Frank Wiekhorst

Targeted delivery of magnetic aerosol droplets to the lung

The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease1, cystic fibrosis2, respiratory infection3 and, more recently, lung cancer4. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date5,6. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles—so-called nanomagnetosols—in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.

Aggregation behaviour of magnetic nanoparticle suspensions investigated by magnetorelaxometry

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 Neel 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.

Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

UNLABELLED To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

How the size distribution of magnetic nanoparticles determines their magnetic particle imaging performance

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.

Cross-validation of microfabricated atomic magnetometers with superconducting quantum interference devices for biomagnetic applications

We compare the performance of a chip-scale atomic magnetometer (CSAM) with that of a superconducting quantum interference device (SQUID) sensor in two biomedical applications. Magnetocardiograms (MCGs) of healthy human subjects were measured simultaneously by a CSAM and a multichannel SQUID sensor in a magnetically shielded room. The typical features of MCGs are resolved by the CSAM, matching the SQUID results. Magnetorelaxometry (MRX) signals of iron nanoparticles were also obtained with the CSAM and compared to similar measurements with a SQUID.

Magnetorelaxometry Assisting Biomedical Applications of Magnetic Nanoparticles

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.

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.

Quantification of specific bindings of biomolecules by magnetorelaxometry

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.

Magnetized Aerosols Comprising Superparamagnetic Iron Oxide Nanoparticles Improve Targeted Drug and Gene Delivery to the Lung

ABSTRACTPurposeTargeted delivery of aerosols could not only improve efficacy of inhaled drugs but also reduce side effects resulting from their accumulation in healthy tissue. Here we investigated the impact of magnetized aerosols on model drug accumulation and transgene expression in magnetically targeted lung regions of unanesthetized mice.MethodsSolutions containing superparamagnetic iron oxide nanoparticles (SPIONs) and model drugs (fluorescein or complexed plasmid DNA) were nebulized to unanesthetized mice under the influence of an external magnetic gradient directed to the lungs. Drug accumulation and transgene expression was subsequently measured at different time points.ResultsWe could demonstrate 2–3 fold higher accumulation of the model drug fluorescein and specific transgene expression in lung regions of mice which had been exposed to an external magnetic gradient during nebulization compared to the control mice without any exposure to magnetic gradient.ConclusionsMagnetized aerosols present themselves as an efficient approach for targeted pulmonary delivery of drugs and gene therapeutic agents in order to treat localized diseases of the deeper airways.

Magnetic nanoparticle imaging by means of minimum norm estimates from remanence measurements

In magnetic nanoparticle imaging, magnetic nanoparticles are coated and functionalized to bind to specific targets. After measuring their magnetic relaxation or remanence, their distribution can be determined by means of inverse methods. The reconstruction algorithm presented in this paper includes first a dipole fit using a Levenberg–Marquardt optimizer to determine the reconstruction plane. Secondly, a minimum norm estimate is obtained on a regular grid placed in that plane. Computer simulations involving different parameter sets and conditions show that the used approach allows for the reconstruction of distributed sources, although the reconstructed shapes are distorted by blurring effects. The reconstruction quality depends on the signal-to-noise ratio of the measurements and decreases with larger sensor-source distances and higher grid spacings. In phantom measurements, the magnetic remanence of nanoparticle columns with clinical relevant sizes is determined with two common measurement systems. The reconstructions from these measurements indicate that the approach is applicable for clinical measurements. Our results provide parameter sets for successful application of minimum norm approaches to Magnetic Nanoparticle Imaging.