are measured in dependence on the field amplitude for selected commercial powders and are discussed in terms of grain size and structure of the particles. For ferromagnetic powders as well as for ferrofluids, results of heating experiments within organic gels in a magnetic high frequency field are reported. The heating effect depends strongly on the magnetic properties of the magnetite particles which may vary appreciably for different samples in dependence on the particle size and microstructure. In particular, the transition from ferromagnetic to superparamagnetic behavior causes changes of the loss mechanism, and accordingly, of the heating effect. The maximum attainable heating effect is discussed in terms of common theoretical models. Rise of temperature at the surface of a small heated sample as well as in its immediate neighborhood in the surrounding medium is measured in dependence on time and is compared with solutions of the corresponding heat conductivity problem. Conclusions with respect to clinical applications are given.

Application of magnetite ferrofluids for hyperthermia

A comparative study is presented for the specific loss power generated by an external magnetic field in superparamagnetic as well as ferromagnetic magnetite particles suspended in molten and solidified gel. The field amplitude dependence of magnetic losses obeys power laws of third order for ferromagnetic samples and second order for superparamagnetic samples, respectively. Calorimetrically determined data are compared with results of hysteresis measurements. Consequences for the application for hyperthermia are discussed.

Magnetic particle hyperthermia?a promising tumour therapy?

We present a critical review of the state of the art of magnetic particle hyperthermia (MPH) as a minimal invasive tumour therapy. Magnetic principles of heating mechanisms are discussed with respect to the optimum choice of nanoparticle properties. In particular, the relation between superparamagnetic and ferrimagnetic single domain nanoparticles is clarified in order to choose the appropriate particle size distribution and the role of particle mobility for the relaxation path is discussed. Knowledge of the effect of particle properties for achieving high specific heating power provides necessary guidelines for development of nanoparticles tailored for tumour therapy. Nanoscale heat transfer processes are discussed with respect to the achievable temperature increase in cancer cells. The need to realize a well-controlled temperature distribution in tumour tissue represents the most serious problem of MPH, at present. Visionary concepts of particle administration, in particular by means of antibody targeting, are far from clinical practice, yet. On the basis of current knowledge of treating cancer by thermal damaging, this article elucidates possibilities, prospects, and challenges for establishment of MPH as a standard medical procedure.

Heating potential of iron oxides for therapeutic purposes in interventional radiology.

RATIONALE AND OBJECTIVES In addition to their diagnostic applications, iron oxides could be used therapeutically to eliminate tumors with heat if their heating powers are adequate. The authors therefore examined the specific absorption rate (SAR) of different iron oxide (magnetite) samples suspended in water and in liquid or solidified gel. MATERIALS AND METHODS The authors compared two ferromagnetic fine powders (total particle size, >350 nm and 100 nm), five superparamagnetic ferrofluidic samples (total particle size, 10-280 nm), and a commercially available contrast medium (ferumoxides injectable solution, Endorem). The SARs of the magnetic material-suspended in distilled water or in liquid or solid agar-were estimated from time-dependent calorimetric measurements during exposure to an alternating current magnetic field (amplitude, 6.5 kA/m; frequency, 400 kHz). RESULTS SARs varied considerably between the different iron oxide samples. The highest value was found for a ferrofluidic sample (>93 W/g), while Endorem had little heating power (<0.1 W/g). The SAR was clearly dependent on the aggregation state of the matrix only for the large-particle-size ferromagnetic sample, yielding the highest values for particle suspensions in water (74 W/g) and lowest for solid agar (8 W/g). The heating power of the smaller-particle-size ferromagnetic sample did not exceed 8 W/g. CONCLUSION Heating powers differed according to the interaction of multiple physical parameters. Iron oxides should be selected carefully for therapeutic applications in magnetic heating.

Magnetic nanoparticle heating and heat transfer on a microscale: Basic principles, realities and physical limitations of hyperthermia for tumour therapy

Abstract In this review article we present basic principles of magnetically induced heat generation of magnetic nanoparticles for application in magnetic particle hyperthermia. After explanation of heating mechanisms, the role of particle–particle as well as particle–tissue interactions is discussed with respect to achievable heating power of the particles inside the tumour. On the basis of heat transfer theory at the micro-scale, the balance between generated and dissipated heat inside the tumour and the resulting damaging effects for biological tissue is examined. The heating behaviour as a function of tumour size is examined in combination with feasible field strength and frequency. Numerical calculations and experimental investigations are used to show the lower tumour size limit for tumour heating to therapeutically suitable temperatures. In summary, this article illuminates practical aspects, limitations, and the state of the art for the application of magnetic heating in magnetic particle hyperthermia as thermal treatment of small tumours.

Validity limits of the Néel relaxation model of magnetic nanoparticles for hyperthermia

The derivation of the optimum mean diameter of magnetic nanoparticles (MNP) for hyperthermia as a tumour therapy in the literature is commonly reduced to application of the Néel relaxation model. Serious restrictions of this model for MNP for hyperthermia are discussed and a way is outlined to a more comprehensive model including hysteresis.

The effect of field parameters, nanoparticle properties and immobilization on the specific heating power in magnetic particle hyperthermia

Magnetic nanoparticles (MNP) are intended for utilization in cancer therapy as they produce damaging heat in the presence of AC magnetic fields. In order to reach the required temperature with minimum particle concentration in tissue the specific heating power (SHP) of MNP should be as high as possible. The aim was to clarify the influence of magnetic field parameters and nanoparticle properties on the SHP. As usual ferrofluids exhibit broad size distributions, a magnetic fractionation of a commercial iron oxide nanoparticle suspension was performed in order to obtain particles with varying properties. The fractions obtained were characterized by means of atomic force microscopy and magnetometry, among other techniques. Frequency spectra of the susceptibility show clear peaks at low frequencies related to the Brown relaxation. This effect vanishes after particle immobilization. Theoretical spectra considering experimentally determined size distributions are in agreement with experimental data. The SHP derived from AC susceptometry is in accordance with that directly determined by calorimetry. A maximum SHP of 160 W g−1 (400 kHz, 8 kA m−1) was detected for the largest particles, showing a behaviour in the transitional regime between superparamagnetic and stable ferromagnetic.

Magnetic nanoparticles for selective heating of magnetically labelled cells in culture: preliminary investigation

The minimally invasive elimination of tumours using heating as a therapeutic agent is an emerging technology in medical applications. Particularly, the intratumoural application of magnetic nanoparticles as potential heating sources when exposed to an alternating magnetic field has been demonstrated. The present work deals with the estimation of the basic relationships when the magnetic material has access and binds to structures on cell membranes of target cells at the tumour region, particularly as a consequence of administration through tumour supplying vessels. Therefore, using mouse endothelial cells in culture, the binding of dextran coated magnetic nanoparticles (mean hydrodynamic particle diameter 65 nm) was modelled using the periodate method. The efficacy of cell labelling was demonstrated by magnetorelaxometry (MRX)—a selective method for the detection of only those magnetic nanoparticles that were immobilized—as well as by electron microscopy and iron staining. The amount of iron immobilized on cells was found to be 153 ± 56 µg Fe per 1 × 107 cells as determined by atomic absorption spectrometry. Moreover, after exposure of those 1 × 107 labelled cells to an alternating magnetic field (frequency 410 kHz, amplitude 11 kA m−1) for 5 min, temperature increases of 2 °C were achieved. The consequences of particle immobilization are reflected by the results of the measurements related to the specific heating power (SHP) of the magnetic material. Basically, the heating potential is explained by the superposition of Brown and Neel relaxation while for immobilized nanoparticles the Brown contribution is absent. In the long term the data could open the door to targeted magnetic heating after further optimization of the heating potential of magnetic material as well as after functionalization with biomolecules which recognize specific structures on the surface of cells at the target region.

Evaluation of temperature increase with different amounts of magnetite in liver tissue samples.

RATIONALE AND OBJECTIVES The biologic effects of magnetically induced heating effects using iron oxide, magnetite, were examined in vitro in liver tissue samples as a first step toward potential applications in cancer therapy. METHODS For the determination of the temperature profile around an iron oxide sample, a cylinder containing 170 mg of magnetite was constructed and placed into pureed liver tissue from pig, together with thermocouples of copper and constantan wires positioned at defined distances from it. Temperature measurements were performed during the exposure to an alternating magnetic field (frequency: 400 kHz; amplitude: approximately 6.5 kA/m) generated by a circular coil (90 mm of diameter). Moreover, variable amounts of magnetite (dissolved in approximately 0.2 mL physiologic saline) were injected directly into carrageenan gels. During the exposure to a magnetic field for 4 minutes the temperature increase was determined in the area of iron oxide deposition using a thermocouple. Additionally, variable amounts of magnetite were injected directly into isolated liver tissue samples (diameter: 20 mm; height: 30 mm) and exposed to a magnetic field for 2 minutes. The extent of the induced macroscopically visible tissue alterations (light brown colorations caused by heating) was examined by means of volume estimations. The degrees of cellular necrosis were investigated by histopathologic studies. RESULTS The temperature profile around a magnetite cylinder revealed a significant decrease of temperature difference between the beginning and the end of heating, depending on increasing distance from the sample center. The extent of the temperature difference correlated with increasing heating time. No significant variations of temperature were observed at a distance of approximately 12 mm from the sample center. A good correlation (r = 0.98) between the injected amounts (31 to 200 mg) and the temperature increase since the start of heating (6.8-33.7 degrees C) in the area of iron oxide deposits was detected. The volume of damaged liver tissue was approximately seven times higher than the injected volume of iron oxide dispersion. Histologically different degrees of cellular necrosis were observed. CONCLUSIONS The parameters determined in this article show that iron oxides are able to induce considerable heating effects in the surroundings. After an adequate optimization of the technical procedure, it is conceivable that heating properties of magnetites can be used in future cancer treatments.