R. Matthew Ferguson

Optimizing magnetite nanoparticles for mass sensitivity in magnetic particle imaging

PURPOSE Magnetic particle imaging (MPI), using magnetite nanoparticles (MNPs) as tracer material, shows great promise as a platform for fast tomographic imaging. To date, the magnetic properties of MNPs used in imaging have not been optimized. As nanoparticle magnetism shows strong size dependence, the authors explore how varying MNP size impacts imaging performance in order to determine optimal MNP characteristics for MPI at any driving field frequency f0. METHODS Monodisperse MNPs of varying size were synthesized and their magnetic properties characterized. Their MPI response was measured experimentally using a custom-built MPI transceiver designed to detect the third harmonic of MNP magnetization. The driving field amplitude H0 = 6 mT micro0(-1) and frequency f0 = 250 kHz were chosen to be suitable for imaging small animals. Experimental results were interpreted using a model of dynamic MNP magnetization that is based on the Langevin theory of superparamagnetism and accounts for sample size distribution and size-dependent magnetic relaxation. RESULTS The experimental results show a clear variation in the MPI signal intensity as a function of MNP diameter that is in agreement with simulated results. A maximum in the plot of MPI signal vs MNP size indicates there is a particular size that is optimal for the chosen f0. CONCLUSIONS The authors observed that MNPs 15 nm in diameter generate maximum signal amplitude in MPI experiments at 250 kHz. The authors expect the physical basis for this result, the change in magnetic relaxation with MNP size, will impact MPI under other experimental conditions.

Monodispersed magnetite nanoparticles optimized for magnetic fluid hyperthermia: Implications in biological systems

Magnetite (Fe(3)O(4)) nanoparticles (MNPs) are suitable materials for Magnetic Fluid Hyperthermia (MFH), provided their size is carefully tailored to the applied alternating magnetic field (AMF) frequency. Since aqueous synthesis routes produce polydisperse MNPs that are not tailored for any specific AMF frequency, we have developed a comprehensive protocol for synthesizing highly monodispersed MNPs in organic solvents, specifically tailored for our field conditions (f = 376 kHz, H(0) = 13.4 kA∕m) and subsequently transferred them to water using a biocompatible amphiphilic polymer. These MNPs (σ(avg.) = 0.175) show truly size-dependent heating rates, indicated by a sharp peak in the specific loss power (SLP, W∕g Fe(3)O(4)) for 16 nm (diameter) particles. For broader size distributions (σ(avg.) = 0.266), we observe a 30% drop in overall SLP. Furthermore, heating measurements in biological medium [Dulbeccos modified Eagle medium (DMEM) + 10% fetal bovine serum] show a significant drop for SLP (∼30% reduction in 16 nm MNPs). Dynamic Light Scattering (DLS) measurements show particle hydrodynamic size increases over time once dispersed in DMEM, indicating particle agglomeration. Since the effective magnetic relaxation time of MNPs is determined by fractional contribution of the Neel (independent of hydrodynamic size) and Brownian (dependent on hydrodynamic size) components, we conclude that agglomeration in biological medium modifies the Brownian contribution and thus the net heating capacity of MNPs.

Tailored magnetic nanoparticles for optimizing magnetic fluid hyperthermia

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 to 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, H₀ = 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 Particle Imaging With Tailored Iron Oxide Nanoparticle 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 sub-optimal for MPI. Here, we describe new tracers tailored to MPIs unique physics, synthesized using an organic-phase process and functionalized to ensure biocompatibility and adequate in vivo circulation time. Tailored tracers showed up to 3 × greater signal-to-noise ratio and better spatial resolution than existing commercial tracers in MPI images of phantoms.

Enhancing cancer therapeutics using size-optimized magnetic fluid hyperthermia

Magnetic fluid hyperthermia (MFH) employs heat dissipation from magnetic nanoparticles to elicit a therapeutic outcome in tumor sites, which results in either cell death (>42 °C) or damage (<42 °C) depending on the localized rise in temperature. We investigated the therapeutic effect of MFH in immortalized T lymphocyte (Jurkat) cells using monodisperse magnetite (Fe(3)O(4)) nanoparticles (MNPs) synthesized in organic solvents and subsequently transferred to aqueous phase using a biocompatible amphiphilic polymer. Monodisperse MNPs, ∼16 nm diameter, show maximum heating efficiency, or specific loss power (watts/g Fe(3)O(4)) in a 373 kHz alternating magnetic field. Our in vitro results, for 15 min of heating, show that only 40% of cells survive for a relatively low dose (490 μg Fe/ml) of these size-optimized MNPs, compared to 80% and 90% survival fraction for 12 and 13 nm MNPs at 600 μg Fe/ml. The significant decrease in cell viability due to MNP-induced hyperthermia from only size-optimized nanoparticles demonstrates the central idea of tailoring size for a specific frequency in order to intrinsically improve the therapeutic potency of MFH by optimizing both dose and time of application.

Size-Dependent Relaxation Properties of Monodisperse Magnetite Nanoparticles Measured Over Seven Decades of Frequency by AC Susceptometry

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.

Magnetic Particle Imaging: A Novel in vivo Imaging Platform for Cancer Detection.

Cancer remains one of the leading causes of death worldwide. Biomedical imaging plays a crucial role in all phases of cancer management. Physicians often need to choose the ideal diagnostic imaging modality for each clinical presentation based on complex trade-offs among spatial resolution, sensitivity, contrast, access, cost, and safety. Magnetic particle imaging (MPI) is an emerging tracer imaging modality that detects superparamagnetic iron oxide (SPIO) nanoparticle tracer with high image contrast (zero tissue background signal), high sensitivity (200 nM Fe) with linear quantitation, and zero signal depth attenuation. MPI is also safe in that it uses safe, in some cases even clinically approved, tracers and no ionizing radiation. The superb contrast, sensitivity, safety, and ability to image anywhere in the body lends MPI great promise for cancer imaging. In this study, we show for the first time the use of MPI for in vivo cancer imaging with systemic tracer administration. Here, long circulating MPI-tailored SPIOs were created and administered intravenously in tumor bearing rats. The tumor was highlighted with tumor-to-background ratio of up to 50. The nanoparticle dynamics in the tumor was also well-appreciated, with initial wash-in on the tumor rim, peak uptake at 6 h, and eventual clearance beyond 48 h. Lastly, we demonstrate the quantitative nature of MPI through compartmental fitting in vivo.

Monodisperse magnetite nanoparticles with nearly ideal saturation magnetization

We present a scalable thermolysis and high temperature oxidation procedure for synthesizing monodisperse magnetite nanoparticles with saturation magnetization of up to 80 emu g−1 (412 kA m−1), 92% of bulk magnetite. Diameters in the 15–30 nm size range are produced from iron oleate via the thermolysis method at 324 °C and varying oleic acid ratios for size control (6.7–7.6 equivalents per Fe). The influence of the iron oleate synthesis procedure on the quality of resulting nanoparticles is examined and the structure of the iron oleate is proposed to have a triironoxonium core [Fe3O+] based on magnetic susceptibility measurements. The thermolysis method is shown to initially give wustite nanoparticles, which are oxidized in situ at 318 °C using 1% oxygen in argon to form highly magnetic magnetite nanoparticles. The use of 1% oxygen offers broad application as a safe and efficient reagent for the high temperature oxidation of nanoparticles. Special consideration to the reproducibility of nanoparticle diameter and monodispersity has uncovered critical factors. Additionally, the reduction of Fe(III) to Fe(II) is shown to occur during the heat up stage of thermolysis, beginning at less than 180 °C and being complete by 320 °C. Evidence for the reduction occurring by the oxidative decarboxylation of oleic acid is presented. Decomposition of the remaining oleic acid is shown to occur by a ketonization reaction producing oleone. The nucleation event and growth of particles is examined by TEM. Comparison of the solvents 1-octadecene and octadecane are presented demonstrating the effect on the reduction of Fe(III) during heat up, the large difference in particle size, and effects on the oxidation rate of iron oxide nanoparticles. Determination of Fe(II) content in magnetic iron oxide nanoparticles by titration is presented.

Tracking short-term biodistribution and long-term clearance of SPIO tracers in magnetic particle imaging

Magnetic particle imaging (MPI) is an emerging tracer-based medical imaging modality that images non-radioactive, kidney-safe superparamagnetic iron oxide (SPIO) tracers. MPI offers quantitative, high-contrast and high-SNR images, so MPI has exceptional promise for applications such as cell tracking, angiography, brain perfusion, cancer detection, traumatic brain injury and pulmonary imaging. In assessing MPIs utility for applications mentioned above, it is important to be able to assess tracer short-term biodistribution as well as long-term clearance from the body. Here, we describe the biodistribution and clearance for two commonly used tracers in MPI: Ferucarbotran (Meito Sangyo Co., Japan) and LS-oo8 (LodeSpin Labs, Seattle, WA). We successfully demonstrate that 3D MPI is able to quantitatively assess short-term biodistribution, as well as long-term tracking and clearance of these tracers in vivo.

First in vivo traumatic brain injury imaging via magnetic particle imaging

Emergency room visits due to traumatic brain injury (TBI) is common, but classifying the severity of the injury remains an open challenge. Some subjective methods such as the Glasgow Coma Scale attempt to classify traumatic brain injuries, as well as some imaging based modalities such as computed tomography and magnetic resonance imaging. However, to date it is still difficult to detect and monitor mild to moderate injuries. In this report, we demonstrate that the magnetic particle imaging (MPI) modality can be applied to imaging TBI events with excellent contrast. MPI can monitor injected iron nanoparticles over long time scales without signal loss, allowing researchers and clinicians to monitor the change in blood pools as the wound heals.