Pulsed MPI Relaxometry of Brownian and Néel Field-Dependent Relaxation in Superparamagnetic Magnetite Nanoparticles Confirm Theory and Simulations.

Superparamagnetic iron oxide nanoparticles (SPIOs) are used as tracers in Magnetic Particle Imaging (MPI). It is crucial to understand the magnetic properties of SPIOs for optimizing MPI imaging contrast, resolution, and sensitivity. Brownian and Néel relaxation theory developed in the early 1950s posits that relaxation times can vary with particle size, shell thickness, medium viscosity, and the applied field strength. Magnetic relaxation can soon provide a unique imaging capability, the ability to distinguish bound from unbound MPI tracers in vivo. Yet experimental validation of these theories has not been completed. In this paper, a novel method of pulsed magnetic field relaxometry is used to directly probe the relaxation behavior of superparamagnetic magnetite nanoparticles over a spectrum of magnetic field amplitudes, providing the first experimental validation of theoretical relaxation models. It is also shown that closed-form approximations generated in the early 1970s accurately match both data and numerical Fokker Planck computational models, which are computationally burdensome. This means researchers can trust these approximations for future modeling. All the findings can be translated to sinusoidal excitations used in conventional MPI scanning trajectories.

Shape Anisotropy-Governed High-Performance Nanomagnetosol for In Vivo Magnetic Particle Imaging of Lungs.

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI. Here, a high-performance nanotracer based on shape anisotropy of magnetic nanoparticles is developed and its use in MPI imaging of the lung is demonstrated. Shape anisotropy proves to be a critical parameter for increasing signal intensity and resolution and exceeding those properties of conventional spherical nanoparticles. The 0D nanoparticles exhibit a 2-fold increase, while the 1D nanorods have a > 5-fold increase in signal intensity when compared to VivoTrax. Newly designed 1D nanorods displayed high signal intensities and excellent resolution in lung images. A spatiotemporal lung imaging study in mice revealed that this tracer offers new opportunities for monitoring disease and guiding intervention.

Adhesion molecule-targeted magnetic particle imaging nanoprobe for visualization of inflammation in acute lung injury.

PURPOSE: Uncontrolled intra-alveolar inflammation is a central pathogenic feature, and its severity translates into a valid prognostic indicator of acute lung injury (ALI). Unfortunately, current clinical imaging approaches are unsuitable for visualizing and quantifying intra-alveolar inflammation. This study aimed to construct a small-sized vascular cell adhesion molecule-1 (VCAM-1)-targeted magnetic particle imaging (MPI) nanoprobe (ESPVPN) to visualize and accurately quantify intra-alveolar inflammation at the molecular level. METHODS: ESPVPN was engineered by conjugating a peptide (VHPKQHRGGSK(Cy7)GC) onto a polydopamine-functionalized superparamagnetic iron oxide core. The MPI performance, targeting, and biosafety of the ESPVPN were characterized. VCAM-1 expression in HUVECs and mouse models was evaluated by western blot. The degree of inflammation and distribution of VCAM-1 in the lungs were assessed using histopathology. The expression of pro-inflammatory markers and VCAM-1 in lung tissue lysates was measured using ELISA. After intravenous administration of ESPVPN, MPI and CT imaging were used to analyze the distribution of ESPVPN in the lungs of the LPS-induced ALI models. RESULTS: The small-sized (~10 nm) ESPVPN exhibited superior MPI performance compared to commercial MagImaging® and Vivotrax, and ESPVPN had effective targeting and biosafety. VCAM-1 was highly expressed in LPS-induced ALI mice. VCAM-1 expression was positively correlated with the LPS-induced dose (R = 0.9381). The in vivo MPI signal showed positive correlations with both VCAM-1 expression (R = 0.9186) and representative pro-inflammatory markers (MPO, TNF-α, IL-6, IL-8, and IL-1ß, R > 0.7). CONCLUSION: ESPVPN effectively targeted inflammatory lungs and combined the advantages of MPI quantitative imaging to visualize and evaluate the degree of ALI inflammation.

Machine Learning and Deep Learning Applications in Magnetic Particle Imaging.

In recent years, magnetic particle imaging (MPI) has emerged as a promising imaging technique depicting high sensitivity and spatial resolution. It originated in the early 2000s where it proposed a new approach to challenge the low spatial resolution achieved by using relaxometry in order to measure the magnetic fields. MPI presents 2D and 3D images with high temporal resolution, non-ionizing radiation, and optimal visual contrast due to its lack of background tissue signal. Traditionally, the images were reconstructed by the conversion of signal from the induced voltage by generating system matrix and X-space based methods. Because image reconstruction and analyses play an integral role in obtaining precise information from MPI signals, newer artificial intelligence-based methods are continuously being researched and developed upon. In this work, we summarize and review the significance and employment of machine learning and deep learning models for applications with MPI and the potential they hold for the future. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 1.

Integration of photomagnetic bimodal imaging to monitor an autogenous exosome loaded platform: unveiling strong targeted retention effects for guiding the photothermal and magnetothermal therapy in a mouse prostate cancer model.

BACKGROUND: Prostate cancer (PCa) is the most prevalent cancer among males, emphasizing the critical need for precise diagnosis and treatment to enhance patient prognosis. Recent studies have extensively utilized urine exosomes from patients with cancer for targeted delivery. This study aimed to employ highly sensitive magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor the targeted delivery of an exosome-loaded platform at the tumour site, offering insights into a potential combined photothermal and magnetic thermal therapy regime for PCa. RESULTS: MPI and FMI were utilized to monitor the in vivo retention performance of exosomes in a prostate tumour mouse model. The exosome-loaded platform exhibited robust homologous targeting ability during imaging (SPIONs@EXO-Dye:66·48%±3·85%; Dye-SPIONs: 34·57%±7·55%, **P<0·01), as verified by in vitro imaging and in vitro tissue Prussian blue staining. CONCLUSIONS: The experimental data underscore the feasibility of using MPI for in vivo PCa imaging. Furthermore, the exosome-loaded platform may contribute to the precise diagnosis and treatment of PCa.

A Novel Field-Free Line Generator for Mechanically Scanned Magnetic Particle Imaging.

In this study, we propose an efficient field-free line (FFL) generator for mechanically driven FFL magnetic particle imaging (MPI) applications. The novel FFL generator comprises pairs of Halbach arrays and bar magnets. The proposed design generates high-gradient FFLs with low-mass permanent magnets, realizing fine spatial resolutions in MPI. We investigate the magnetic field generated using simulations and experiments. Our results show that the FFL generator yields a high gradient of 4.76 T/m at a cylindrical field of view of 30 mm diameter and a 70 mm open bore. A spatial resolution of less than 3.5 mm was obtained in the mechanically driven FFL-MPI.

First Superferromagnetic Remanence Characterization and Scan Optimization for Super-Resolution Magnetic Particle Imaging.

Magnetic particle imaging (MPI) is a sensitive, high-contrast tracer modality that images superparamagnetic iron oxide nanoparticles, enabling radiation-free theranostic imaging. MPI resolution is currently limited by scanner and particle constraints. Recent tracers have experimentally shown 10× resolution and signal improvements with dramatically sharper M-H curves. Experiments show a dependence on interparticle interactions, conforming to literature definitions of superferromagnetism. We thus call our tracers superferromagnetic iron oxide nanoparticles (SFMIOs). While SFMIOs provide excellent signal and resolution, they exhibit hysteresis with non-negligible remanence and coercivity. We provide the first quantitative measurements of SFMIO remanence decay and reformation using a novel multiecho pulse sequence. We characterize MPI scanning with remanence decay and coercivity and describe an SNR-optimized pulse sequence for SFMIOs under human electromagnetic safety limitations. The resolution from SFMIOs could enable clinical MPI with 10× reduced scanner selection fields, reducing hardware costs by up to 100×.

SMART RHESINs-Superparamagnetic Magnetite Architecture Made of Phenolic Resin Hollow Spheres Coated with Eu(III) Containing Silica Nanoparticles for Future Quantitative Magnetic Particle Imaging Applications.

Magnetic particle imaging (MPI) is a powerful and rapidly growing tomographic imaging technique that allows for the non-invasive visualization of superparamagnetic nanoparticles (NPs) in living matter. Despite its potential for a wide range of applications, the intrinsic quantitative nature of MPI has not been fully exploited in biological environments. In this study, a novel NP architecture that overcomes this limitation by maintaining a virtually unchanged effective relaxation (Brownian plus Néel) even when immobilized is presented. This superparamagnetic magnetite architecture made of phenolic resin hollow spheres coated with Eu(III) containing silica nanoparticles (SMART RHESINs) was synthesized and studied. Magnetic particle spectroscopy (MPS) measurements confirm their suitability for potential MPI applications. Photobleaching studies show an unexpected photodynamic due to the fluorescence emission peak of the europium ion in combination with the phenol formaldehyde resin (PFR). Cell metabolic activity and proliferation behavior are not affected. Colocalization experiments reveal the distinct accumulation of SMART RHESINs near the Golgi apparatus. Overall, SMART RHESINs show superparamagnetic behavior and special luminescent properties without acute cytotoxicity, making them suitable for bimodal imaging probes for medical use like cancer diagnosis and treatment. SMART RHESINs have the potential to enable quantitative MPS and MPI measurements both in mobile and immobilized environments.

Sensitive and quantitative in vivo analysis of PD-L1 using magnetic particle imaging and imaging-guided immunotherapy.

PURPOSE: The programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) expression correlate with the immunotherapeutic response rate. The sensitive and non-invasive imaging of immune checkpoint biomarkers is favorable for the accurate detection and characterization, image-guided immunotherapy in cancer precision medicine. Magnetic particle imaging (MPI), as a novel and emerging imaging modality, possesses the advantages of high sensitivity, no image depth limitation, positive contrast, and absence of radiation. Hence, in this study, we performed the pioneer investigation of monitoring PD-L1 expression using MPI and the MPI-guided immunotherapy. METHODS: We developed anti-PD-L1 antibody (aPDL1)-conjugated magnetic fluorescent hybrid nanoparticles (MFNPs-aPDL1) and utilized MPI in combination with fluorescence imaging (FMI) to dynamically monitor and quantify PD-L1 expression in various tumors with different PD-L1 expression levels. The ex vivo real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescence staining analysis were further performed to validate the in vivo imaging observation. Moreover, the MPI was further performed for the guidance of immunotherapy. RESULTS: Our data showed that PD-L1 expression can be specifically and sensitively monitored and quantified using MPI and FMI imaging methods, which were validated by ex vivo qPCR and western blotting analysis. In addition, MPI-guided PD-L1 immunotherapy can enhance the effectiveness of cancer immunotherapy. CONCLUSION: To our best knowledge, this is the pioneer study to utilize MPI in combination with a newly developed MFNPs-aPDL1 imaging probe to dynamically visualize and quantify PD-L1 expression in tumor microenvironment. This imaging strategy may facilitate the clinical optimization of immunotherapy management.

Magnetic Particle Imaging of Magnetotactic Bacteria as Living Contrast Agents Is Improved by Altering Magnetosome Arrangement.

Superparamagnetic iron oxide nanoparticles (SPIONs) can be used as imaging agents to differentiate between normal and diseased tissue or track cell movement. Magnetic particle imaging (MPI) detects the magnetic properties of SPIONs, providing quantitative and sensitive image data. MPI performance depends on the size, structure, and composition of nanoparticles. Magnetotactic bacteria produce magnetosomes with properties similar to those of synthetic nanoparticles, and these can be modified by mutating biosynthetic genes. The use of Magnetospirillum gryphiswaldense, MSR-1 with a mamJ deletion, containing clustered magnetosomes instead of typical linear chains, resulted in improved MPI signal and resolution. Bioluminescent MSR-1 with the mamJ deletion were administered into tumor-bearing and healthy mice. In vivo bioluminescence imaging revealed the viability of MSR-1, and MPI detected signals in livers and tumors. The development of living contrast agents offers opportunities for imaging and therapy with multimodality imaging guiding development of these agents by tracking the location, viability, and resulting biological effects.

In Vivo Cellular Magnetic Imaging: Labeled vs. Unlabeled Cells.

Superparamagnetic iron oxide (SPIO)-labeling of cells has been applied for magnetic resonance imaging (MRI) cell tracking for over 30 years, having resulted in a dozen or so clinical trials. SPIO nanoparticles are biodegradable and can be broken down into elemental iron, and hence the tolerance of cells to magnetic labeling has been overall high. Over the years, however, single reports have accumulated demonstrating that the proliferation, migration, adhesion and differentiation of magnetically labeled cells may differ from unlabeled cells, with inhibition of chondrocytic differentiation of labeled human mesenchymal stem cells (hMSCs) as a notable example. This historical perspective provides an overview of some of the drawbacks that can be encountered with magnetic labeling. Now that magnetic particle imaging (MPI) cell tracking is emerging as a new in vivo cellular imaging modality, there has been a renaissance in the formulation of SPIO nanoparticles this time optimized for MPI. Lessons learned from the occasional past pitfalls encountered with SPIO-labeling of cells for MRI may expedite possible future clinical translation of (combined) MRI/MPI cell tracking.

Sensitive and specific detection of breast cancer lymph node metastasis through dual-modality magnetic particle imaging and fluorescence molecular imaging: a preclinical evaluation.

PURPOSE: A sensitive and specific imaging method to detect metastatic cancer cells in lymph nodes to detect the early-stage breast cancer is still a challenge. The purpose of this study was to investigate a novel breast cancer-targeting and tumour microenvironment ATP-responsive superparamagnetic iron oxide nanoparticles (SPIOs) imaging probe (abbreviated as SPIOs@A-T) that was developed to detect lymph node metastasis through fluorescence molecular imaging (FMI) and magnetic particle imaging (MPI). METHODS: The conjugation of the targeted peptide CREKA and SPIOs was via linker sulfo-SMCC, while the dsDNA-Cy5.5 was modified on SPIOs through the conjugation between maleimide group in sulfo-SMCC and sulfydryl group in dsDNA-Cy5.5. SPIOs@A-T was characterised for its imaging properties, targeting ability and toxicity in vitro. Mice with metastatic lymph node (MLN) of breast cancer were established to evaluate the FMI and MPI imaging strategy in vivo. Healthy mice with normal lymph node (NLN) were used as control group. Histological examination and biosafety evaluation were performed for further assessment. RESULTS: After injection with SPIOs@A-T, the obvious high fluorescent intensity and MPI signal were observed in MLN group than those in NLN group. FMI can specifically light up MLN using an ATP-responsive fluorescence design. On the other hand, MPI could complement the limitation of imaging depth from FMI and could detect MLN more sensitively. Besides, the biosafety evaluation results showed SPIOs@A-T had no detectable biological toxicity. CONCLUSION: SPIOs@A-T imaging probe in combination with FMI and MPI can provide a promising novel method for the precise detection of MLN in vivo.

Mixed Metal Metal-Organic Frameworks Derived Carbon Supporting ZnFe2O4/C for High-Performance Magnetic Particle Imaging.

Recently, magnetic particle imaging (MPI) has shown diverse biomedical applications such as cell tracking, lung perfusion, image-guided hyperthermia, and so forth. However, the currently reported MPI agents cannot achieve the possible theoretical detection limit of MPI (20 nM). A previous theoretical study has shown that the MPI performance of superparamagnetic iron oxide nanoparticles (SPIONs) can be enhanced by carbon supporting and metal doping. In the current study, a series of mixed metal metal-organic framework-derived carbon supporting SPIONs were synthesized by pyrolysis. Among the synthesized SPIONs, the MPI signal intensity of ZnFe2O4/C@PDA was found to be 4.7 times higher than the commercial MPI contrast (Vivotrax) having the same Fe concentration. ZnFe2O4/C@PDA also showed the highest MPI intensity in tumor-bearing-mice among all tested samples. Furthermore, they were found highly biocompatible and showed linear cell quantification. This work can open new avenues for the design and development of novel and high-performance MPI agents.

1D imaging of a superparamagnetic iron oxide nanoparticle distribution by a single-sided FFL magnetic particle imaging scanner.

Magnetic Particle Imaging (MPI) is an emerging imaging modality that has a potential of complimenting other imaging modalities in clinical practice. Despite many efforts to scale up MPI hardware to date no MPI systems have been demonstrated to accommodate full body imaging. Previously, we introduced hardware and characterized a prototype of a single-sided MPI scanner, where all coils are confined to a single-side of the device, which provides a subject with unrestricted access to the scanning area although with a limited penetration depth. The major difference in our design from the first reported single-sided scanner is in incorporating a field-free line instead of a field-free point, which generally promises higher sensitivity and more robust image reconstruction. However, as inherent to any single-sided configurations the fields in our device are spatially inhomogeneous making it challenging to apply existing imaging techniques. For our specific geometry we implemented spatial encoding scheme and imaging in time-domain making the image reconstruction fast. In this work we present one dimensional imaging of multiple rods phantoms with a single-sided field-free line MPI scanner. The results demonstrate that our scanner is capable of one dimensional imaging of phantoms with a spatial resolution of at least 7 mm without image processing.

Magnetic Particle Imaging: Current and Future Applications, Magnetic Nanoparticle Synthesis Methods and Safety Measures.

Magnetic nanoparticles (MNPs) have a wide range of applications; an area of particular interest is magnetic particle imaging (MPI). MPI is an imaging modality that utilizes superparamagnetic iron oxide particles (SPIONs) as tracer particles to produce highly sensitive and specific images in a broad range of applications, including cardiovascular, neuroimaging, tumor imaging, magnetic hyperthermia and cellular tracking. While there are hurdles to overcome, including accessibility of products, and an understanding of safety and toxicity profiles, MPI has the potential to revolutionize research and clinical biomedical imaging. This review will explore a brief history of MPI, MNP synthesis methods, current and future applications, and safety concerns associated with this newly emerging imaging modality.

Albumin-Coated Single-Core Iron Oxide Nanoparticles for Enhanced Molecular Magnetic Imaging (MRI/MPI).

Colloidal stability of magnetic iron oxide nanoparticles (MNP) in physiological environments is crucial for their (bio)medical application. MNP are potential contrast agents for different imaging modalities such as magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). Applied as a hybrid method (MRI/MPI), these are valuable tools for molecular imaging. Continuously synthesized and in-situ stabilized single-core MNP were further modified by albumin coating. Synthesizing and coating of MNP were carried out in aqueous media without using any organic solvent in a simple procedure. The additional steric stabilization with the biocompatible protein, namely bovine serum albumin (BSA), led to potential contrast agents suitable for multimodal (MRI/MPI) imaging. The colloidal stability of BSA-coated MNP was investigated in different sodium chloride concentrations (50 to 150 mM) in short- and long-term incubation (from two hours to one week) using physiochemical characterization techniques such as transmission electron microscopy (TEM) for core size and differential centrifugal sedimentation (DCS) for hydrodynamic size. Magnetic characterization such as magnetic particle spectroscopy (MPS) and nuclear magnetic resonance (NMR) measurements confirmed the successful surface modification as well as exceptional colloidal stability of the relatively large single-core MNP. For comparison, two commercially available MNP systems were investigated, MNP-clusters, the former liver contrast agent (Resovist), and single-core MNP (SHP-30) manufactured by thermal decomposition. The tailored core size, colloidal stability in a physiological environment, and magnetic performance of our MNP indicate their ability to be used as molecular magnetic contrast agents for MPI and MRI.

Single-Sided Magnetic Particle Imaging Device with Field-Free-Line Geometry for in-vivo Imaging Applications.

Magnetic Particle Imaging (MPI) has shown great promise to surpass existing in vivo imaging modalities in some clinical applications. However, one of the challenges to MPI being translated into clinical practice has been the ability to scale up the selection field coils to surround a human body while being able to generate and drive a sufficiently strong magnetic field gradient. These requirements impose safety concerns as well as prohibitively high-power consumption in devices with large cylindrical volume. Therefore, we consider an alternative approach such as a single-sided topology, in which all the hardware is located on one side of the imaging volume accommodating larger subjects. Moreover, different from the previously implemented field-free point single-sided scanners, we realized a field-free line geometry providing, in principle, factor of ten higher signal and benefiting from a more robust back-projection image reconstruction technique. In this work, we present and characterize a first prototype of a single-sided MPI device with field-free-line geometry suited for in-vivo imaging of small animals as well as regions of interest in humans.

Magnetic Particle Imaging: Current Applications in Biomedical Research.

Magnetic particle imaging (MPI) is a new imaging modality with the potential for high-resolution imaging while retaining the noninvasive nature of other current modalities such as magnetic resonance imaging (MRI) and positron emission tomography (PET). It is able to track location and quantities of special superparamagnetic iron oxide nanoparticles without tracing any background signal. MPI utilizes the unique, intrinsic aspects of the nanoparticles: how they react in the presence of the magnetic field, and the subsequent turning off of the field. The current group of nanoparticles that are used in MPI are usually commercially available for MRI. Special MPI tracers are in development by many groups that utilize an iron-oxide core encompassed by various coatings. These tracers would solve the current obstacles by altering the size and material of the nanoparticles to what is required by MPI. In this review, the theory behind and the development of these tracers are discussed. In addition, applications such as cell tracking, oncology imaging, neuroimaging, and vascular imaging, among others, stemming from the implementation of MPI into the standard are discussed. Level of Evidence: 5 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2020;51:1659-1668.

Combining magnetic particle imaging and magnetic fluid hyperthermia for localized and image-guided treatment.

Magnetic fluid hyperthermia (MFH) has been widely investigated as a treatment tool for cancer and other diseases. However, focusing traditional MFH to a tumor deep in the body is not feasible because the in vivo wavelength of 300 kHz very low frequency (VLF) excitation fields is longer than 100 m. Recently we demonstrated that millimeter-precision localized heating can be achieved by combining magnetic particle imaging (MPI) with MFH. In principle, real-time MPI imaging can also guide the location and dosing of MFH treatments. Hence, the combination of MPI imaging plus real time localized MPI-MFH could soon permit closed-loop high-resolution hyperthermia treatment. In this review, we will discuss the fundamentals of localized MFH (e.g. physics and biosafety limitations), hardware implementation, MPI real-time guidance, and new research directions on MPI-MFH. We will also discuss how the scale up to human-sized MPI-MFH scanners could proceed.

Simultaneous Coercivity and Size Determination of Magnetic Nanoparticles.

Magnetic nanoparticles are increasingly employed in biomedical applications such as disease detection and tumor treatment. To ensure a safe and efficient operation of these applications, a noninvasive and accurate characterization of the particles is required. In this work, a magnetic characterization technique is presented in which the particles are excited by specific pulsed time-varying magnetic fields. This way, we can selectively excite nanoparticles of a given size so that the resulting measurement gives direct information on the size distribution without the need for any a priori assumptions or complex postprocessing procedures to decompose the measurement signal. This contrasts state-of-the-art magnetic characterization techniques. The possibility to selectively excite certain particle types opens up perspectives in "multicolor" particle imaging, where different particle types need to be imaged independently within one sample. Moreover, the presented methodology allows one to simultaneously determine the size-dependent coercivity of the particles. This is not only a valuable structure-property relation from a fundamental point of view, it is also practically relevant to optimize applications like magnetic particle hyperthermia. We numerically demonstrate that the novel characterization technique can accurately reconstruct several particle size distributions and is able to retrieve the coercivity-size relation of the particles. The developed technique advances current magnetic nanoparticle characterization possibilities and opens up exciting pathways for biomedical applications and particle imaging procedures.