Surface coatings are important components of Magnetic Particle Imaging (MPI) tracers – they preserve their key properties responsible for optimum tracer performance in physiological environments. In vivo, surface coatings form a physical barrier between the hydrophobic SPION cores and the physiological environment, and their design dictates the blood half-life and biodistribution of MPI tracers. Here we show the effect of tuning poly(ethylene glycol) (PEG)-based surface coatings on both in vitro and in vivo (mouse model) MPI performance of SPIONs. Our results showed that varying PEG molecular weight had a profound impact on colloidal stability, characterized using Dynamic Light Scattering (DLS), and the m’(H) response of SPIONs, measured in a 25 kHz/20 mTμ0−1max Magnetic Particle Spectrometer (MPS). Increasing PEG molecular weight from 5 kDa to 20 kDa preserved colloidal stability and m’(H) response of ~25 nm SPIONs – the optimum core diameter for MPI – in serum-rich cell culture medium for up to 24 hours. Furthermore, we compared the in vivo circulation time of SPIONs as a function of hydrodynamic diameter and showed that clustered SPIONs can adversely affect blood half-life; critically, SPIONs with clusters had 5 times shorter blood half-life than individually coated SPIONs. We anticipate that the development of MPI SPION tracers with long blood half-lives have potential not only in vascular imaging applications, but also enable opportunities in molecular targeting and imaging – a critical step towards early cancer detection using the new MPI modality.
Blood half-life; Magnetic Particle Imaging; Superparamagnetic Iron Oxide Nanoparticles
Magnetic particle imaging (MPI) is an attractive new modality for imaging distributions of iron oxide nanoparticle tracers in vivo. With exceptional contrast, high sensitivity, and good spatial resolution, MPI shows promise for clinical imaging in angiography and oncology. Critically, MPI requires high-quality iron oxide nanoparticle tracers with tailored magnetic and surface properties to achieve its full potential. In this review, we discuss optimizing iron oxide nanoparticles’ physical, magnetic, and pharmacokinetic properties for MPI, highlighting results from our recent work in which we demonstrated tailored, biocompatible iron oxide nanoparticle tracers that provided two times better linear spatial resolution and five times better signal-to-noise ratio than Resovist.
iron oxide nanoparticles; magnetic particle imaging; magnetic relaxation
Superparamagnetic iron oxide nanoparticles with highly nonlinear magnetic behavior are attractive for biomedical applications like magnetic particle imaging and magnetic fluid hyperthermia. Such particles display interesting magnetic properties in alternating magnetic fields and here we document experiments that show differences between the magnetization dynamics of certain particles in frozen and melted states. This effect goes beyond the small temperature difference (ΔT ~ 20 °C) and we show the dynamics to be a mixture of Brownian alignment of the particles and Néel rotation of their moments occurring in liquid particle suspensions. These phenomena can be modeled in a stochastic differential equation approach by postulating log-normal distributions and partial Brownian alignment of an effective anisotropy axis. We emphasize that precise particle-specific characterization through experiments and nonlinear simulations is necessary to predict dynamics in solution and optimize their behavior for emerging biomedical applications including magnetic particle imaging.
Using the thermal decomposition of organometallics method we have synthesized high-quality, iron oxide nanoparticles of tailorable size up to ~15nm and transferred them to a water phase by coating with a biocompatible polymer. The magnetic behavior of these particles was measured and fit to a log-normal distribution using the Chantrell method and their polydispersity was confirmed to be very narrow. By performing calorimetry measurements with these monodisperse particles we have unambiguously demonstrated, for the first time, that at a given frequency, heating rates of superparamagnetic particles are dependent on particle size, in agreement with earlier theoretical predictions.
Magnetic fluid hyperthermia; Nanoparticle; Magnetic relaxation; Superparmagnetism
Sensitivity and spatial resolution in Magnetic Particle Imaging are affected by magnetic properties of the nanoparticle tracers used during imaging. Here, we have carried out a comprehensive magnetic characterization of single-core iron oxide nanoparticles that were designed for MPI. We used ac susceptometry, fluxgate magnetorelaxometry, and magnetic particle spectroscopy to evaluate the tracer’s magnetic core size, hydrodynamic size, and magnetic anisotropy. Our results present a self-consistent set of magnetic and structural parameters for the tracers that is consistent with direct measurements of size using transmission electron microscopy and dynamic light scattering and that can be used to better understand their MPI performance.
The magnetic response of magnetic particle imaging (MPI) tracers varies with the slew rate of the applied magnetic field, as well as with the tracer's average magnetic core size. Currently, 25 kHz and 20 mT/μ0 drive fields are common in MPI, but lower field amplitudes may be necessary for patient safety in future designs. We studied how several different sizes of monodisperse MPI tracers behaved under different drive field amplitude and frequency, using magnetic particle spectrometry and ac hysteresis for drive field conditions at 16, 26, and 40 kHz, with field amplitudes from 5 to 40 mT/μ0. We observed that both field amplitude and frequency can influence the tracer behavior, but that the magnetic behavior is consistent when the slew rate (the product of field amplitude and frequency) is consistent. However, smaller amplitudes provide a correspondingly smaller field of view, sometimes resulting in excitation of a minor hysteresis loop.
AC hysteresis; iron oxide nanoparticles; magnetic particle imaging (MPI); magnetic particle spectrometry (MPS); MPI tracers
Magnetic Particle Imaging (MPI) shows promise for medical imaging, particularly in angiography of patients with chronic kidney disease. As the first biomedical imaging technique that truly depends on nanoscale materials properties, MPI requires highly optimized magnetic nanoparticle tracers to generate quality images. Until now, researchers have relied on tracers optimized for MRI T2*-weighted imaging that are suboptimal for MPI. Here, we describe new tracers tailored to MPI's unique physics, synthesized using an organic-phase process and functionalized to ensure biocompatibility and adequate in vivo circulation time. Tailored tracers showed up to 3x greater SNR and better spatial resolution than existing commercial tracers in MPI images of phantoms.
Magnetic Particle Imaging; biomedical imaging; superparamagnetic iron oxides
Magnetic particle imaging (MPI) is a promising medical imaging technology that uses iron oxide nanoparticles (NPs) as clinically safe tracers. The core and hydrodynamic size of these NPs determine the signal intensity and spatial resolution in MPI, whilst their monodispersity when preserved during the biomedical applications, generates a consistently high quality MPI image. Using an effective process to coat the synthesized NPs with amine terminated PEG molecules, we show by dynamic light scattering (DLS) that they are water-soluble with long-term stability in biological media such as phosphate buffered saline (PBS) and sodium bicarbonate buffers and Dulbecco’s modified Eagle medium (DMEM) enriched with 10% fetal bovine serum (FBS). Further, using magnetic particle spectroscopy (MPS), to measure the particle response function (PRF), defined as the derivative of the magnetization of the nanoparticles, we predict the MPI performance of these nanoparticles at a driving field frequency of 25 kHz. The MPS efficacy of the functionalized nanoparticles was also monitored over time, and both signal intensity and resolution remained unchanged even after seven days of incubation. This is attributed to the dominant contribution of the Néel relaxation mechanism of the monodisperse and highly stable nanoparticles, which was preserved through the incubation period.
Biomedical engineering; functionalization; iron oxide nanoparticles; magnetic particle imaging (MPI)
Magnetic relaxation is exploited in innovative biomedical applications of magnetic particles such as magnetic particle imaging (MPI), magnetic fluid hyperthermia, and bio-sensing. Relaxation behavior should be optimized to achieve high performance imaging, efficient heating, and good SNR in bio-sensing. Using two AC susceptometers with overlapping frequency ranges, we have measured the relaxation behavior of a series of monodisperse magnetic particles and demonstrated that this approach is an effective way to probe particle relaxation characteristics from a few Hz to 10 MHz, the frequencies relevant for MPI, hyperthermia, and sensing.
AC susceptometry; magnetic particle imaging; magnetic particles; magnetization reversal
Magnetic Particle Imaging (MPI) is a new biomedical imaging modality that produces real-time, high-resolution tomographic images of superparamagnetic iron oxide (SPIO) nanoparticle tracer distributions. In this study, we synthesized monodisperse tracers for enhanced MPI performance and investigated both, their blood clearance time using a 25 kHz magnetic particle spectrometer (MPS), and biodistribution using a combination of quantitative T2-weighted MRI and tissue histology. In vitro and in vivo MPI performance of our magnetic nanoparticle tracers (MNTs), subject to biological constraints, were compared to commercially available SPIOs (Resovist). Monodisperse MNTs showed a 2-fold greater signal per unit mass, and 20% better spatial resolution. In vitro evaluation of tracers showed that MPI performance of our MNTs is preserved in blood, serum-rich cell culture medium and gel; thus independent of changes in hydrodynamic volume and fluid viscosity – a critical prerequisite for in vivo MPI. In a rodent model, our MNTs circulated for 15 minutes – 3× longer than Resovist – and supported our in vitro evaluation that MPI signal is preserved in the physiological environment. Furthermore, MRI and histology analysis showed that MNTs distribute in the reticuloendothelial system (RES) in a manner similar to clinically approved SPIO agents. MNTs demonstrating long-circulation times and optimized MPI performance show potential as angiography tracers and blood-pool agents for the emerging MPI imaging modality.
Magnetic Fluid Hyperthermia (MFH) is a promising approach towards adjuvant cancer therapy that is based on the localized heating of tumors using the relaxation losses of iron oxide magnetic nanoparticles (MNPs) in alternating magnetic fields (AMF). In this study, we demonstrate optimization of MFH by tailoring MNP size to an applied AMF frequency. Unlike conventional aqueous synthesis routes, we use organic synthesis routes that offer precise control over MNP size (diameter ~ 10–25 nm), size distribution and phase purity. Furthermore, the particles are successfully transferred to the aqueous phase using a biocompatible amphiphilic polymer, and demonstrate long-term shelf life. A rigorous characterization protocol ensures that the water-stable MNPs meet all the critical requirements: (1) uniform shape and monodispersity, (2) phase purity, (3) stable magnetic properties approaching that of the bulk, (4) colloidal stability, (5) substantial shelf life and (6) pose no significant in vitro toxicity. Using a dedicated hyperthermia system, we then identified that 16 nm monodisperse MNPs (σ ~ 0.175) respond optimally to our chosen AMF conditions (f = 373 kHz, Ho = 14 kA/m); however, with a broader size distribution (σ ~ 0.284) the Specific Loss Power (SLP) decreases by 30%. Finally, we show that these tailored MNPs demonstrate maximum hyperthermia efficiency by reducing viability of Jurkat cells in vitro, suggesting our optimization translates truthfully to cell populations. In summary, we present a way to intrinsically optimize MFH by tailoring the MNPs to any applied AMF, a required precursor to optimize dose and time of treatment.
Magnetic Fluid Hyperthermia; in vitro hyperthermia; monodisperse iron oxide magnetic nanoparticles; cytotoxicity
MnO nanoparticles have been tested to engineer a delayed increase in MRI T1 relaxivity caused by cellular uptake via endocytosis into acidic compartments. Various coatings on core-shell structured MnO nanoparticles were tested for those that had the lowest T1 relaxivity at pH 7.4, a pH where MnO does not dissolve into Mn2+ ions. The rate of dissolution and release of Mn2+ of the different coated MnO particles as well as changes in T1 relaxivity were measured at pH 5, a pH routinely obtained in the endosomal-lysosomal pathway. Of a number of coatings, silica coated MnO (MnO@SiO2) had the lowest relaxivity at pH 7.4 (0.29 mM−1sec−1). About one third of the MnO dissolved within 20 min and the T1 relaxivity increased to that of free Mn2+ (6.10 mM−1sec−1) after three days at pH 5. MRI of MnO@SiO2 particles injected into the rat brain showed time-dependent signal changes consistent with the in vitro rates. Thalamocortical tract-tracing could be observed due to the released Mn2+. Intravenous infusion of MnO@SiO2 particles showed little enhancement in any tissue except gallbladder. The gallbladder enhancement was interpreted to be due to endocytosis by liver cells and excretion of Mn2+ ions into the gallbladder. The MnO@SiO2 core-shell nanoparticles show the best potential for delaying the release of MRI contrast until endocytosis into low pH compartments activate MRI contrast. The delayed enhancement may have benefits for targeting MRI contrast to specific cells and surface receptors that are known to be recycled by endocytosis.
manganese enhanced MRI; MnO nanoparticle; contrast agent; pH-responsive
Magnetic nanoparticles are promising molecular imaging agents due to their relative high relaxivity and the potential to modify surface functionality to tailor biodistribution. In this work we describe the synthesis of magnetic nanoparticles using organic solvents with organometallic precursors. This method results in nanoparticles that are highly crystalline, and have uniform size and shape. The ability to create a monodispersion of particles of the same size and shape results in unique magnetic properties that can be useful for biomedical applications with MR imaging. Before these nanoparticles can be used in biological applications, however, means are needed to make the nanoparticles soluble in aqueous solutions and the toxicity of these nanoparticles needs to be studied.
We have developed two methods to surface modify and transfer these nanoparticles to the aqueous phase using the biocompatible co-polymer, Pluronic F127. Cytotoxicity was found to be dependent on the coating procedure used. Nanoparticle effects on a cell-culture model was quantified using concurrent assaying; a LDH assay to determine cytotoxicity and an MTS assay to determine viability for a 24 hour incubation period. Concurrent assaying was done to insure that nanoparticles did not interfere with the colorimetric assay results.
This report demonstrates that a monodispersion of nanoparticles of uniform size and shape can be manufactured. Initial cytotoxicity testing of new molecular imaging agents need to be carefully constructed to avoid interference and erroneous results.
MRI; molecular imaging; nanoparticles; superparamagnetic agents; cytotoxicity; Colorimetric Assay; Pluronics
Biomedical nanomagnetics is a multidisciplinary area of research in science, engineering and medicine with broad applications in imaging, diagnostics and therapy. Recent developments offer exciting possibilities in personalized medicine provided a truly integrated approach, combining chemistry, materials science, physics, engineering, biology and medicine, is implemented. Emphasizing this perspective, here we address important issues for the rapid development of the field, i.e., magnetic behavior at the nanoscale with emphasis on the relaxation dynamics, synthesis and surface functionalization of nanoparticles and core-shell structures, biocompatibility and toxicity studies, biological constraints and opportunities, and in vivo and in vitro applications. Specifically, we discuss targeted drug delivery and triggered release, novel contrast agents for magnetic resonance imaging, cancer therapy using magnetic fluid hyperthermia, in vitro diagnostics and the emerging magnetic particle imaging technique, that is quantitative and sensitive enough to compete with established imaging methods. In addition, the physics of self-assembly, which is fundamental to both biology and the future development of nanoscience, is illustrated with magnetic nanoparticles. It is shown that various competing energies associated with self-assembly converge on the nanometer length scale and different assemblies can be tailored by varying particle size and size distribution. Throughout this paper, while we discuss our recent research in the broad context of the multidisciplinary literature, we hope to bridge the gap between related work in physics/chemistry/engineering and biology/medicine and, at the same time, present the essential concepts in the individual disciplines. This approach is essential as biomedical nanomagnetics moves into the next phase of innovative translational research with emphasis on development of quantitative in vivo imaging, targeted and triggered drug release, and image guided therapy including validation of delivery and therapy response.
Biomedical engineering; diagnostics; imaging; magnetic relaxation; nanotechnology; small particles; superparamagnetism; therapy
Magnetic particle imaging (MPI) is a powerful new research and diagnostic imaging platform that is designed to image the amount and location of superparamagnetic nanoparticles in biological tissue. Here, we present mathematical modeling results that show how MPI sensitivity and spatial resolution both depend on the size of the nanoparticle core and its other physical properties, and how imaging performance can be effectively optimized through rational core design. Modeling is performed using the properties of magnetite cores, since these are readily produced with a controllable size that facilitates quantitative imaging. Results show that very low detection thresholds (of a few nanograms Fe3O4) and sub-millimeter spatial resolution are possible with MPI.
Magnetic nanoparticle; Magnetic particle imaging; Iron oxide nanoparticle; Contrast agent; Molecular imaging