Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging.

Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of X-ray CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide a suboptimal MPI signal, and further limit MPI's in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t1/2) would be a versatile MPI tracer with widespread applications. Here we show that a long circulating polyethylene glycol (PEG)-coated SPIO tracer, LS-008, provides excellent colloidal stability and a persistent intravascular MPI signal, showing its potential as the first blood pool tracer optimized for MPI. We evaluated variations of PEG coating and found that colloidal stability of tracers improved with the increasing PEG molecular weight (keeping PEG loading constant). Blood circulation in mice, evaluated using Magnetic Particle Spectrometry (MPS), showed that the t1/2 of SPIO tracers varied with both PEG molecular weight and loading. LS-008, coated with 20 kDa PEG at 18.8% loading capacity, provided the most promising long-term colloidal stability with a t1/2 of about 105 minutes in mice. In vivo MPI imaging with LS-008 using a 7 T/m/µ0 3D x-space MPI mouse scanner revealed a prolonged intravascular signal (3-5 hours) post-injection. Our results show the optimized magnetic properties and long systemic retention of LS-008 making it a promising blood pool MPI tracer, with potential to enable MPI imaging in cardio- and cerebrovascular disease models, and solid tumor quantification and imaging via enhanced permeation and retention.

Finite magnetic relaxation in x-space magnetic particle imaging: Comparison of measurements and ferrohydrodynamic models.

Magnetic Particle Imaging (MPI) is an emerging tomographic imaging technology that detects magnetic nanoparticle tracers by exploiting their non-linear magnetization properties. In order to predict the behavior of nanoparticles in an imager, it is possible to use a non-imaging MPI relaxometer or spectrometer to characterize the behavior of nanoparticles in a controlled setting. In this paper we explore the use of ferrohydrodynamic magnetization equations for predicting the response of particles in an MPI relaxometer. These include a magnetization equation developed by Shliomis (Sh) which has a constant relaxation time and a magnetization equation which uses a field-dependent relaxation time developed by Martsenyuk, Raikher and Shliomis (MRSh). We compare the predictions from these models with measurements and with the predictions based on the Langevin function that assumes instantaneous magnetization response of the nanoparticles. The results show good qualitative and quantitative agreement between the ferrohydrodynamic models and the measurements without the use of fitting parameters and provide further evidence of the potential of ferrohydrodynamic modeling in MPI.

Eddy current-shielded x-space relaxometer for sensitive magnetic nanoparticle characterization.

The development of magnetic particle imaging (MPI) has created a need for optimized magnetic nanoparticles. Magnetic particle relaxometry is an excellent tool for characterizing potential tracers for MPI. In this paper, we describe the design and construction of a high-throughput tabletop relaxometer that is able to make sensitive measurements of MPI tracers without the need for a dedicated shield room.

Noise performance of a precision pulsed electromagnet power supply for magnetic resonance imaging.

Prepolarized magnetic resonance imaging (PMRI) uses two pulsed electromagnets to achieve high-field image quality with the benefits of low-field data acquisition. The principal challenge with all resistive MRI systems is the implementation of a highly precise magnet current supply. The noise current through the magnet is fundamentally limited by the current transducer used to provide feedback and the voltage reference used to generate the demand signal. Field instability in the main field magnet can both corrupt the received data and degrade the robustness of Carr¿Purcell¿Meiboom¿Gill (CPMG) echo trains, which are paramount to efficient imaging in PMRI. In this work, we present the magnet control system that achieved sufficient field stability for PMRI at $0.5/0.13$ T, identify the dominant sources of noise in the control system, examine the imaging artifacts that can occur if the field stability is insufficient, and identify how the design can be improved for better field stability, should it be required for future implementations of PMRI.

Identification of ENV determinants in V3 that influence the molecular anatomy of CCR5 utilization.

The V3 loop of the ENV glycoprotein exerts a dominant influence on the interaction of gp120 with coreceptors. Primary env genes cloned from sequential isolates from two seroconverters revealed Pro-->Ala conversion in the conserved GPG motif of the V3 crown in seven of 17 R5 ENV. ENV containing the GPG motif in the V3 crown had fusogenic activity with chimeric receptors containing either the N terminus or loops of CCR5, whereas those with the GAG variant utilized only the former. Site-directed mutagenesis of multiple primary and prototypic R5 env genes demonstrated that the GPG motif was necessary for dual utilization of the N terminus and body of CCR5 in both gain and loss-of-function experiments. All ENV containing the GPG V3 crown showed CCR5 binding in the presence of soluble CD4, whereas it was not detected with the GAG variants. Molecular dynamic simulations of a V3 peptide predicts that the Pro-->Ala substitution results in a conformational change with loss of the crown structure. These studies demonstrate that sequences in the third hypervariable region determine the specificity of coreceptor utilization for fusion, and that a conserved motif in the crown directly influences the molecular anatomy of the interaction between gp120 and CCR5.

MR imaging of articular cartilage using driven equilibrium.

The high incidence of osteoarthritis and the recent advent of several new surgical and non-surgical treatment approaches have motivated the development of quantitative techniques to assess cartilage loss. Although magnetic resonance (MR) imaging is the most accurate non-invasive diagnostic modality for evaluating articular cartilage, improvements in spatial resolution, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) would be valuable. Cartilage presents an imaging challenge due to its short T(2) relaxation time and its low water content compared with surrounding materials. Current methods sacrifice cartilage signal brightness for contrast between cartilage and surrounding tissue such as bone, bone marrow, and joint fluid. A new technique for imaging articular cartilage uses driven equilibrium Fourier transform (DEFT), a method of enhancing signal strength without waiting for full T(1) recovery. Compared with other methods, DEFT imaging provides a good combination of bright cartilage and high contrast between cartilage and surrounding tissue. Both theoretical predictions and images show that DEFT is a valuable method for imaging articular cartilage when compared with spoiled gradient-recalled acquisition in the steady state (SPGR) or fast spin echo (FSE). The cartilage SNR for DEFT is as high as that of either FSE or SPGR, while the cartilage-synovial fluid CNR of DEFT is as much as four times greater than that of FSE or SPGR. Implemented as a three-dimensional sequence, DEFT can achieve coverage comparable to that of other sequences in a similar scan time. Magn Reson Med 42:695-703, 1999.

Resistive homogeneous MRI magnet design by matrix subset selection.

A new technique for designing resistive homogeneous multicoil magnets for magnetic resonance imaging (MRI) is presented. A linearly independent subset of coils is chosen from a user-defined feasible set using an efficient numerical algorithm. The coil currents are calculated using a linear least squares algorithm to minimize the deviation of the actual magnetic field from the target field. The solutions are converted to practical coils by rounding the currents to integer ratios, selecting the wire gauge, and optimizing the coil cross-sections. To illustrate the technique, a new design of a short, homogeneous MRI magnet suitable for low-field human torso imaging is presented. Magnets that satisfy other constraints on access and field uniformity can also be designed. Compared with conventional techniques that employ harmonic expansions, this technique is flexible, simple to implement, and numerically efficient.

Pulsed saturation transfer contrast.

In vivo 1H conventional NMR image contrast generation usually relies on the macroscopic T1 and T2 relaxation parameters of the tissues of interest. Recently cross-relaxation related image contrast has been reported by Wolff and Balaban in animal models. Due primarily to the broad lineshape of the intended saturation spin pool and the use of off-resonance irradiation, high specific absorption rate and an auxiliary RF amplifier have been necessary to produce these images. The relatively long spin-lattice relaxation property of this spin pool, however, suggests the use of pulse methods to achieve saturation. In this paper, we show that short-T2 spin pools can be selectively saturated with short intense RF pulses. Cross-relaxation time constants can be measured using the technique of saturation recovery. In vivo magnetization-transfer-weighted images can be produced using pulses on commercial whole-body imagers without additional hardware.

MR angiography by selective inversion recovery.

A modified inversion-recovery sequence is introduced which performs subtraction angiography by varying time-of-flight effects of blood flowing into an imaged slab. The selective 180 degrees excitation inverts different regions between measurements to isolate arterial and/or venous blood. On normal human subjects, high-resolution carotid artery angiograms have been obtained.