Silvio Dutz

Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles.

Due to their unique magnetic properties, excellent biocompatibility as well as multi-purpose biomedical potential (e.g., applications in cancer therapy and general drug delivery), superparamagnetic iron oxide nanoparticles (SPIONs) are attracting increasing attention in both pharmaceutical and industrial communities. The precise control of the physiochemical properties of these magnetic systems is crucial for hyperthermia applications, as the induced heat is highly dependent on these properties. In this review, the limitations and recent advances in the development of superparamagnetic iron oxide nanoparticles for hyperthermia are presented.

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.

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.

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 multicore nanoparticles for hyperthermia--influence of particle immobilization in tumour tissue on magnetic properties.

When using magnetic nanoparticles as a heating source for magnetic particle hyperthermia it is of particular interest to know if the particles are free to move in the interstitial fluid or are fixed to the tumour tissue. The immobilization state determines the relaxation behaviour of the administered particles and thus their specific heating power. To investigate this behaviour, magnetic multicore nanoparticles were injected into experimentally grown tumours in mice and magnetic heating treatment was carried out in an alternating magnetic field (H = 25 kA m(-1), f = 400 kHz). The tested particles were well suited for magnetic heating treatment as they heated a tumour of about 100 mg by about 22 K within the first 60 s. Upon sacrifice, histological tumour examination showed that the particles form spots in the tissue with a mainly homogeneous particle distribution in these spots. The magnetic ex vivo characterization of the removed tumour tissue gave clear evidence for the immobilization of the particles in the tumour tissue because the particles in the tumour showed the same magnetic behaviour as immobilized particles. Therefore, the particles are not able to rotate and a temperature increase due to Brown relaxation can be neglected. To accurately estimate the heating potential of magnetic materials, the respective environments influencing the nanoparticle mobility status have to be taken into account.

Magnetic and fluorescent core-shell nanoparticles for ratiometric pH sensing.

This paper describes the preparation of nanoparticles composed of a magnetic core surrounded by two successive silica shells embedding two fluorophores, showing uniform nanoparticle size (50-60 nm in diameter) and shape, which allow ratiometric pH measurements in the pH range 5-8. Uncoated iron oxide magnetic nanoparticles (∼10 nm in diameter) were formed by the coprecipitation reaction of ferrous and ferric salts. Then, they were added to a water-in-oil microemulsion where the hydrophilic silica shells were obtained through hydrolysis and condensation of tetraethoxyorthosilicate together with the corresponding silylated dye derivatives-a sulforhodamine was embedded in the inner silica shell and used as the reference dye while a pH-sensitive fluorescein was incorporated in the outer shell as the pH indicator. The magnetic nanoparticles were characterized using vibrating sample magnetometry, dynamic light scattering, transmission electron microscopy, x-ray diffraction and Fourier transform infrared spectroscopy. The relationship between the analytical parameter, that is, the ratio of fluorescence between the sensing and reference dyes versus the pH was adjusted to a sigmoidal fit using a Boltzmann type equation giving an apparent pK(a) value of 6.8. The fluorescence intensity of the reference dye did not change significantly (∼3.0%) on modifying the pH of the nanoparticle dispersion. Finally, the proposed method was statistically validated against a reference procedure using samples of water and physiological buffer with 2% of horse serum, indicating that there are no significant statistical differences at a 95% confidence level.

Sensitive High Frequency AC Susceptometry in Magnetic Nanoparticle Applications

We report on the development of a sensitive high frequency susceptometer capable of measuring in the frequency range from 25 kHz up to 10 MHz with a volume susceptibility sensitivity of 3.5×l0−5 at 100 kHz corresponding to about 0.3% of the measured AC susceptibility. In combination with the previous reported DynoMag system capable of measuring dynamic magnetic properties in the range from 1 Hz to 200 kHz we are thus able to measure dynamic magnetic properties between 1 Hz to 10 MHz with high magnetic sensitivity. We will show AC susceptometry applications and results within the fields of magnetic hyperthermia and dynamic magnetic characterization of magnetic nanoparticle system with different particle sizes and magnetic properties.

Intentional formation of a protein corona on nanoparticles: Serum concentration affects protein corona mass, surface charge, and nanoparticle–cell interaction

The protein corona, which immediately is formed after contact of nanoparticles and biological systems, plays a crucial role for the biological fate of nanoparticles. In the here presented study we describe a strategy to control the amount of corona proteins which bind on particle surface and the impact of such a protein corona on particle-cell interactions. For corona formation, polyethyleneimine (PEI) coated magnetic nanoparticles (MNP) were incubated in a medium consisting of fetal calf serum (FCS) and cell culture medium. To modulate the amount of proteins bind to particles, the composition of the incubation medium was varied with regard to the FCS content. The protein corona mass was estimated and the size distribution of the participating proteins was determined by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, the zeta potential of incubated particles was measured. Human blood-brain barrier-representing cell line HBMEC was used for in vitro incubation experiments. To investigate the consequences of the FCS dependent protein corona formation on the interaction of MNP and cells flow cytometry and laser scanning microscopy were used. Zeta potential as well as SDS-PAGE clearly reveal an increase in the amount of corona proteins on MNP with increasing amount of FCS in incubation medium. For MNP incubated with lower FCS concentrations especially medium-sized proteins of molecular weights between 30kDa and 100kDa could be found within the protein corona, whereas for MNP incubated within higher FCS concentrations the fraction of corona proteins of 30kDa and less increased. The presence of the protein corona reduces the interaction of PEI-coated MNP with HBMEC cells within a 30min-incubation.