Quantification of Lipoprotein Uptake in Vivo Using Magnetic Particle Imaging and Spectroscopy.

Lipids are a major source of energy for most tissues, and lipid uptake and storage is therefore crucial for energy homeostasis. So far, quantification of lipid uptake in vivo has primarily relied on radioactive isotope labeling, exposing human subjects or experimental animals to ionizing radiation. Here, we describe the quantification of in vivo uptake of chylomicrons, the primary carriers of dietary lipids, in metabolically active tissues using magnetic particle imaging (MPI) and magnetic particle spectroscopy (MPS). We show that loading artificial chylomicrons (ACM) with iron oxide nanoparticles (IONPs) enables rapid and highly sensitive post hoc detection of lipid uptake in situ using MPS. Importantly, by utilizing highly magnetic Zn-doped iron oxide nanoparticles (ZnMNPs), we generated ACM with MPI tracer properties superseding the current gold-standard, Resovist, enabling quantification of lipid uptake from whole-animal scans. We focused on brown adipose tissue (BAT), which dissipates heat and can consume a large part of nutrient lipids, as a model for tightly regulated and inducible lipid uptake. High BAT activity in humans correlates with leanness and improved cardiometabolic health. However, the lack of nonradioactive imaging techniques is an important hurdle for the development of BAT-centered therapies for metabolic diseases such as obesity and type 2 diabetes. Comparison of MPI measurements with iron quantification by inductively coupled plasma mass spectrometry revealed that MPI rivals the performance of this highly sensitive technique. Our results represent radioactivity-free quantification of lipid uptake in metabolically active tissues such as BAT.

Characterization of noise and background signals in a magnetic particle imaging system.

Magnetic particle imaging (MPI) is a novel technology, which opens new possibilities for promising biomedical applications. MPI uses magnetic fields to generate a specific response from magnetic nanoparticles (MNPs), to determine their spatial location non-invasively and without using ionizing radiation. One open challenge of MPI is to achieve further improvements in terms of sensitivity to translate the currently preclinical performed research into clinical applications. In this work, we study the noise and background signals of our preclinical MPI system, to identify and characterize disturbing signal contributions. The current limit of detection achieved with our device was determined previously to be20ng of iron. Based on the results presented in this work, we describe possible hardware and software improvements and estimate that the limit of detection could be lowered to about 1-2 ng. Additionally, a long-term analysis of the scanner performance over the last 3 years is presented, which proved to be an easy and effective way to monitor possible changes or damage of hardware components. All the presented results were obtained by analysing empty scanner measurements and the presented methodology can easily be adapted for different scanner types, to compare their performances.

Lissajous scanning magnetic particle imaging as a multifunctional platform for magnetic hyperthermia therapy.

The use of engineered nanoscale magnetic materials in healthcare and biomedical technologies is rapidly growing. Two examples which have recently attracted significant attention are magnetic particle imaging (MPI) for biological monitoring, and magnetic field hyperthermia (MFH) for cancer therapy. Here for the first time, the capability of a Lissajous scanning MPI device to act as a standalone platform to support the application of MFH cancer treatment is presented. The platform is shown to offer functionalities for nanoparticle localization, focused hyperthermia therapy application, and non-invasive tissue thermometry in one device. Combined, these capabilities have the potential to significantly enhance the accuracy, effectiveness and safety of MFH therapy. Measurements of nanoparticle hyperthermia during protracted exposure to the MPI scanner's 3D imaging field sequence revealed spatially focused heating, with a maximum that is significantly enhanced compared with a simple 1-dimensional sinusoidal excitation. The observed spatial heating behavior is qualitatively described based on a phenomenological model considering torques exerted in the Brownian regime. In vitro cell studies using a human acute monocytic leukemia cell line (THP-1) demonstrated strong suppression of both structural integrity and metabolic activity within 24 h following a 40 min MFH treatment actuated within the Lissajous MPI scanner. Furthermore, reconstructed MPI images of the nanoparticles distributed among the cells, and the temperature-sensitivity of the MPI imaging signal obtained during treatment are demonstrated. In summary, combined Lissajous MPI and MFH technologies are presented; demonstrating for the first time their potential for cancer treatment with maximum effectiveness, and minimal collateral damage to surrounding tissues.

Ex vivo magnetic particle imaging of vascular inflammation in abdominal aortic aneurysm in a murine model.

Abdominal aortic aneurysms (AAAs) are currently one of the leading causes of death in developed countries. Inflammation is crucial in the disease progression, having a substantial impact on various determinants in AAAs development. Magnetic particle imaging (MPI) is an innovative imaging modality, enabling the highly sensitive detection of magnetic nanoparticles (MNPs), suitable as surrogate marker for molecular targeting of vascular inflammation. For this study, Apolipoprotein E-deficient-mice underwent surgical implantation of osmotic minipumps with constant Angiotensin II infusion. After 3 and 4 weeks respectively, in-vivo-magnetic resonance imaging (MRI), ex-vivo-MPI and ex-vivo-magnetic particle spectroscopy (MPS) were performed. The results were validated by histological analysis, immunohistology and laser ablation-inductively coupled plasma-mass spectrometry. MR-angiography enabled the visualization of aneurysmal development and dilatation in the experimental group. A close correlation (R = 0.87) with histological area assessment was measured. Ex-vivo-MPS revealed abundant iron deposits in AAA samples and ex-vivo histopathology measurements were in good agreement (R = 0.76). Ex-vivo-MPI and MPS results correlated greatly (R = 0.99). CD68-immunohistology stain and Perls'-Prussian-Blue-stain confirmed the colocalization of macrophages and MNPs. This study demonstrates the feasibility of ex-vivo-MPI for detecting inflammation in AAA. The quantitative ability for mapping MNPs establishes MPI as a promising tool for monitoring inflammatory progression in AAA in an experimental setting.

Cellular uptake of magnetic nanoparticles imaged and quantified by magnetic particle imaging.

Magnetic particle imaging (MPI) is a non-invasive, non-ionizing imaging technique for the visualization and quantification of magnetic nanoparticles (MNPs). The technique is especially suitable for cell imaging as it offers zero background contribution from the surrounding tissue, high sensitivity, and good spatial and temporal resolutions. Previous studies have demonstrated that the dynamic magnetic behaviour of MNPs changes during cellular binding and internalization. In this study, we demonstrate how this information is encoded in the MPI imaging signal. Through MPI imaging we are able to discriminate between free and cell-bound MNPs in reconstructed images. This technique was used to image and quantify the changes that occur in-vitro when free MNPs come into contact with cells and undergo cellular-uptake over time. The quantitative MPI results were verified by colorimetric measurements of the iron content. The results showed a mean relative difference between the MPI results and the reference method of 23.8% for the quantification of cell-bound MNPs. With this technique, the uptake of MNPs in cells can be imaged and quantified directly from the first MNP cell contact, providing information on the dynamics of cellular uptake.

Continuously manufactured single-core iron oxide nanoparticles for cancer theranostics as valuable contribution in translational research.

Micromixer technology was used to manufacture magnetic single core iron oxide nanoparticles that combine imaging as well as therapeutic functions. In a continuous, scalable and highly controllable manner, synthesis with biocompatible educts via an aqueous synthesis route was performed. Size control by varying relevant process parameters e.g. temperature was confirmed by transmission electron microscopy measurements of experimental series demonstrating the exceptional size control and homogeneity. Furthermore, analytical centrifugation evidenced the stably dispersed state of the single core nanoparticles in aqueous media. Size controlled production of single-core iron oxide nanoparticles was used to design optimized nanoparticles with a core diameter of about 30 nm, showing high signal amplitudes in Magnetic Particle Imaging (MPI) as a promising MPI tracer material. Moreover, therapeutic potential of these particles in magnetic fluid hyperthermia was evaluated and specific absorption rates (SAR values) up to 1 kW per g(Fe) were obtained, which exceed the comparable SAR value of Resovist® by more than a factor of three. Relaxometry measurements clearly confirmed the capacity of these single-core magnetic nanoparticles to generate significant T 2-weighted magnetic resonance imaging (MRI) contrast that potentially allows multimodal imaging for monitoring the particles in vivo in a theranostic application scenario. Finally, first cell viability and apoptosis tests on endothelial cells did not show any cytotoxicity certifying a good biocompatibility of the iron oxide nanoparticles. This microtechnological approach provides reproducible, scalable single core iron oxide nanoparticles as highly performing tracers for MPI diagnosis as well as efficient heat generators for hyperthermia therapy. These preliminary results contribute to translational research in image guided cancer therapy - a further step from basic research to future medicine.

Improved sensitivity and limit-of-detection using a receive-only coil in magnetic particle imaging.

Magnetic particle imaging (MPI) is an imaging modality capable of quantitatively determining the 3D distribution of a magnetic nanoparticle (MNP) ensemble. In this work, we present a method for reducing the MNP limit of detection by employing a new receive-only coil (Rx-coil) for signal acquisition. The new signal detector is designed to improve the sensitivity and thus quality of reconstructed images. We present characterization measurements conducted with the prototype Rx-coil installed in a preclinical MPI scanner. The gradiometric design of the Rx-coil attenuates the unwanted signal contributions arising from the excitation field, leading to a 17 dB lower background level compared to the conventional dual-purpose coil (TxRx-coil), which is crucial for detecting low amounts of MNP. Network analyzer measurements of the frequency-dependent coil sensitivity, as well as spectral analysis of recorded MPI data demonstrate an overall increase of the coil sensitivity of about +12 dB for the Rx-coil. Comparisons of the sensitivity distributions revealed no significant degradations in terms of homogeneity for the Rx-coil compared to the TxRx-coil in an imaging volume of 6 × 3 × 3 cm3. Finally, the limit of detection was determined experimentally for each coil type using a serial dilution of MNPs, resulting in values of 133 ng of iron for the conventional TxRx-coil and 20 ng for the new Rx-coil, using an acquisition time of 2 s. A linear relationship between the reconstructed signal intensities and the iron mass in the samples was observed with coefficients of determination (R2) of above 99% in the range of the limit of detection to 3 103ng(Fe). These results open the way for improved image quality and faster acquisition time in pre-clinical MPI scanners.