Dietmar Eberbeck

The investigation of the rotational dynamics of magnetic nanoparticles in magnetic fields is of academic interest but also important for applications such as magnetic particle imaging where the particles are exposed to magnetic fields with amplitudes of up to 25 mT. We have experimentally studied the dependence of Brownian and Néel relaxation times on ac and dc magnetic field amplitude using ac susceptibility measurements in the frequency range between 2 Hz and 9 kHz for field amplitudes up to 9 mT. As samples, single-core iron oxide nanoparticles with core diameters between 20 nm and 30 nm were used either suspended in water-glycerol mixtures or immobilized by freeze-drying. The experimentally determined relaxation times are compared with theoretical models. It was found that the Néel relaxation time decays much faster with increasing field amplitude than the Brownian one. Whereas the dependence of the Brownian relaxation time on the ac and dc field amplitude can be well explained with existing theoretical models, a proper model for the dependence of the Néel relaxation time on ac field amplitude for particles with random distribution of easy axes is still lacking. The extrapolation of the measured relaxation times of the 25 nm core diameter particles to a 25 mT ac field with an empirical model predicts that the Brownian mechanism clearly co-determines the dynamics of magnetic nanoparticles in magnetic particle imaging applications, in agreement with magnetic particle spectroscopy data.

Spatial and temporal resolution of magnetic particle imaging (MPI), a powerful technique for biomedical imaging, depends crucially on the magnetic properties of the magnetic nanoparticle (MNP) tracer. The authors establish the relation of the static and the dynamic magnetization behavior of various MNP preparations to their MPI performance. While MNPs with a mean diameter of 6 nm achieve only 0.2% of the theoretical maximum amplitude of the third harmonic (at 25 kA/m drive field strength), those with 19 nm diameter attain 57%. The good performance of Resovist, a clinically approved contrast agent for magnetic resonance imaging, is explained by the presence of MNP aggregates.

For a variety of magnetically based biomedical applications, it is advantageous to use sedimentation stable suspensions of relatively large (d>20 nm) magnetic core–shell nanoparticles. Water-based suspensions of multicore nanoparticles were prepared by coating of the particles (synthesized by means of a modified alkaline precipitation method) with a carboxymethyldextran shell. The resulting ferrofluids were structurally and magnetically characterized. It was found that these fluids show a specific heating power of about 60 W/g (f=400 kHz, H=10 kA/m). This value was increased up to 330 W/g by a simple fractionation method based on centrifugation. Finally, the cellular uptake of the multicore nanoparticles was demonstrated.

Due to their biocompatibility and small size, iron oxide magnetic nanoparticles (MNP) can be guided to virtually every biological environment. MNP are susceptible to external magnetic fields and can thus be used for transport of drugs and genes, for heat generation in magnetic hyperthermia or for contrast enhancement in magnetic resonance imaging of biological tissue. At the same time, their magnetic properties allow one to develop sensitive and specific measurement methods to non-invasively detect MNP, to quantify MNP distribution in tissue and to determine their binding state. In this article, we review the application of magnetorelaxometry (MRX) for MNP detection. The underlying physical properties of MNP responsible for the generation of the MRX signal with its characteristic parameters of relaxation amplitude and relaxation time are described. Existing single and multi-channel MRX devices are reviewed. Finally, we thoroughly describe some applications of MRX to cellular MNP quantification, MNP organ distribution and MNP-based binding assays. Providing specific MNP signals, a detection limit down to a few nanogram MNP, in-vivo capability in conscious animals and measurement times of a few seconds, MRX is a valuable tool to improve the application of MNP for diagnostic and therapeutic purposes.

Biocompatible magnetic nanoparticles are interesting tracers for diagnostic imaging techniques, including magnetic resonance imaging and magnetic particle imaging (MPI). Here, we will present our studies of the physical and especially magnetic properties of dextran coated multicore magnetic iron oxide nanoparticles, with promising high MPI signals revealed by magnetic particle spectroscopy (MPS) measurements. The Nanomag-MIP particles with a hydrodynamic diameter of 106 nm show an increase of the MPS amplitude by a factor of about two at the 3rd harmonic, as compared to Resovist. In particular, the signal improves progressively with the order of the harmonic, a prerequisite for better spatial resolution. To understand this behavior, we investigated the samples using quasistatic magnetization measurements yielding bimodal size distributions for both systems, and magnetorelaxometry providing the mean effective anisotropy constant. The mean effective magnetic diameter of the dominant larger size mode is 19 nm with a dispersion parameter of σ = 0.3 for Nanomag-MIP, and 22 nm with σ = 0.25 for Resovist. However, about 80% of the magnetic nanoparticles of Nanomag-MIP belong to this larger size mode whereas in Resovist only 30% do. The remaining Resovist particles are in the range of 5 nm, and, in practice, do not contribute to the MPI signal.

The promising potential of superparamagnetic iron oxide nanoparticles (SPIONs) in various nanomedical applications has been frequently reported.However, although many different synthesis methods, coatings, and functionalization techniques have been described, not many core-shell SPION drug delivery systems are available for clinicians at the moment.Here, bovine serum albumin was adsorbed onto lauric acid-stabilized SPIONs.The agglomeration behavior, zeta potential, and their dependence on the synthesis conditions were characterized with dynamic light scattering.The existence and composition of the core-shell-matrix structure was investigated by transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential measurements.We showed that the iron oxide cores form agglomerates in the range of 80 nm.Moreover, despite their remarkably low tendency to aggregate even in a complex media like whole blood, the SPIONs still maintained their magnetic properties and were well attractable with a magnet.The magnetic properties were quantified by vibrating sample magnetometry and a superconducting quantum interference device.Using flow cytometry, we further investigated the effects of the different types of nanoparticle coating on morphology, viability, and DNA integrity of Jurkat cells.We showed that by addition of bovine serum albumin, the toxicity of nanoparticles is greatly reduced.We also investigated the effect of the particles on the growth of primary human endothelial cells to further demonstrate the biocompatibility of the particles.As proof of principle, we showed that the hybrid-coated particles are able to carry payloads of up to 800 μg/mL of the cytostatic drug mitoxantrone while still staying colloidally stable.The drug-loaded system exhibited excellent therapeutic potential in vitro, exceeding that of free mitoxantrone.In conclusion, we have synthesized a biocompatible ferrofluid that shows great potential for clinical application.The synthesis is straightforward and reproducible and thus easily translatable into a good manufacturing practice environment.

The magnetic properties of monodisperse FeO–Fe3O4 nanoparticles with different mean sizes and volume fractions of FeO synthesized via decomposition of iron oleate were correlated to their crystallographic and phase compositional features by exploiting high resolution transmission electron microscopy, X-ray diffraction, Mössbauer spectroscopy and field and zero field cooled magnetization measurements. A model describing the phase transformation from a pure Fe3O4 phase to a mixture of Fe3O4, FeO and interfacial FeO–Fe3O4 phases as the particle size increases was established. The reduced magnetic moment in FeO–Fe3O4 nanoparticles was attributed to the presence of differently oriented Fe3O4 crystalline domains in the outer layers and paramagnetic FeO phase. The exchange bias energy, dominating magnetization reversal mechanism and superparamagnetic blocking temperature in FeO–Fe3O4 nanoparticles depend strongly on the relative volume fractions of FeO and the interfacial phase.

A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 μg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of -45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In conclusion, combination of dextran-coated SPIONs with hyaluronic acid and cisplatin represents a promising approach for magnetic drug targeting in the treatment of cancer.

The aggregation behaviour of magnetic nanoparticles (MNP) is a decisive factor for their application in medicine and biotechnology. We extended the moment superposition model developed earlier for describing the Néel relaxation of an ensemble of immobilized particles with a given size distribution by including the Brownian relaxation mechanism. The resulting cluster moment superposition model is used to characterize the aggregation of magnetic nanoparticles in various suspensions in terms of mean cluster size, aggregate fraction, and size dispersion. We found that in stable ferrofluids 50%–80% of larger magnetic nanoparticles are organized in dimers and trimers. The scaling of the relaxation curves with respect to MNP concentration is found to be a sensitive indicator of the tendency of a MNP suspension to form large aggregates, which may limit the biocompatibility of the preparation. Scaling violation was observed in aged water based ferrofluids, and may originate from damaged MNP shells. In biological media such as foetal calf serum, bovine serum albumin, and human serum we observed an aggregation behaviour which reaches a maximum at a specific MNP concentration. We relate this to agglutination of the particles by macromolecular bridges between the nanoparticle shells. Analysis of the scaling behaviour helps to identify the bridging component of the suspension medium that causes agglutination.

Targeting of viral vectors is a major challenge for in vivo gene delivery, especially after intravascular application. In addition, targeting of the endothelium itself would be of importance for gene-based therapies of vascular disease. Here, we used magnetic nanoparticles (MNPs) to combine cell transduction and positioning in the vascular system under clinically relevant, nonpermissive conditions, including hydrodynamic forces and hypothermia. The use of MNPs enhanced transduction efficiency of endothelial cells and enabled direct endothelial targeting of lentiviral vectors (LVs) by magnetic force, even in perfused vessels. In addition, application of external magnetic fields to mice significantly changed LV/MNP biodistribution in vivo. LV/MNP-transduced cells exhibited superparamagnetic behavior as measured by magnetorelaxometry, and they were efficiently retained by magnetic fields. The magnetic interactions were strong enough to position MNP-containing endothelial cells at the intima of vessels under physiological flow conditions. Importantly, magnetic positioning of MNP-labeled cells was also achieved in vivo in an injury model of the mouse carotid artery. Intravascular gene targeting can be combined with positioning of the transduced cells via nanomagnetic particles, thereby combining gene- and cell-based therapies.

Abstract The quantitative measurement of the magnetization of individual magnetic nanoparticles (MNPs) using magnetic force microscopy (MFM) is described. Quantitative measurement is realized by calibration of the MFM signal using an MNP reference sample with traceably determined magnetization. A resolution of the magnetic moment of the order of 10 −18 A m 2 under ambient conditions is demonstrated, which is presently limited by the tip's magnetic moment and the noise level of the instrument. The calibration scheme can be applied to practically any magnetic force microscope and tip, thus allowing a wide range of future applications, for example in nanomagnetism and biotechnology.

The optimization of magnetic nanoparticles (MNPs) as markers for magnetic particle imaging (MPI) requires an understanding of the relationship between the harmonics spectrum and the structural and magnetic properties of the MNPs. Although magnetic particle spectroscopy (MPS) – carried out at the same excitation frequency as the given MPI system – represents a straightforward technique to study MNPs for their suitability for MPI, a complete understanding of the mechanisms and differences between different tracer materials requires additional measurements of the static and dynamic magnetic behavior covering additional field and time ranges. Furthermore, theoretical models are needed, which correctly account for the static and dynamic magnetic properties of the markers. In this paper, we give an overview of currently used theoretical models for the explanation of amplitude and phase of the harmonics spectra as well as of the various static and dynamic magnetic techniques, which are applied for the comprehensive characterization of MNPs for MPI. We demonstrate on two multicore MNP model systems, Resovist® and FeraSpin™ Series, how a detailed picture of the MPI performance can be obtained by combining various static and dynamic magnetic measurements.

Synthesis of novel magnetic multicore particles (MCP) in the nano range, involves alkaline precipitation of iron(II) chloride in the presence of atmospheric oxygen. This step yields green rust, which is oxidized to obtain magnetic nanoparticles, which probably consist of a magnetite/maghemite mixed-phase. Final growth and annealing at 90°C in the presence of a large excess of carboxymethyl dextran gives MCP very promising magnetic properties for magnetic particle imaging (MPI), an emerging medical imaging modality, and magnetic resonance imaging (MRI). The magnetic nanoparticles are biocompatible and thus potential candidates for future biomedical applications such as cardiovascular imaging, sentinel lymph node mapping in cancer patients, and stem cell tracking. The new MCP that we introduce here have three times higher magnetic particle spectroscopy performance at lower and middle harmonics and five times higher MPS signal strength at higher harmonics compared with Resovist®. In addition, the new MCP have also an improved in vivo MPI performance compared to Resovist®, and we here report the first in vivo MPI investigation of this new generation of magnetic nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising tools for the treatment of different diseases.Their magnetic properties enable therapies involving magnetic drug targeting (MDT), hyperthermia or imaging.Depending on the intended treatment, specific characteristics of SPIONs are required.While particles used for imaging should circulate for extended periods of time in the vascular system, SPIONs intended for MDT or hyperthermia should be accumulated in the target area to come into close proximity of, or to be incorporated into, specific tumor cells.In this study, we determined the impact of several accurately characterized SPION types varying in size, zeta potential and surface coating on various human breast cancer cell lines and endothelial cells to identify the most suitable particle for future breast cancer therapy.We analyzed cellular SPION uptake, magnetic properties, cell proliferation and toxicity using atomic emission spectroscopy, magnetic susceptometry, flow cytometry and microscopy.The results demonstrated that treatment with dextran-coated SPIONs (SPION Dex ) and lauric acid-coated SPIONs (SPION LA ) with an additional protein corona formed by human serum albumin (SPION LA-HSA ) resulted in very moderate particle uptake and low cytotoxicity, whereas SPION LA had in part much stronger effects on cellular uptake and cellular toxicity.In summary, our data show significant dose-dependent and particle type-related response differences between various breast cancer and endothelial cells, indicating the utility of these particle types for distinct medical applications.

Many efforts are made worldwide to establish magnetic fluid hyperthermia (MFH) as a treatment for organ-confined tumors. However, translation to clinical application hardly succeeds as it still lacks of understanding the mechanisms determining MFH cytotoxic effects. Here, we investigate the intracellular MFH efficacy with respect to different parameters and assess the intracellular cytotoxic effects in detail. For this, MiaPaCa-2 human pancreatic tumor cells and L929 murine fibroblasts were loaded with iron-oxide magnetic nanoparticles (MNP) and exposed to MFH for either 30 min or 90 min. The resulting cytotoxic effects were assessed via clonogenic assay. Our results demonstrate that cell damage depends not only on the obvious parameters bulk temperature and duration of treatment, but most importantly on cell type and thermal energy deposited per cell during MFH treatment. Tumor cell death of 95% was achieved by depositing an intracellular total thermal energy with about 50% margin to damage of healthy cells. This is attributed to combined intracellular nanoheating and extracellular bulk heating. Tumor cell damage of up to 86% was observed for MFH treatment without perceptible bulk temperature rise. Effective heating decreased by up to 65% after MNP were internalized inside cells.

Cell replacement in the heart is considered a promising strategy for the treatment of post-infarct heart failure. Direct intramyocardial injection of cells proved to be the most effective application route, however, engraftment rates are very low (<5%) strongly hampering its efficacy. Herein we combine magnetic nanoparticle (MNP) loading of EGFP labeled embryonic cardiomyocytes (eCM) and embryonic stem cell-derived cardiomyocytes (ES-CM) with application of custom designed magnets to enhance their short and long-term engraftment. To optimize cellular MNP uptake and magnetic force within the infarct area, first numerical simulations and experiments were performed in vitro. All tested cell types could be loaded efficiently with SOMag5-MNP (200 pg/cell) without toxic side effects. Application of a 1.3 T magnet at 5 mm distance from the heart for 10 min enhanced engraftment of both eCM and ES-CM by approximately 7 fold at 2 weeks and 3.4 fold (eCM) at 8 weeks after treatment respectively and also strongly improved left ventricular function at all time points. As underlying mechanisms we found that application of the magnetic field prevented the initial dramatic loss of cells via the injection channel. In addition, grafted eCM displayed higher proliferation and lower apoptosis rates. Electron microscopy revealed better differentiation of engrafted eCM, formation of cell to cell contacts and more physiological matrix formation in magnet-treated grafts. These results were corroborated by gene expression data. Thus, combination of MNP-loaded cells and magnet-application strongly increases long-term engraftment of cells addressing a major shortcoming of cardiomyoplasty.

Systematic studies of the magnetic properties of magnetic nanoparticles from FeraSpin R and the FeraSpin Series with respect to their suitability as tracers for magnetic particle imaging are presented. Magnetic particle spectroscopy measurements indicate that FeraSpin R exhibits a harmonic spectrum very similar to that of Resovist, whereas FeraSpin L, XL, and XXL show a 2.5-fold increase of harmonic amplitudes compared to FeraSpin R. To understand the differences between the various samples of the FeraSpin Series, representing size-selected, narrowly distributed particles of identical composition extracted from FeraSpin R, measurements of the ac susceptibility (ACS), magnetorelaxometry (MRX), and static <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">M</i> - <i xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">H</i> curves were performed on suspended and immobilized particle samples. ACS and MRX measurements on immobilized samples indicate a wide distribution of anisotropy energies despite the narrow distribution of hydrodynamic sizes. Static magnetization measurements show that all samples exhibit a bimodal distribution of magnetic moments: The fraction of larger moments corresponds to the contribution from the overall particle core, whereas the smaller is attributed to the contribution from the crystallites comprising the core.

Cardiovascular disease is often caused by endothelial cell (EC) dysfunction and atherosclerotic plaque formation at predilection sites. Also surgical procedures of plaque removal cause irreversible damage to the EC layer, inducing impairment of vascular function and restenosis. In the current study we have examined a potentially curative approach by radially symmetric re-endothelialization of vessels after their mechanical denudation. For this purpose a combination of nanotechnology with gene and cell therapy was applied to site-specifically re-endothelialize and restore vascular function. We have used complexes of lentiviral vectors and magnetic nanoparticles (MNPs) to overexpress the vasoprotective gene endothelial nitric oxide synthase (eNOS) in ECs. The MNP-loaded and eNOS-overexpressing cells were magnetic, and by magnetic fields they could be positioned at the vascular wall in a radially symmetric fashion even under flow conditions. We demonstrate that the treated vessels displayed enhanced eNOS expression and activity. Moreover, isometric force measurements revealed that EC replacement with eNOS-overexpressing cells restored endothelial function after vascular injury in eNOS–/– mice ex and in vivo. Thus, the combination of MNP-based gene and cell therapy with custom-made magnetic fields enables circumferential re-endothelialization of vessels and improvement of vascular function.

The magnetic particle spectrum (MPS) of bacterial magnetosomes, isolated from Magnetospirillum gryphiswaldense, is measured and compared to that of the current “gold standard”, Resovist®. It is shown that the amplitudes of the magnetosomes’ harmonics by far exceed that of Resovist®; the amplitude of the third harmonic is higher by a factor of 7, and is the highest value obtained for iron oxide nanoparticles to date.

Various nanoparticle systems have been developed for medical applications in recent years. For constant improvement of efficacy and safety of nanoparticles, a close interdisciplinary interplay between synthesis, physicochemical characterizations and toxicological investigations is urgently needed. Based on combined toxicological data, we follow a “safe-by design” strategy for our superparamagnetic iron oxide nanoparticles (SPION). Using complementary interference-free toxicological assay systems, we initially identified agglomeration tendencies in physiological fluids, strong uptake by cells and improvable biocompatibility of lauric acid (LA)-coated SPIONs (SPIONLA). Thus, we decided to further stabilize those particles by an artificial protein corona consisting of serum albumin. This approach finally lead to increased colloidal stability, augmented drug loading capacity and improved biocompatibility in previous in vitro assays. Here, we show in whole blood ex vivo and on isolated red blood cells (RBC) that a protein corona protects RBCs from hemolysis by SPIONs.

Magnetic nanoparticles can be used in medicine in vivo as contrast agents and as a drug carrier system for chemotherapeutics. Thus local cancer therapy is performed with Magnetic Drug Targeting (MDT) and allows a specific delivery of therapeutic agents to desired targets, i.e., tumors, by using a chemotherapeutic substance bound to magnetic nanoparticles and focused with an external magnetic field to the tumor after intraarterial application. Important for this therapeutic principle is the distribution of the particles in the whole organism and especially in the tumor. Therefore we used magnetorelaxometry to quantify ferrofluids delivered after MDT. Tissue samples of some mm 3 volume of a VX2 squamous cell carcinoma were measured by magnetic relaxation and the amount of iron was determined using the original ferrofluid suspension as a reference. From this the distribution of the magnetic particles within the slice of tumor was reconstructed. Histological cross-sections of the respective tumor offer the opportunity to map quantitatively the particle distribution and the vascularisation in the targeted tumor on a microscopic scale. Our data show that the integral method magnetorelaxometry and microscopic histological methods can complete each other efficiently.

A magnetorelaxometry system based on sensitive fluxgate magnetometers for the analysis of the relaxation behavior of magnetic nanoparticles is presented. The system is tested with a dilution series of magnetite. The results are directly compared with data obtained with a SQUID magnetorelaxometry system measured on the same samples. Advantages of using fluxgates rather than SQUIDs for magnetorelaxometry are discussed.

The knowledge of the physico-chemical characteristics of magnetic nanoparticles (MNPs) is essential to enhance the efficacy of MNP-based therapeutic treatments (e.g. magnetic heating, magnetic drug targeting). According to the literature, the MNP uptake by cells may depend on the coating of MNPs, the surrounding medium as well as on the aggregation behaviour of the MNPs. Therefore, in this study, the aggregation behaviour of MNPs in various media was investigated. MNPs with different coatings were suspended in cell culture medium (CCM) containing fetal calf serum (FCS) and the distribution of the hydrodynamic sizes was measured by magnetorelaxometry (MRX). FCS as well as bovine serum albumin (BSA) buffer (phosphate buffered saline with 0.1% bovine serum albumin) may induce MNP aggregation. Its strength depends crucially on the type of coating. The degree of aggregation in CCM depends on its FCS content showing a clear, local maximum at FCS concentrations, where the IgG concentration (part of FCS) is of the order of the MNP number concentration. Thus, we attribute the observed aggregation behaviour to the mechanism of agglutination of MNPs by serum compartments as for example IgG. No aggregation was induced for MNPs coated with dextran, polyarabic acid or sodium phosphate, respectively, which were colloidally stable in CCM.

Background: Magnetic drug targeting (MDT) is an effective alternative for common drug applications, which reduces the systemic drug load and maximizes the effect of, eg, chemotherapeutics at the site of interest.After the conjugation of a magnetic carrier to a chemotherapeutic agent, the intra-arterial injection into a tumor-afferent artery in the presence of an external magnetic field ensures the accumulation of the drug within the tumor tissue. Materials and methods:In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) coated with lauric acid and human serum albumin as carriers for paclitaxel (SPION LA-HSA-Ptx ).To investigate whether this particle system is suitable for a potential treatment of cancer, we investigated its physicochemical properties by dynamic light scattering, ζ potential measurements, isoelectric point titration, infrared spectroscopy, drug release quantification, and magnetic susceptibility measurements.The cytotoxic effects were evaluated using extensive toxicological methods using flow cytometry, IncuCyte ® live-cell imaging, and growth experiments on different human breast cancer cell lines in two-and three-dimensional cell cultures. Conclusion:The data showed that next to their high magnetization capability, SPION LA-HSA-Ptx have similar cytostatic effects on human breast cancer cells as pure paclitaxel, suggesting their usage for future MDT-based cancer therapy.

Abstract Quantitative knowledge about the spatial distribution and local environment of magnetic nanoparticles (MNPs) inside an organism is essential for guidance and improvement of biomedical applications such as magnetic hyperthermia and magnetic drug targeting. Magnetorelaxometry (MRX) provides such quantitative information by detecting the magnetic response of MNPs following a fast change in the applied magnetic field. In this article, we review our MRX based procedures that enable both the characterization and the quantitative imaging of MNPs in a biomedical environment. MRX characterization supported the selection of an MNP system with colloidal stability and suitable cellular MNP uptake. Spatially resolved MRX, a procedure employing multi-channel MRX measurements allowed for These MRX based measurement and analysis procedures have substantially supported the development of MNP based biomedical applications.

The binding reaction of the biomolecules streptavidin and anti-biotin antibody, both labelled by magnetic nanoparticles (MNP), to biotin coated on agarose beads, was quantified by magnetorelaxometry (MRX). Highly sensitive SQUID-based MRX revealed the immobilization of the MNP caused by the biotin-streptavidin coupling. We found that about 85% of streptavidin-functionalised MNP bound specifically to biotin-agarose beads. On the other hand only 20% of antibiotin-antibody functionalised MNP were specifically bound. Variation of the suspension medium revealed in comparison to phosphate buffer with 0.1% bovine serum albumin a slight change of the binding behaviour in human serum, probably due to the presence of functioning (non heated) serum proteins. Furthermore, in human serum an additional non-specific binding occurs, being independent from the serum protein functionality. The presented homogeneous bead based assay is applicable in simple, uncoated vials and it enables the assessment of the binding kinetics in a volume without liquid flow. The estimated association rate constant for the MNP-labelled streptavidin is by about two orders of magnitude smaller than the value reported for free streptavidin. This is probably due to the relatively large size of the magnetic markers which reduces the diffusion of streptavidin. Furthermore, long time non-exponential kinetics were observed and interpreted as agglutination of the agarose beads.

Magnetic nanoparticles have been investigated for biomedical applications for more than 30 years. The development of biocompatible nanosized drug delivery systems for specific targeting of therapeutics is imminent in medical research, especially for treating cancer and vascular diseases. We used drug-labeled magnetic iron oxide nanoparticles, which were attracted to an experimental tumor in rabbits with an external magnetic field (magnetic drug targeting, MDT). Aim of this study was to detect and quantify the biodistribution of the magnetic nanoparticles by magnetorelaxometry. The study shows higher amount of nanoparticles in the tumor after intraarterial application and MDT compared to intravenous administration.

Abstract Nanoparticles experience increasing interest for a variety of medical and pharmaceutical applications. When exposing nanomaterials, e.g., magnetic iron oxide nanoparticles (MNP), to human blood, a protein corona consisting of various components is formed immediately. The composition of the corona as well as its amount bound to the particle surface is dependent on different factors, e.g., particle size and surface charge. The actual composition of the formed protein corona might be of major importance for cellular uptake of magnetic nanoparticles. The aim of the present study was to analyze the formation of the protein corona during in vitro serum incubation in dependency of incubation time and temperature. For this, MNP with different shells were incubated in fetal calf serum (FCS, serving as protein source) within a water bath for a defined time and at a defined temperature. Before and after incubation the particles were characterized by a variety of methods. It was found that immediately (seconds) after contact of MNP and FCS, a protein corona is formed on the surface of MNP. This formation led to an increase of particle size and a slight agglomeration of the particles, which was relatively constant during the first minutes of incubation. A longer incubation (from hours to days) resulted in a stronger agglomeration of the FCS incubated MNP. Quantitative analysis (gel electrophoresis) of serum-incubated particles revealed a relatively constant amount of bound proteins during the first minutes of serum incubation. After a longer incubation (&gt;20 min), a considerably higher amount of surface proteins was determined for incubation temperatures below 40 °C. For incubation temperatures above 50 °C, the influence of time was less significant which might be attributed to denaturation of proteins during incubation. Overall, analysis of the molecular weight distribution of proteins found in the corona revealed a clear influence of incubation time and temperature on corona composition.

Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted great attention in many biomedical fields and are used in preclinical/experimental drug delivery, hyperthermia and medical imaging. In this study, biocompatible magnetite drug carriers, stabilized by a dextran shell, were developed to carry tissue plasminogen activator (tPA) for targeted thrombolysis under an external magnetic field. Different concentrations of active tPA were immobilized on carboxylated nanoparticles through carbodiimide-mediated amide bond formation. Evidence for successful functionalization of SPIONs with carboxyl groups was shown by Fourier transform infrared spectroscopy. Surface properties after tPA immobilization were altered as demonstrated by dynamic light scattering and ζ potential measurements. The enzyme activity of SPION-bound tPA was determined by digestion of fibrin-containing agarose gels and corresponded to about 74% of free tPA activity. Particles were stored for three weeks before a slight decrease in activity was observed. tPA-loaded SPIONs were navigated into thrombus-mimicking gels by external magnets, proving effective drug targeting without losing the protein. Furthermore, all synthesized types of nanoparticles were well tolerated in cell culture experiments with human umbilical vein endothelial cells, indicating their potential utility for future therapeutic applications in thromboembolic diseases.

Magnetic drug targeting is the use of coated magnetic nanoparticles as carriers for cytostatic drugs. After intraarterial application of these carriers, they are attracted with an external magnetic field to, for example, an experimental VX2 tumour. The biological compatibility of this system depends on several physiological and physical parameters. We established an in vitro model to simulate in vivo conditions in a circulating system consisting of a circuit with an intact bovine femoral artery close to an external magnetic field. Nanoparticle suspensions were applied by a side inlet. After the magnetisation procedure particle size, concentration and distribution was examined.

The binding of monoclonal antibodies labelled with magnetic nanoparticles to CD61 surface proteins expressed by platelets in whole blood samples was measured by magnetorelaxometry. This technique is sensitive to immobilization of the magnetic labels upon binding. Control experiments with previous saturation of the epitopes on the platelet surfaces demonstrated the specificity of the binding. The kinetics of the antibody antigen reaction is accessible with a temporal resolution of 12 s. The minimal detectable platelet concentration is about 2000 μL−1 (sample volume 150 μL). The proportionality of the magnetic relaxation amplitude to the number of bound labels allows a quantification of the antibody binding capacity.

Uniformly sized and shaped iron oxide nanoparticles with a mean size of 25 nm were synthesized via decomposition of iron-oleate. High resolution transmission electron microscopy and Mössbauer spectroscopy investigations revealed that the particles are spheres primarily composed of Fe3O4 with a small fraction of FeO. From Mössbauer and static magnetization measurements, it was deduced that the particles are superparamagnetic at room temperature. The hydrophobic particles were successfully transferred into water via PEGylation using nitrodopamine as an anchoring group. IR spectroscopy and thermogravimetric analysis showed the success and efficiency of the phase transfer reaction. After PEGylation, the particles retained monodispersity and their magnetic core remained intact as proven by photon cross-correlation spectroscopy, ac susceptibility, and transmission electron microscopy. The particle aqueous suspensions revealed excellent water stability over a month of monitoring and also against temperature up to 40 °C. The particles exhibited a moderate cytotoxic effect on in vitro cultured bone marrow-derived macrophages and no release of inflammatory or anti-inflammatory cytokines. The PEGylated particles were functionalized with Herceptin antibodies via a conjugation chemistry, their response to a rotating magnetic field was studied using a fluxgate-based setup and was compared with the one recorded for hydrophobic and PEGylated particles. The particle phase lag rose after labeling with Herceptin, indicating the successful conjugation of Herceptin antibodies to the particles.

In the field of vascular gene therapy, targeting systems are promising advancements to improve site-specificity of gene delivery. Here, we studied whether incorporation of magnetic nanoparticles (MNP) with different magnetic properties into ultrasound sensitive microbubbles may represent an efficient way to enable gene targeting in the vascular system after systemic application. Thus, we associated novel silicon oxide-coated magnetic nanoparticle containing microbubbles (SO-Mag MMB) with lentiviral particles carrying therapeutic genes and determined their physico-chemical as well as biological properties compared to MMB coated with polyethylenimine-coated magnetic nanoparticles (PEI-Mag MMB). While there were no differences between both MMB types concerning size and lentivirus binding, SO-Mag MMB exhibited superior characteristics regarding magnetic moment, magnetizability as well as transduction efficiency under static and flow conditions in vitro. Focal disruption of lentiviral SO-Mag MMB by ultrasound within isolated vessels exposed to an external magnetic field decisively improved localized VEGF expression in aortic endothelium ex vivo and enhanced the angiogenic response. Using the same system in vivo, we achieved a highly effective, site-specific lentiviral transgene expression in microvessels of the mouse dorsal skin after arterial injection. Thus, we established a novel lentiviral MMB technique, which has great potential towards site-directed vascular gene therapy.

Magnetic particle imaging (MPI) is a new imaging technique that detects the spatial distribution of magnetic nanoparticles (MNP) with the option of high temporal resolution. MPI relies on particular MNP as tracers with tailored characteristics for improvement of sensitivity and image resolution. For this reason, we developed optimized multicore particles (MCP 3) made by coprecipitation via synthesis of green rust and subsequent oxidation to iron oxide cores consisting of a magnetite/maghemite mixed phase. MCP 3 shows high saturation magnetization close to that of bulk maghemite and provides excellent magnetic particle spectroscopy properties which are superior to Resovist® and any other up to now published MPI tracers made by coprecipitation. To evaluate the MPI characteristics of MCP 3 two kinds of tube phantoms were prepared and investigated to assess sensitivity, spatial resolution, artifact severity, and selectivity. Resovist® was used as standard of comparison. For image reconstruction, the regularization factor was optimized, and the resulting images were investigated in terms of quantifying of volumes and iron content. Our results demonstrate the superiority of MCP 3 over Resovist® for all investigated MPI characteristics and suggest that MCP 3 is promising for future experimental in vivo studies.

Magnetorelaxometry (MRX) is a sensitive measurement technique frequently employed in biomedical applications for imaging magnetic nanoparticles (MNP). In this article, we employ a first principles model to investigate the effects of different iron oxide MNP sample properties on the Néel relaxation time constant τN in magnetorelaxometry. Using this model, we determined that dipolar interactions start to have an impact on the MRX signal from Fe concentrations of 100 mmol/l and result in a smaller τN. Additionally, the micromagnetic damping constant, closely related to τN, was found to be between 0.0005 and 0.002 by comparison to an MRX measurement of iron oxide particles. This is significantly lower compared to the bulk value of 0.07 for this material.

Magnetic nanoparticles (MNPs) are used in different biomedical applications, whereby each application requires specific particle properties. To fulfill these requirements, particle properties have to be optimized by means of variation of crystal structure, particle size, and size distribution. To this aim, improved aqueous precipitation procedures for magnetic iron oxide nanoparticle synthesis were developed. One procedure focused on the cyclic growth of MNPs without nucleation of new particle cores during precipitation. The second novel particle type are magnetic multicore nanoparticles, which consist of single cores of approximately 10 nm forming dense clusters in the size range from 40 to 80 nm. Their highest potential features these multicore particles in hyperthermia application. In our in vivo experiments, therapeutically suitable temperatures were reached after 20 s of heating for a particle concentration in the tumor of 1% and field parameters of H=24 kA/m and f=410 kHz. This review on our recent investigations for particle optimization demonstrates that tuning magnetic properties of MNPs can be obtained by the alteration of their structure, size, and size distribution. This can be realized by means of control of particle size during synthesis or subsequent size-dependent fractionation. The here-developed particles show high potential for biomedical applications.

Resovist® originally developed as a clinical liver contrast agent for Magnetic Resonance Imaging exhibits also an outstanding performance as a tracer in Magnetic Particle Imaging (MPI). In order to study the physical mechanism of the high MPI performance of Resovist®, we applied asymmetric flow field–flow fractionation (A4F) and static magnetic fractionation (SMF) to separate Resovist® into a set of fractions with defined size classes. As A4F based on an elution method separates MNP according to their hydrodynamic size, SMF fractionates a particle distribution by its magnetic moment. The obtained fractions of both separation techniques were then magnetically characterized by magnetorelaxometry measurements to extract the corresponding effective magnetic anisotropy and hydrodynamic size distribution parameters. Additionally, the MPI performance of each fraction was assessed using magnetic particle spectroscopy. With both separation techniques fractions (normalized to their iron amount) an MPI signal gain of a factor of two could be obtained, even though the distribution of effective anisotropy and hydrodynamic size were significantly different. Relating these findings to the results from magnetic characterization allows for a better understanding of the underlying mechanisms of MPI performance of Resovist®. This knowledge may help to improve the design of novel MPI tracers and development of separation methods.

As emerging responsive materials, ferrogels have demonstrated significant potential for applications in areas of engineering to regenerative medicine. Promising techniques to study the behavior of magnetic nanoparticles (MNPs) in such matrices include magnetic particle spectroscopy (MPS) and magnetorelaxometry (MRX). This work investigated the magnetic response of gelatin-based ferrogels with increasing temperatures, before and after high energy crosslinking. The particle response was characterized by the nonlinear magnetization using MPS and quasistatic magnetization measurements as well as MRX to discriminate between Néel and Brownian relaxation mechanisms. The effective magnetic response of MNPs in gelatin was suppressed, indicating that the magnetization of the ferrogels was strongly influenced by competing dipole-dipole interactions. Significant changes in the magnetic behavior were observed across the gelatin sol-gel transition, as influenced by the matrix viscosity. These relaxation processes were modeled by Fourier transformation of the Langevin function, combined with a Debye term for the nonlinear magnetic response, for single core MNPs embedded in matrices of changing viscosities. Using high energy electron irradiation as a crosslinking method, modified ferrogels exhibited thermal stability on a range of timescales. However, MRX relaxation times revealed a slight softening around the gelatin sol-gel transition felt by the smallest particles, demonstrating a high sensitivity to observe local changes in the viscoelasticity. Overall, MPS and MRX functioned as non-contact methods to observe changes in the nanorheology around the native sol-gel transition and in crosslinked ferrogels, as well as provided an understanding of how MNPs were integrated into and influenced by the surrounding matrix.

Tailored ferrogel bioactuators are feasible by arresting nanoparticles in simple gelatin gels with the help of electron beam treatment.

For the preclinical development of magnetic particle imaging (MPI) in general, and the exploration of possible new clinical applications of MPI in particular, tailored MPI tracers with surface properties optimized for the intended use are needed. Here we present the synthesis of magnetic multicore particles (MCPs) modified with polyethylene glycol (PEG) for use as blood pool MPI tracers. To achieve the stealth effect the carboxylic groups of the parent MCP were activated and coupled with pegylated amines (mPEG-amines) with different PEG-chain lengths from 2 to 20 kDa. The resulting MCP-PEG variants with PEG-chain lengths of 10 kDa (MCP-PEG10K after one pegylation step and MCP-PEG10K2 after a second pegylation step) formed stable dispersions and showed strong evidence of a successful reaction of MCP and MCP-PEG10K with mPEG-amine with 10 kDa, while maintaining their magnetic properties. In rats, the mean blood half-lives, surprisingly, were 2 and 62 min, respectively, and therefore, for MCP-PEG10K2, dramatically extended compared to the parent MCP, presumably due to the higher PEG density on the particle surface, which may lead to a lower phagocytosis rate. Because of their significantly extended blood half-life, MCP-PEG10K2 are very promising as blood pool tracers for future in vivo cardiovascular MPI.

Background: The regenerative potential of the heart after injury is limited. Therefore, cell replacement strategies have been developed. However, the engraftment of transplanted cells in the myocardium is very inefficient. In addition, the use of heterogeneous cell populations precludes the reproducibility of the outcome. Methods: To address both issues, in this proof of principle study, we applied magnetic microbeads for combined isolation of eGFP+ embryonic cardiac endothelial cells (CECs) by antigen-specific magnet-associated cell sorting (MACS) and improved engraftment of these cells in myocardial infarction by magnetic fields. Results: MACS provided CECs of high purity decorated with magnetic microbeads. In vitro experiments revealed that the angiogenic potential of microbead-labeled CECs was preserved and the magnetic moment of the cells was strong enough for site-specific positioning by a magnetic field. After myocardial infarction in mice, intramyocardial CEC injection in the presence of a magnet resulted in a strong improvement of cell engraftment and eGFP+ vascular network formation in the hearts. Hemodynamic and morphometric analysis demonstrated augmented heart function and reduced infarct size only when a magnetic field was applied. Conclusion: Thus, the combined use of magnetic microbeads for cell isolation and enhanced cell engraftment in the presence of a magnetic field is a powerful approach to improve cell transplantation strategies in the heart.

1 Abstract The cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB) in vitro , load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers (∼4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by ∼4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43 + mFB provides strong protection against post-infarct ventricular tachycardia (VT) in vivo , as VT incidence is reduced by ∼50 % at two and eight weeks after cell injection. Thus, ex vivo gene and subsequent in vivo cell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.

The ion exchange mediated binding of magnetic nanoparticles (MNP) to modified latex spheres and yeast cells was quantified using magnetorelaxometry. By fitting subsequently recorded relaxation curves, the kinetics of the binding reactions was extracted. The signal of MNP with weak ion exchanger groups bound to latex and yeast cells scales linearly with the concentration of latex beads or yeast cells whereas that of MNP with strong ion exchanger groups is proportional to the square root of concentration. The binding of the latter leads to a much stronger aggregation of yeast cells than the former MNP.

Magnetic particle imaging (MPI) is a new imaging technique for visualizing the three-dimensional distribution of superparamagnetic iron oxide nanoparticles with specific properties (MPI tracers). Initial results obtained with MPI using superparamagnetic iron oxide as blood pool markers suggest that the method has great potential for cardiovascular imaging. Conversely, no clinically approved MPI tracers currently exist that could be used to exploit this potential of MPI. This article describes thermal decomposition and coprecipitation, two relevant methods for synthesizing and optimizing superparamagnetic iron oxide nanoparticles for MPI. Furthermore it summarizes the recent literature on MPI tracers and explores what can be learned from structural studies with Resovist(®) for novel synthesis approaches.

The structure and the magnetisation behaviour of two different systems of magnetic nanoparticles (MNP), namely Resovist® with a wide core size distribution (diameter, σ=0.3) and SHP-20 with a rather narrow distribution (σ=0.1), were investigated by magnetorelaxometry (MRX) and magnetisation measurements in a wide concentration range. MRX on fluid and solid suspensions yielded the distribution of hydrodynamic diameters and effective magnetic anisotropy energies (EA), where towards higher iron concentrations the spatial particle correlation, i.e. aggregation, and also the width of the EA distribution were increased significantly. It was further found that these effects quantitatively depend on the suspension medium, where an increased salt concentration enhanced the aggregate size distribution and EA dispersion. At mentioned higher MNP concentrations, the quasistatic magnetisation, normalised with respect to the iron content, decreased by up to 40%. In the case of SHP-20, where single core MNPs dominate, the maximum of this drop down of the magnetisation occurred at a field strength that corresponds to the strength of mean squared dipolar interaction.

The agglutination of probes, i.e., biomolecules labeled by magnetic nanoparticles, due to their binding to complement analyte molecules (e.g., biomolecules) was quantified by magnetorelaxometry in terms of the mean and the width of the size distribution of the formed aggregates. We observed a clear maximum of the agglutination at a specific analyte-to-probe concentration ratio. By means of controlled variation of this ratio, the concentration of an analyte in solution can be measured in turbid media by two step preparation using magnetic measurement techniques without the need of a solid phase for immobilization of analyte or probe.

Magnetic nanoparticles are very useful for various medical applications where each application requires particles with specific magnetic properties. In this paper we describe the modification of the magnetic properties of magnetic multicore nanoparticles (MCNPs) by size dependent fractionation. This classification was carried out by means of asymmetric flow field-flow fractionation (AF4). A clear increase of the particle size with increasing elution time was confirmed by multi-angle laser light scattering coupled to the AF4 system, dynamic light scattering and Brownian diameters determined by magnetorelaxometry. In this way 16 fractions of particles with different hydrodynamic diameters, ranging between around 100 and 500 nm, were obtained. A high reproducibility of the method was confirmed by the comparison of the mean diameters of fractions of several fractionation runs under identical conditions. The hysteresis curves were measured by vibrating sample magnetometry. Starting from a coercivity of 1.41 kA m(-1) for the original MCNPs the coercivity of the particles in the different fractions varied from 0.41 to 3.83 kA m(-1). In our paper it is shown for the first time that fractions obtained from a broad size distributed MCNP fluid classified by AF4 show a strong correlation between hydrodynamic diameter and magnetic properties. Thus we state that AF4 is a suitable technology for reproducible size dependent classification of magnetic multicore nanoparticles suspended as ferrofluids.

Typically, the dynamic behaviour of magnetic nanoparticles is investigated by measuring their response to externally applied magnetic fields. In contrast, we present a study of the magnetic fluctuations in an ensemble of magnetic nanoparticles recorded in the absence of any external excitation. Several samples of magnetic nanoparticles with varying particle size, composition, and environment were investigated. We interpret the thermal magnetic noise spectrum to estimate particle size distributions and compare these to the distributions derived from magnetorelaxometry measurements of the same samples.

Quantitative imaging of magnetic nanoparticles by

The characterization of the size distribution of magnetic nanoparticles is an important step for the evaluation of their suitability for many different applications like magnetic hyperthermia, drug targeting or Magnetic Particle Imaging. We present a new method based on the iterative Kaczmarz algorithm that enables the reconstruction of the size distribution from magnetization measurements without a priori knowledge of the distribution form. We show in simulations that the method is capable of very exact reconstructions of a given size distribution and, in that, is highly robust to noise contamination. Moreover, we applied the method on the well characterized FeraSpin™ series and obtained results that were in accordance with literature and boundary conditions based on their synthesis via separation of the original suspension FeraSpin R. It is therefore concluded that this method is a powerful and intuitive tool for reconstructing particle size distributions from magnetization measurements.

We studied the magnetic resonance imaging liver contrast agent Resovist by a variety of magnetic measurement techniques, in order to understand the physical mechanism of their high magnetic particle imaging (MPI) performance, with a focus on the size-dependent contributions to the MPI signal. To this end, we used asymmetric flow field-flow fractionation to separate Resovist into a set of fractions with defined hydrodynamic diameters. The individual fractions were magnetically characterized by static magnetization and magnetorelaxometry measurements to obtain the corresponding effective magnetic anisotropy and effective size distribution parameters. In addition, the MPI performance of each fraction was assessed by magnetic particle spectroscopy. We observed an MPI signal gain of about 100% with respect to their iron amount for the best fraction. Relating these finding to the results from magnetic characterization provides more insight into the mechanisms of MPI performance of Resovist. This knowledge may help to improve the design of novel MPI tracers.

Large magnetosomes of 40 nm diameter were characterised by altogether four different methods, i.e. DC-magnetometry and magnetorelaxometry as integral tools, and atomic and magnetic force microscopy as microscopic tools. The results suggest that the integral hysteretic behaviour of magnetosomes can be understood as a superposition of their microscopic behaviour, ignoring interaction between the particle moments.

Magnetorelaxometry can be applied for the comprehensive and fast characterization of magnetic core-shell nanoparticles. The magnetic relaxation of magnetic nanoparticle samples measured with a differential fluxgate-having the potential for a standard testing tool-and a low- T <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">c</sub> SQUID system-acting as a highly sensitive reference system-is compared. It is shown that magnetorelaxation curves agree, i.e., they are not influenced by the different experimental setup. Furthermore, utilizing tiny coils as calibration standards, the measured magnetic flux density can be referred to a magnetic moment of the sample, and measurement data can be quantitatively transferred from one system to the other.

Magnetorelaxometry imaging (MRXI) is a non-invasive, quantitative imaging technique for magnetic nanoparticles (MNPs). The image resolution of this technique significantly depends on the relaxation amplitude (ΔB). For this work, we measured the room temperature (299 K) relaxation signals of eight commercial MNP sample systems with different magnetic properties, in both fluid and immobilized states, in order to select the most suitable sample for a particular MRXI setting. Additionally, the effect of elevated temperatures (up to hyperthermia temperature, 335 K) on the relaxation signals of four different MNP systems (Synomag, Perimag, BNF and Nanomag) in both states were investigated. The ΔBvalues of fluid samples significantly decreased with increasing temperature, and the behaviour for immobilized samples depended on their blocking temperature (TB). For samples withTB< 299 K, ΔBalso decreased with increasing temperature. Whereas for samples withTB> 299 K, the opposite behaviour was observed. These results are beneficial for improving the image resolution in MRXI and show, among the investigated systems, and for our setup, Synomag is the best candidate for futurein vitroandin vivostudies. This is due to its consistently high ΔBbetween 299 and 335 K in both states. Our findings demonstrate the feasibility of temperature imaging by MRXI.

The magnetization behavior of frozen ferrofluids shows a typical glassy behavior, e.g., a maximum in the zero field cooled magnetization at Tm; irreversibility and longtime relaxation of residual magnetization, but is distinct from those of canonical spin glasses. They exhibit many similarities with concentrated and re-entrant spin glasses and some with random magnetic anisotropy systems, for which the inhomogeneity of magnetic structure is a characteristic feature. It is suggested that a phase with weak irreversibility, ranging from T̃f<2Tm, is determined by magnetic clusters. A crossover to a phase with strong irreversibility at the fictitious freezing temperature T̃f is deduced from the change of Tm(H)-characteristic in conjunction with the onset of magnetic hysteresis. The variance of dipole interaction 〈E2dd〉1/2 for randomly ordered frozen moments were calculated for the investigated ferrofluids. The result Tm≈2〈E2dd〉1/2 supports the hypothesis of the existence of clusters with non-randomly ordered moments around Tm. From the field dependence of the relaxation behavior and from the ratio T̃f/〈E2dd〉1/2 it was concluded that the ferrofluid with an extended net-like aggregate structure enters in the state with strong irreversibility at significantly higher rescaled temperatures, rather than those with compact, isolated particle clusters.

Abstract A system of magnetic nanoparticles (MNPs) and modified latex spheres was used serving as a model for studying binding reactions. The binding of MNPs on latex is estimated by the change of the magnetic relaxation properties of the MNP measured by a SQUID‐based magnetorelaxometry measurement system. By fitting of subsequently recorded relaxation curves, the kinetics of the binding reactions, i.e. the evolution of the fraction of bound MNPs, was extracted. The signal of bound MNPs scales linearly with the concentration of latex beads. For low latex concentrations the kinetics are described by a simple aggregation model, providing information about the density and probability of bindings to the target surface. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Tumors grown on animals and treated with magnetic drug targeting and magnetic hyperthermia have been analyzed by microcomputed X-ray tomography to study the three-dimensional nanoparticle distribution. The measurements have been performed in two laboratories, with a polychromatic X-ray cone beam as well as with monochromatic parallel beam. Due to the poor resolution in the first case, the distribution of the magnetic nanoparticles can be studied only qualitatively. With the polychromatic beam semi-quantitative results can be achieved. In this paper, the results from both methods are presented and compared.

Magnetorelaxometry and thermal magnetic noise spectroscopy are two magnetic characterization techniques enabling one to estimate the magnetic nanoparticle hydrodynamic size distribution.Both techniques are based on the same physical principle, i.e. the thermal fluctuations of the magnetic moment.In the case of magnetorelaxometry these fluctuations give rise to a relaxing magnetic moment after an externally applied magnetic field is switched off, whereas thermal magnetic noise spectra are measured in the absence of any external excitation.Hence, thermal magnetic noise spectroscopy is an equilibrium measurement technique.Here, we compare the similarity and complementarity of both methods and conclude that, for particles within both methods' sensitivity range, they give the same estimate for the size distribution.For small particles (or samples with low viscosities), the used setup is not sufficiently sensitive to accurately estimate the size distribution from the relaxometry signal whereas this is still possible with thermal magnetic noise spectroscopy.For larger particles, however, magnetorelaxometry is the preferred method because of its higher signal to noise ratio and faster measurement time.

Abstract Noninvasive medical imaging of blood flow relies on mapping the transit of a contrast medium bolus injected intravenously. This has the draw-back that the front of the bolus widens until the tissue of interest is reached and quantitative flow parameters are not easy to obtain. Here, we introduce high resolution (millimeter/millisecond) 3D magnetic tracking of a single microsphere locally probing the flow while passing through a vessel. With this, we successfully localize and evaluate diameter constrictions in an arteria phantom after a single passage of a microsphere. We further demonstrate the potential for clinical application by tracking a microsphere smaller than a red blood cell.

Magnetic particle imaging (MPI) is a noninvasive tomographic imaging modality for the quantitative visualization of magnetic nanoparticles (MNPs) with high temporal and spatial resolution. The general capability of MPI for cell tracking (e.g., monitoring living cells labeled with MNPs) has successfully been shown. MNPs in cell culture media are often subjected to structural and magnetic changes. In addition to the deteriorating reproducibility, this also complicates the systematic study of the relationship between the MNP properties and their cellular uptake for MPI. Here, we present a method for the preparation of magnetically labeled THP-1 (Tamm–Horsfall Protein-1) monocytes that are used in MPI cell tracking. The method development was performed using two different MPI tracers, which exhibited electrostatic and steric stabilizations, respectively. In the first step, the interaction between the MNPs and cell culture media was investigated and adjusted to ensure high structural and magnetic stability. Furthermore, the influences of the incubation time, MNP concentration used for cellular uptake, and individual preparation steps (e.g., the washing of cells) were systematically investigated. Finally, the success of the developed loading method was demonstrated by the MPI measurements. The presented systematic investigation of the factors that influence the MNP loading of cells will help to develop a reliable and reproducible method for MPI monocyte tracking for the early detection of inflammation in the future.

Diagnostic imaging is of utmost importance for clinical routine and research and is also gaining more and more relevance in preclinical research. Magnetic particle imaging (MPI) as a new imaging modality may open new perspectives in the field. Iron oxide magnetic nanoparticles (MNPs) are already used as MRI contrast agents are of general interest for various other biomedical applications, and are also promising as MPI tracers. However, to provide the desired performance for MPI, it is still necessary to optimize the particles signal efficacy. Optimization remains an unexpected challenge and, as a consequence, considerable importance is being given to the research of MNPs, where efforts have been placed to understand the relation between particle structure and particle magnetic properties in more detail. In the present study, two clustered core MNPs exhibiting similar structures, but significant differences in their magnetic particle spectra, are investigated. Their static and dynamic magnetic properties are analyzed to understand the reasons for such differences as well as to gain a better insight of their relation to the particle structure.

Ferromagnetic metallic nanoparticles were produced by laser evaporation with vapour condensation in an aggregation gas. From iron rich Fe–Si and Fe–Co targets solid alloy particles with α-Fe structure and a mean diameter of 10 nm were obtained. Using a gas pressure of 150 mbar an α-Fe content up to 90 wt% and a saturation magnetisation of 1.4 T were found.

Delivery of tiny aerosol droplets containing magnetic nanoparticles (MNP) to specific regions in the lungs guided by an external magnetic gradient field is a novel way of Magnetic Drug Targeting, which should allow to deposit high drug doses to a cancerous lung region together with reduced side-effects in unaffected tissue. Currently, this method is investigated in a pig lung model, a model being very similar to the human lung. The development of this procedure requires detailed knowledge about the biodistribution of MNP in different parts of the lung. Magnetorelaxometry (MRX) as a quantitative detection technique is used to determine the MNP distribution throughout the pig lungs after the aerosol targeting application. To this end, we extended our MRX measurement procedure to quantify the magnetic nanoparticle uptake in larger tissue samples with inhomogeneous particle distribution. Here, we present the results of the MRX quantification for an isolated pig lung. The absolute MNP uptake for individual lung lobes and the tissue concentration distribution over the whole lung is provided.

Particle size distribution, structure, and magnetic correlations of magnetite particles in ferrofluids are studied with X-ray diffraction methods and electron microscopy. The accordance of the size distributions obtained from small-angle X-ray scattering (SAXS), wide angle X-ray diffraction (XRD), and transmission electron microscopy (TEM) is demonstrated. Under the influence of a magnetic field the particles of ferrofluids aggregate to oblong and directed particle clusters. They have a small extension in field direction, caused by a wide size distribution and the high thermal energy of the particles. The ferrofluids described here are suitable to simulate the crystallographic situation of the Finemet alloys in the state of best soft magnetic properties. Die Teilchengrößenverteilung, Struktur sowie die magnetische Korrelation der Magnetitteilchen eines Ferrofluids werden mit röntgenographischen Methoden und Transmissionselektronenmikroskopie (TEM) untersucht. Eine Übereinstimmung der Teilchengrößenverteilungen, die mittels Röntgenklein-winkelstreuung, Röntgendiffraktometrie und TEM bestimmt werden, kann nachgewiesen werden. Die Teilchen des untersuchten Ferrofluids bilden unter Magnetfeldeinfluß längliche Cluster, die aufgrund der breiten Teilchengrößenverteilung und hohen thermischen Energie der Magnetitteilchen nur eine geringe Ausdehnung in Feldrichtung haben. Die hier beschriebenen Ferrofluide sind dazu geeignet, die kristallographische Situation der Finemet-Legierungen im Zustand der besten weichmagnetischen Eigenschaften zu simulieren.

Aim of this study was the investigation of the suitability of magnetic multicore nanoparticles (MCNP) for magnetic particle imaging. For this, MCNP of different cluster sizes were investigated. To obtain a set of samples which differ in their cluster sizes the MCNP were classified into fractions of different mean sizes by centrifugation. By the fractionation particles with hydrodynamic diameters from 100 to 800 nm were obtained. Magnetic measurements confirmed a correlation of the hydrodynamic size with the effective magnetic volume of the particles in these fractions – e.g., with increasing particle size the coercivity of the particles varied from 3.5 to 25.8 Oe. Magnetic particle spectrometry investigations showed a clear dependence of the quality of MPS signal on the hydrodynamic diameter of the particles and thus the cluster size. In particular the amplitude ratio of the higher (15...40) harmonics to the 3rd harmonic span over one order of magnitude, where the smaller MCNP showed the highest values.

The size and the size dispersion of the composite particles of ferrofluids were determined assuming a lognormal distribution of core radii. Small-angle X-ray scattering data were fitted by the theoretical scattering function of two-phase spheres. Reliable results were obtained, because the scattering share of the surface layer can be taken into account. The particles aggregate at high as well as very low concentrations. After freezing of the carrier liquid, the particles within the clusters come together tightly. The measured minimal particle distance gives information about the effective surface-layer thickness. Two types of aggregates, namely compact clusters and extended net-like aggregates, were distinct in middle length scales.

Typically, magnetic iron oxide nanoparticles (MNP) with core diameter in the range of about 16 nm to 22 nm are accessible by magnetorelaxometric (MRX) measurements at room temperature whereas the relaxation of smaller particles is too fast to be observed with a conventional MRX setup. In order to extend the size limitation towards smaller particles, we suggest applying temperature dependent magnetorelaxometry (TMRX). In this study, we outline and validate the procedure experimentally for temperatures between 5 K and 200 K on in-vitro preparations of MNP using a conventional MPMS SQUID magnetometer. On this basis, we applied TMRX for the in-vitro quantification of small sized MNP uptake by tumor cells, i.e. on HeLa and Jurkat tumor cell lines, reaching a detection limit of about 100 ng. We further showed that TMRX signals are characteristic for particular MNP preparations, opening the possibility to observe changes in the particle size distribution during the uptake of MNP by a biological system.

The future of Magnetic Particle Imaging (MPI), as a tracer-based imaging modality, crucially relies on the development of high-performing tracers. Due to their ideal structural and magnetic properties, biogenic nanoparticles extracted from magnetotactic bacteria are promising candidates for MPI tracer research. In the present study we investigate the potential of bacterial magnetosomes, extracted from wild-type bacteria of the strain Magnetospirillum gryphiswaldense and various mutants thereof, as new tracer materials for MPI. Furthermore, we investigate the structural and magnetic properties of the magnetosomes as well as their suitability as Magnetic Resonance Imaging (MRI) agents in order to explain differences in MPI and MRI efficacies.

Different very dilute suspensions of magnetic nanoparticles (magnetite surrounded by an organic shell) in water (ferrofluids) were investigated using small-angle X-ray scattering. It is shown that the scattering originates not only from noncorrelated core–shell nanoparticles, but also from larger structures. By modelling, these structures can be identified as close-packed clusters consisting of core–shell particles (core diameter ∼10 nm). The analysis of the radial distance distribution function, obtained by Fourier transformation of the scattered intensity, reveals a lower bound of the mean cluster size of about 40 nm. The formation of clusters is persistent, even in very dilute suspensions.

Functionalized magnetic nanoparticles are increasingly used as probes in biomolecule detection. We compared two different techniques, which provide information on the state of the magnetic particle system. The dynamics of an ensemble of magnetic nanoparticles was probed measuring the response its magnetisation both on an alternating magnetic field by AC-susceptometry and on a jump of external magnetic field by magnetorelaxometry. In order to compare both techniques, we studied the binding of streptavidin functionalized nanoparticles (fluidMAG/BC-SAV) to biotin-agarose beads and to biotinylated prostate specific antigens (PSA-10). By both techniques we observed specific changes in shape and amplitude of the characteristic signals due the binding of the particles. Therewith the signals of bound and unbound probes can be discriminated and a homogeneous assay without time-comsuming washing steps is realized. The AC susceptometry method provides a robust and sensitive measurement technology. Magnetorelaxometry, utilizing superconducting quantum interference devices (SQUIDs) as magnetic field sensors, owns a much shorter measurement time and has the potential of an even higher sensitivity, at the expense of a considerably increased technological effort.

We investigate the magnetic relaxation behavior of magnetic nanoparticles (MNP) under the influence of shear flow. To this end, we employed magnetorelaxometry (MRX), which is a very sensitive technique to measure the magnetization decay (magnetic relaxation) of MNP after polarizing their magnetic moments in a magnetic field. For the measurements, we developed a fluidic setup to measure the magnetic relaxation of MNP dispersions passing at specific flow rates through a capillary tube inside the magnetizing coil of the MRX device. We observed a decrease of the two characteristic MRX parameters, the relaxation time (up to 60%) and relaxation amplitude (up to 45%), with increasing flow rate (up to 16 ml min−1) compared to the corresponding values measured at zero shear rate. Further, two different regimes of magnetic relaxation behavior under shear flow could be distinguished: for low MNP concentrations the relaxation time was concentration independent, while for higher MNP concentrations an additional increase of relaxation values by about 13% was observed. This is attributed to MNP interparticle interactions. Since dipole–dipole interactions could be ruled out, we concluded that hydrodynamic interactions are the cause for the shear flow MRX behavior in the high MNP concentration regime.

No obvious differences between the structures of the different particles were found, yet their MPI efficacy varies significantly: the MPS amplitude differs by a factor of up to 6 in the lower and 11 in the higher harmonics between the highest (#1) and lowest (#2) MPI efficacy particles synthesized here. In comparison to Resovist and FeraSpin R this means an improvement by a factor of about three in the lower and two in the higher harmonics in case of the high efficacy particles (#1). Our results from static magnetization measurements allow to quantitatively understand this increase. Such an increase does not represent the theoretical limit, but so far similar performance was only found for size optimized particles obtained from the best state-of-the-art clustered core MPI tracer Resovist and FeraSpin R from aqueous synthesis [2,3] as well as certain mono-crystalline core particles from organic synthesis [4].

The Magnetic Particle Spectroscopy (MPS)-amplitudes were measured on 7 suspensions of magnetite based magnetic particles (MNP) differing in core size and magnetic anisotropy. The distributions of the effective domain sizes, estimated by means of quasistatic M(H) measurements and Magnetorelaxometry (MRX), matches well the core size distribution for the single core MNP-systems estimated by electron microscopy. Two systems, namely Resovist and M4E clearly exhibit a bimodal domain size distribution. It was shown, that the MPS amplitudes strongly increase with increasing domain size up to 21 nm, the mean value of the larger fraction of Resovist. For M4E with a mean size of the larger fraction of 33 nm the measured MPS-amplitudes became much smaller than those of Resovist, in particular for the higher harmonics. That behaviour was attributed to the mean anisotropy energy of these MNPs, estimated by MRX, exceeding that of Resovist by one order of magnitude. The effect of the MNP’s magnetic anisotropy is also supported by comparison of measured MPS-amplitudes with those which were calculated on the base of M(H)-data.

Magnetization measurements on Resovist MNP, the agent presently used for magnetic particle imaging (MPI), reveal that there are small single core MNP as well as clusters of MNP within the size range of 20-50 nm, in good agreement with electron microscopic data and light scattering results. The data of the integral measurement method of magnetorelaxometry also support the existence of (magnetic) aggregates. From the calculatated relative MPI signal strength we conclude that mainly these aggregates contribute to the MPI signal.

Using well-established measurement techniques like transmission electron microscopy (TEM), dynamic light scattering (DLS), small and wide angle X-ray scattering (SAXS, WAXS), susceptometry, and magnetorelaxometry, the distribution of the physical and magnetic size (magnetic moments) and magnetic anisotropy of a variety of structurally different magnetic nanoparticle samples (MNPs) is analyzed and compared. A term which accounts for the presence of weak magnetic areas (WMAs) within the MNPs was introduced to the widespread analysis model for M(H) data, enabling a consistent interpretation of the data in most of the systems. A comparison of the size distributions as obtained for the physical and the magnetic diameter suggests a multidomain structure for three single core systems under investigation, in all probability evoked by the presence of a wustite phase, as identified by WAXS. Analyzing the relationship d < dm < dc between the average single core diameter d, the effective magnetic (domain) size dm and the cluster diameter dc quantitatively, two qualitatively different magnetic structures in multicore MNP (MCMNP) systems were identified: (i) The magnetic moments of single cores within the MCMNP of fluidMAG tend to build flux closure structures, driven by dipole–dipole interaction. (ii) The magnetic behavior of Resovist® was attributed to the presence of domain sizes of about 12 nm within MCMNP, exceeding the single core diameters of 5 nm. Thereby, WAXS revealed a bimodal crystallite size distribution suggesting a crystallite merging process within the MCMNP. The value of the effective magnetic moment of these MCMNP could be explained within the presented “random moment cluster model” (RMCM). We conclude that the combination of physical and magnetic structure parameters obtained from complementary measurement methods allows a reliable assessment of the magnetic structure of single and multicore MNPs.

Abstract Magnetic nanoparticles (MNPs) are key elements in several biomedical applications, e.g., in cancer therapy. Here, the MNPs are remotely manipulated by magnetic fields from outside the body to deliver drugs or generate heat in tumor tissue. The efficiency and success of these approaches strongly depend on the spatial distribution and quantity of MNPs inside a body and interactions of the particles with the biological matrix. These include dynamic processes of the MNPs in the organism such as binding kinetics, cellular uptake, passage through cell barriers, heat induction and flow. While magnetic measurement methods have been applied so far to resolve the location and quantity of MNPs for therapy monitoring, these methods can be advanced to additionally access these particle–matrix interactions. By this, the MNPs can further be utilized as probes for the physical properties of their molecular environment. In this review, we first investigate the impact of nanoparticle–matrix interactions on magnetic measurements in selected experiments. With these results, we then advanced the imaging modalities magnetorelaxometry imaging and magnetic microsphere tracking to spatially resolve particle–matrix interactions.

Meaningful applications of magnetic nanoparticles (MNP) in biomedicine require the ability to quantify MNP in a variety of environments and biological materials (cells, tissue, and organs). Here we describe a method for the integral, noninvasive quantification of MNP. Our method is based on magnetorelaxometry (MRX), it relies on the detection of their magnetic stray fields which permeate practically unaltered virtually any biological material. MRX provides a specific signal which is not affected by dia- and paramagnetic signals from the biological matrix. We describe how to conduct the MRX experiments and use MNP-assisted gene transfection as the example. The quantification is based on the comparison of the MRX signal of a sample and an appropriate reference sample.

Magnetic particle imaging (MPI) allows quantitative evaluation of the spatial distribution of superparamagnetic iron oxide (SPIO) nanoparticles in the body. With a spatial resolution similar to magnetic resonance imaging (MRI), but superior temporal resolution, MPI has potential for different diagnostic applications. In addition to technical requirements, preclinical and clinical applications of this novel imaging modality require SPIO tracers optimized for MPI. This article discusses the suitability of Resovist as an MPI tracer and challenges and future prospects of tracer development.

In magnetic fluid hyperthermia / thermal ablation (MFH), superparamagnetic iron oxide nanoparticles (MNP) exposed to an externally applied alternating magnetic field generate heat specifically in the tumor region, which inactivates cancer cells with minimal side-effects to the normal tissue. The quantity of MNP needs to be thoroughly controlled to govern adequate heat production in the carcinoma region. We demonstrate the capability of magnetorelaxometry (MRX) for the non-invasive quantification and localization of MNP accumulation in small animal models. The results of our advanced MRX measurements using a 304-multichannel bio-magnetic SQUID system on two mice hosting two different carcinoma models (9L/lacZ, MD-AMB-435) are presented. The position and magnitude of the magnetic moment is reconstructed from the measured spatial magnetic field distribution by a magnetic dipole model fit applying a Levenberg-Marquadt algorithm. Therewith, the center of mass of the MNP accumulation in the tumor region of the mouse and moreover the amount of MNP in the determined region is quantified. This study shows that magnetorelaxometry is well suited for in vivo monitoring of MNP accumulation in hyperthermia application during cancer therapy.

If a sample of magnetic nanoparticles (MNP) contains two groups of different mean size, (as is the case for, e.g., Resovist <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">®</sup> [1]), bimodal fit from M(H) measurement data may reveal the bimodality. However this estimation may fail if the mean particle size of the two groups is too similar. Here we suggest magnetic separation as a useful tool for analyzing such MNP samples. To this end, we have implemented the static magnetic separation with a commercial soft magnetic spheres filled column (Miltenyi) in cascaded runs at different field strengths.

Currently, one of the main issues to improve the image quality of Magnetic Particle Imaging (MPI), besides the development of applicable MPI scanner systems and reconstruction methods, is the improvement of magnetic properties of magnetic nanoparticles (MNP), the so-called MPI tracer. Optimized tracers potentially enhance mass sensitivity and spatial resolution of MPI and may be the key for successful clinical MPI [1].

How immobilization of MPI tracers changes the MPS-signal? To address this question we immobilized a sample with single core and a sample with multicore magnetic nanoparticles (MNP) in different matrices. In order to catch a possible effect of dipolar interaction between MNP, here we focus on large, high performing MNP which are preferable for MPI. The knowledge, how the immobilization affects MPS amplitude as well as MPI performance is important for the measurement of quantitative distribution of tracers (quantitative imaging) and for proper quantification of them by MPS, e.g. in cells and in MPS-based binding assays.

Summary form only given. This research focuses on the design of magnetic nanoparticles particles (MNPs) and their assemblies for specific applications in biomedicine, combining high functional activity as drug and gene delivery vectors and sufficient magnetic responsiveness to make magnetic targeting feasible. The resulting materials should be also suitable as magnetic particle imaging (MPI) and magnetic resonance imaging (MRI) tracer. MPS measurements were carried out for tailor-made magnetic nanoparticles selected for cell labeling, assembling of magnetic delivery non-viral and viral vectors. Another aspect of the investigation is to understand how cellular confinement and clustering of the MNPs and their assemblies in labeled or magnetofected cells influence the magnetic behavior of the particles and the output signal in MPS. In particular, internalization of SO-Mag5 nanoparticles in HUVEC has not changed the MPS output. Understanding the role of nanointeractions in tracer characteristics is of importance for design of efficient magnetic vectors for targeting of theragnostics with optimized performance in MPI.

Objectives: In the past we showed, that magnetic field assisted transplantation of MNP loaded cells results in prominent long term cell engraftment and improvement of the left ventricular function of cryolesioned murine hearts. In the present study we have investigated the underlying mechanical and biological mechanisms as well as the effects of MNP loading on the electrophysiological characteristics of the transplanted embryonic cardiomyocytes (eCM) and the infarct zone.

Cancer is one of the most deadly and widespread diseases nowadays. Local cancer treatments are gaining strong importance. Magnetic Drug Targeting and magnetic heating treatment are minimal invasive cancer treatments that make use of magnetic nanoparticles as drug carriers in the first case and to induce heat transfer in the second case. For MDT the application of drugs, bound to magnetic nanoparticles, is realized via the tumor supplying vessels while a strong magnetic field gradient influences the flow and directs the nanoparticles to the respective region. In order to understand the mechanisms behind this magnetically controlled drug delivery, an ex-vivo artery model has been established. To study the amount and the distribution of magnetic nanoparticles within the arteries, microcomputed tomography and magnetorelaxometry have been used as analytical techniques. MRX provides very sensitively the amount of magnetic nanoparticles, while microcomputed tomography based on a synchrotron beam line enables 3-dimensional non-destructive examination of the distribution of the magnetic nanoparticles at a spatial resolution of a few micrometers. In this paper we present first results concerning the quantitative study of accumulation of nanoparticles within bovine arteries streamed with magnetic nanoparticles.

Abstract Ferrofluids are being considered as an aid for local cancer treatments, such as Magnetic Drug Targeting (MDT) and Magnetic Hyperthermia (MHT). Both methods make use of the strong influence of a magnetic field on the nanoparticles, with the aim of treating the cancer locally while reducing, or even eliminating, the side effects that usually occur during conventional cancer treatments. Microcomputed tomography analysis has been performed on tumour tissue after MDT and MHT in order to examine the distribution of the magnetic nanoparticles within the tissue. The majority of the measurements has been performed in a laboratory based on a polychromatic X‐ray source. The strong energy dependence of the attenuation coefficient and the occurrence of the so called beam hardening artefacts make the quantitative evaluation of data acquired with polychromatic tomography equipment very difficult. In this paper we present a cross‐calibration method for magnetorelaxometry and polychromatic X‐ray tomography for biological tissue samples enriched with magnetic nanoparticles. (© 2009 Wiley‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

We demonstrate the quantitative measurement of the magnetization of individual magnetic nanoparticles (MNP) using a magnetic force microscope (MFM). The quantitative measurement is realized by calibration of the MFM signal using an MNP reference sample with traceably determined magnetization. A resolution of the magnetic moment of the order of 10^(-18) Am^2 under ambient conditions is demonstrated which is presently limited by the tip's magnetic moment and the noise level of the instrument. The calibration scheme can be applied to practically any MFM and tip thus allowing a wide range of future applications e.g. in nanomagnetism and biotechnology.