Roadmap on magnetic nanoparticles in nanomedicine.

Magnetic nanoparticles (MNPs) represent a class of small particles typically with diameters ranging from 1 to 100 nanometers. These nanoparticles are composed of magnetic materials such as iron, cobalt, nickel, or their alloys. The nanoscale size of MNPs gives them unique physicochemical (physical and chemical) properties not found in their bulk counterparts. Their versatile nature and unique magnetic behavior make them valuable in a wide range of scientific, medical, and technological fields. Over the past decade, there has been a significant surge in MNP-based applications spanning biomedical uses, environmental remediation, data storage, energy storage, and catalysis. Given their magnetic nature and small size, MNPs can be manipulated and guided using external magnetic fields. This characteristic is harnessed in biomedical applications, where these nanoparticles can be directed to specific targets in the body for imaging, drug delivery, or hyperthermia treatment. Herein, this roadmap offers an overview of the current status, challenges, and advancements in various facets of MNPs. It covers magnetic properties, synthesis, functionalization, characterization, and biomedical applications such as sample enrichment, bioassays, imaging, hyperthermia, neuromodulation, tissue engineering, and drug/gene delivery. However, as MNPs are increasingly explored for in vivo applications, concerns have emerged regarding their cytotoxicity, cellular uptake, and degradation, prompting attention from both researchers and clinicians. This roadmap aims to provide a comprehensive perspective on the evolving landscape of MNP research.

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.

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×.

Temperature-Dependent Changes in Resolution and Coercivity of Superparamagnetic and Superferromagnetic Iron Oxide Nanoparticles.

Magnetic Particle Imaging (MPI) is a tracer-based imaging modality with immense promise as a radiation-free alternative to nuclear medicine imaging techniques. Nuclear medicine requires "hot chemistry" wherein radioactive tracers must be synthesized on-site, requiring expensive infrastructure and labor costs. MPI's magnetic nanoparticles, superparamagnetic iron oxide nanoparticles (SPIOs), have no significant signal decay over time which removes cost barriers associated with nuclear medicine studies such as FDG-PET. While SPIOs are the current industry standard MPI tracer, recent developments in synthesizing superferromagnetic iron oxide nanoparticles (SFMIOs) and high resolution SPIOs (HR-SPIOs), a new class of nanoparticle with almost zero coercivity, have yielded a 30-fold improvement in resolution (0.4 mT) and SNR. To better understand the long-term performance of these new nanoparticles, this investigation reports changes in SPIO (VivoTrax Plus), HR-SPIO, and SFMIO resolution, along with SFMIO coercivity, at low temperatures (-2, 2 °C) and room temperature (18-22 °C) over 12 weeks. We find that changes in HR-SPIO resolution are more sensitive to storage temperature than SFMIOs. Additionally, we observe no appreciable difference in SFMIO coercivity between the two temperatures over time. These results can inform research on optimizing tracer synthesis while lending practical information to future hospitals about the highly accessible conditions for the transit and storage of tracers.

Non-radioactive and sensitive tracking of neutrophils towards inflammation using antibody functionalized magnetic particle imaging tracers.

White blood cells (WBCs) are a key component of the mammalian immune system and play an essential role in surveillance, defense, and adaptation against foreign pathogens. Apart from their roles in the active combat of infection and the development of adaptive immunity, immune cells are also involved in tumor development and metastasis. Antibody-based therapeutics have been developed to regulate (i.e. selectively activate or inhibit immune function) and harness immune cells to fight malignancy. Alternatively, non-invasive tracking of WBC distribution can diagnose inflammation, infection, fevers of unknown origin (FUOs), and cancer. Magnetic Particle Imaging (MPI) is a non-invasive, non-radioactive, and sensitive medical imaging technique that uses safe superparamagnetic iron oxide nanoparticles (SPIOs) as tracers. MPI has previously been shown to track therapeutic stem cells for over 87 days with a ~200 cell detection limit. In the current work, we utilized antibody-conjugated SPIOs specific to neutrophils for in situ labeling, and non-invasive and radiation-free tracking of these inflammatory cells to sites of infection and inflammation in an in vivo murine model of lipopolysaccharide-induced myositis. MPI showed sensitive detection of inflammation with a contrast-to-noise ratio of ~8-13.

Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications.

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.

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.