Influence of clustering on the magnetic properties and hyperthermia performance of iron oxide nanoparticles.

Clustering of magnetic nanoparticles can drastically change their collective magnetic properties, which in turn may influence their performance in technological or biomedical applications. Here, we investigate a commercial colloidal dispersion (FeraSpinTMR), which contains dense clusters of iron oxide cores (mean size around 9 nm according to neutron diffraction) with varying cluster size (about 18-56 nm according to small angle x-ray diffraction), and its individual size fractions (FeraSpinTMXS, S, M, L, XL, XXL). The magnetic properties of the colloids were characterized by isothermal magnetization, as well as frequency-dependent optomagnetic and AC susceptibility measurements. From these measurements we derive the underlying moment and relaxation frequency distributions, respectively. Analysis of the distributions shows that the clustering of the initially superparamagnetic cores leads to remanent magnetic moments within the large clusters. At frequencies below 105 rad s-1, the relaxation of the clusters is dominated by Brownian (rotation) relaxation. At higher frequencies, where Brownian relaxation is inhibited due to viscous friction, the clusters still show an appreciable magnetic relaxation due to internal moment relaxation within the clusters. As a result of the internal moment relaxation, the colloids with the large clusters (FS-L, XL, XXL) excel in magnetic hyperthermia experiments.

Multi-color magnetic nanoparticle imaging using magnetorelaxometry.

Magnetorelaxometry (MRX) is a well-known measurement technique which allows the retrieval of magnetic nanoparticle (MNP) characteristics such as size distribution and clustering behavior. This technique also enables the non-invasive reconstruction of the spatial MNP distribution by solving an inverse problem, referred to as MRX imaging. Although MRX allows the imaging of a broad range of MNP types, little research has been done on imaging different MNP types simultaneously. Biomedical applications can benefit significantly from a measurement technique that allows the separation of the resulting measurement signal into its components originating from different MNP types. In this paper, we present a theoretical procedure and experimental validation to show the feasibility of MRX imaging in reconstructing multiple MNP types simultaneously. Because each particle type has its own characteristic MRX signal, it is possible to take this a priori information into account while solving the inverse problem. This way each particle type's signal can be separated and its spatial distribution reconstructed. By assigning a unique color code and intensity to each particle type's signal, an image can be obtained in which each spatial distribution is depicted in the resulting color and with the intensity measuring the amount of particles of that type, hence the name multi-color MNP imaging. The theoretical procedure is validated by reconstructing six phantoms, with different spatial arrangements of multiple MNP types, using MRX imaging. It is observed that MRX imaging easily allows up to four particle types to be separated simultaneously, meaning their quantitative spatial distributions can be obtained.

Magnetic particle spectroscopy allows precise quantification of nanoparticles after passage through human brain microvascular endothelial cells.

Crossing the blood-brain barrier is an urgent requirement for the treatment of brain disorders. Superparamagnetic iron oxide nanoparticles (SPIONs) are a promising tool as carriers for therapeutics because of their physical properties, biocompatibility, and their biodegradability. In order to investigate the interaction of nanoparticles with endothelial cell layers in detail, in vitro systems are of great importance. Human brain microvascular endothelial cells are a well-suited blood-brain barrier model. Apart from generating optimal conditions for the barrier-forming cell units, the accurate detection and quantification of SPIONs is a major challenge. For that purpose we use magnetic particle spectroscopy to sensitively and directly quantify the SPION-specific iron content. We could show that SPION concentration depends on incubation time, nanoparticle concentration and location. This model system allows for further investigations on particle uptake and transport at cellular barriers with regard to parameters including particles' shape, material, size, and coating.

Quantitative imaging of magnetic nanoparticles by magnetorelaxometry with multiple excitation coils.

New therapies against cancer based on magnetic nanoparticles (MNPs) require a quantitative spatially resolved imaging of MNPs inside a body. In magnetorelaxometry (MRX), a distribution of nanoparticles can be quantified non-invasively by measuring its relaxation after removal of an external magnetizing field. Conventionally, in MRX the sample is exposed to a homogeneous magnetizing field resulting in a quantitative reconstruction with rather poor spatial resolution. Theoretical work suggests an improvement of spatial resolution may be achieved by a sequential application of inhomogeneous fields magnetizing only parts of a sample. Here, we experimentally demonstrate the feasibility of this approach by reconstructing a nanoparticle distribution inside a compact three-dimensional volume phantom made of 54 gypsum cubes (1 cm(3) cube(-1)), of which 12 gypsum cubes were filled with MNPs. Using 48 small excitation coils surrounding the phantom, a sequence of MRX signals was obtained where only those MNPs near an individual coil contribute. By combined evaluation of these 48 MRX measurements, the positions and content of the 12 MNP-filled cubes could be determined accurately with a deviation below 4%, while by conventional homogeneous MRX only the MNP content was reconstructable with a deviation of about 9%. The results demonstrate the improvement of quantitative MRX imaging by using sequential activation of multiple magnetizing fields.

The influence of hydrodynamic diameter and core composition on the magnetoviscous effect of biocompatible ferrofluids.

Suspensions of magnetic nanoparticles have received increasing interest in the biomedical field. While these ferrofluids are already used for magnetic resonance imaging, emerging research on cancer treatment focuses, for example, on employing the particles as drug carriers, or using them in magnetic hyperthermia to destroy diseased cells by heating of the particles. To enable safe and effective applications, an understanding of the flow behaviour of the ferrofluids is essential. Regarding the applications mentioned above, in which flow phenomena play an important role, viscosity under the influence of an external magnetic field is of special interest. In this respect, the magnetoviscous effect (MVE) leading to an increasing viscosity if an external magnetic field of a certain strength is applied, is well-known for singlecore ferrofluids used in the engineering context. In the biomedical context, multicore ferrofluids are preferred in order to avoid remanence magnetization and to enable a deposition of the particles by the organism without complications. This study focuses on a comparison of the MVE for three ferrofluids whose composition is identical except in relation to their hydrodynamic diameter and core composition-one of the fluids contains singlecore particles, while the other two feature multicore particles. This enables confident conclusions about the influence of those parameters on flow behaviour under the influence of a magnetic field. The strong effects found for two of the fluids should be taken into account, both in future investigations and in the potential use of such ferrofluids, as well as in manufacturing, in relation to the optimization of flow behaviour.

Magnetorelaxometry for localization and quantification of magnetic nanoparticles for thermal ablation studies.

In magnetic heating treatments, intratumorally injected superparamagnetic iron oxide nanoparticles (MNP) exposed to an externally applied alternating magnetic field generate heat, specifically at the tumor region. This inactivates cancer cells with minimal side effects to the normal tissue. Therefore, the quantity of MNP needs to be thoroughly controlled to govern adequate heat production. Here, 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 MRX measurements using a multichannel vector magnetometer system with 304 SQUIDs (superconductive quantum interference device) on three mice hosting different carcinoma models (9L/lacZ and MD-AMB-435) are presented. The position and magnitude of the magnetic moment are reconstructed from measured spatial magnetic field distributions by a magnetic dipole model fit applying a Levenberg-Marquadt algorithm. Therewith, the center of gravity and the total amount of MNP accumulation in the mice are determined. Additionally, for a fourth mouse the distribution of MNP over individual organs and the tumor is analyzed by single-channel SQUID measurements, obtaining a sensitive spatial quantification. This study shows that magnetorelaxometry is well suited to monitor MNP accumulation before cancer therapy, with magnetic heating being an important precondition for treatment success.

Magnetorelaxometric quantification of magnetic nanoparticles in an artery model after ex vivo magnetic drug targeting.

In magnetic drug targeting a chemotherapeutic agent is bound to coated magnetic nanoparticles, which are administered to the blood vessel system and subsequently focused by an external applied magnetic field. The optimization of intra-arterial magnetic drug targeting (MDT) requires detailed knowledge about the biodistribution of particles in the artery and the respective surrounding after the application. Here, we demonstrate the potential of magnetorelaxometry for quantifying the distribution of magnetic nanoparticles in the artery. To this end, we present a magnetorelaxometry investigation of a MDT study in an artery model. In particular, the absolute magnetic nanoparticle accumulation along the artery as well as the uptake profile along the region around the MDT-magnet position was quantified.

Quantification of magnetic nanoparticles by magnetorelaxometry and comparison to histology after magnetic drug targeting.

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 mm3 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.