Through-Space Multinuclear Magnetic Resonance Signal Enhancement Induced by Parahydrogen and Radiofrequency Amplification by Stimulated Emission of Radiation.

Hyperpolarized (i.e., polarized far beyond the thermal equilibrium) nuclear spins can result in the radiofrequency amplification by stimulated emission of radiation (RASER) effect. Here, we show the utility of RASER to amplify nuclear magnetic resonance (NMR) signals of solute and solvent molecules in the liquid state. Specifically, parahydrogen-induced RASER was used to spontaneously enhance nuclear spin polarization of protons and heteronuclei (here 19F and 31P) in a wide range of molecules. The magnitude of the effect correlates with the T1 relaxation time of the target nuclear spins. A series of control experiments validate the through-space dipolar mechanism of the RASER-assisted polarization transfer between the parahydrogen-polarized compound and to-be-hyperpolarized nuclei of the target molecule. Frequency-selective saturation of the RASER-active resonances was used to control the RASER and the amplitude of spontaneous polarization transfer. Spin dynamics simulations support our experimental RASER studies. The enhanced NMR sensitivity may benefit various NMR applications such as mixture analysis, metabolomics, and structure determination.

Parahydrogen-Induced Polarization Relayed via Proton Exchange.

The hyperpolarization of nuclear spins is a game-changing technology that enables hitherto inaccessible applications for magnetic resonance in chemistry and biomedicine. Despite significant advances and discoveries in the past, however, the quest to establish efficient and effective hyperpolarization methods continues. Here, we describe a new method that combines the advantages of direct parahydrogenation, high polarization (P), fast reaction, and low cost with the broad applicability of polarization transfer via proton exchange. We identified the system propargyl alcohol + pH2 → allyl alcohol to yield 1H polarization in excess of P ≈ 13% by using only 50% enriched pH2 at a pressure of ≈1 bar. The polarization was then successfully relayed via proton exchange from allyl alcohol to various target molecules. The polarizations of water and alcohols (as target molecules) approached P ≈ 1% even at high molar concentrations of 100 mM. Lactate, glucose, and pyruvic acid were also polarized, but to a lesser extent. Several potential improvements of the methodology are discussed. Thus, the parahydrogen-induced hyperpolarization relayed via proton exchange (PHIP-X) is a promising approach to polarize numerous molecules which participate in proton exchange and support new applications for magnetic resonance.

Performance and reproducibility of 13C and 15N hyperpolarization using a cryogen-free DNP polarizer.

The setup, operational procedures and performance of a cryogen-free device for producing hyperpolarized contrast agents using dissolution dynamic nuclear polarization (dDNP) in a preclinical imaging center is described. The polarization was optimized using the solid-state, DNP-enhanced NMR signal to calibrate the sample position, microwave and NMR frequency and power and flip angle. The polarization of a standard formulation to yield ~ 4 mL, 60 mM 1-13C-pyruvic acid in an aqueous solution was quantified in five experiments to P(13C) = (38 ± 6) % (19 ± 1) s after dissolution. The mono-exponential time constant of the build-up of the solid-state polarization was quantified to (1032 ± 22) s. We achieved a duty cycle of 1.5 h that includes sample loading, monitoring the polarization build-up, dissolution and preparation for the next run. After injection of the contrast agent in vivo, pyruvate, pyruvate hydrate, lactate, and alanine were observed, by measuring metabolite maps. Based on this work sequence, hyperpolarized 15N urea was obtained (P(15N) = (5.6 ± 0.8) % (30 ± 3) s after dissolution).

On magnetic dipole-dipole interactions of nanoparticles in magnetic particle imaging.

Magnetic dipole-dipole (MDD) interactions between iron oxide nanoparticles can influence the sensitivity, image resolution and quantification of magnetic particle imaging (MPI). For the first time, the Landau-Lifshitz-Gilbert equation (LLG) for MDD interactions has been solved to investigate the effect of MDD interactions on the MPI spectrum. It was found that at concentrations above 39 mmol(Fe) l-1, MDD interactions significantly influence MPI spectra. This influence increases with increasing harmonics, which means first harmonics should be preferred for iron quantification. Since ≈1018 particles are neglected in the LLG compared to in an MPI experiment, the calculated limit below which MDD interactions can be neglected is only a bound. The true limit is therefore below the calculated limit of 39 mmol(Fe) l-1, because all other neglected particles also contribute to deviations in the MPI spectra via MDD interactions. Therefore, a quantum mechanical bound on the influence of MDD interactions is calculated, including up to 1015 particles. Analysis of the bound as a function of the particle number provides a valuable insight into the influence of the large number of particles neglected in numerical simulations. Both results are compared with concentrations in biomedical MPI experiments. We conclude that the standard approximation of an absence of MDD interactions in MPI experiments must be handled more carefully. Our method of incorporating MDD interactions into the LLG can be easily implemented as part of model-based reconstruction to increase the sensitivity, image resolution and quantitative tracer detection during MPI.

Increasing the sensitivity for stem cell monitoring in system-function based magnetic particle imaging.

The use of superparamagnetic iron oxide nanoparticles (SPIONs) has provided new possibilities in biophysics and biomedical imaging technologies. The magnetization dynamics of SPIONs, which can be influenced by the environment, are of central interest. In this work, different biological SPION environments are used to investigate three different calibration methods for stem cell monitoring in magnetic particle imaging. It is shown that calibrating using SPIONs immobilized via agarose gel or intracellular uptake results in superior stem cell image quality compared to mobile SPIONs in saline. This superior image quality enables more sensitive localization and identification of a significantly smaller number of magnetically labeled stem cells. The results are important for cell tracking and monitoring of future SPION based therapies such as hyperthermia based cancer therapies, targeted drug delivery, or tissue regeneration approaches where it is crucial to image a sufficiently small number of SPIONs interacting with biological matter.

Sensitivity Enhancement in Magnetic Particle Imaging by Background Subtraction.

Biomedical applications such as cell tracking and angiography require the detection of low concentrations of superparamagnetic iron oxide nanoparticles (SPIOs) for imaging purposes. Magnetic particle imaging (MPI) is a new technology which enables the quantitative and time-resolved localization of SPIO distributions. However, the minimum concentration at which the SPIOs can be reconstructed with a suitable quality still remains to be investigated. In this work we examine the background signals in raw data that were measured without any SPIOs in the scanner tube. We show that a background subtraction in combination with a frequency cutoff for the dynamic part of the background signal lowers the detection limit for SPIOs in MPI up to a factor of ten. In-vivo mouse experiments show that for early time points from when the tracer enters the vena cava a reconstructed image of sufficient quality can only be obtained when a background subtraction is performed.

Magnetic Particle / Magnetic Resonance Imaging: In-Vitro MPI-Guided Real Time Catheter Tracking and 4D Angioplasty Using a Road Map and Blood Pool Tracer Approach.

PURPOSE: In-vitro evaluation of the feasibility of 4D real time tracking of endovascular devices and stenosis treatment with a magnetic particle imaging (MPI) / magnetic resonance imaging (MRI) road map approach and an MPI-guided approach using a blood pool tracer. MATERIALS AND METHODS: A guide wire and angioplasty-catheter were labeled with a thin layer of magnetic lacquer. For real time MPI a custom made software framework was developed. A stenotic vessel phantom filled with saline or superparamagnetic iron oxide nanoparticles (MM4) was equipped with bimodal fiducial markers for co-registration in preclinical 7T MRI and MPI. In-vitro angioplasty was performed inflating the balloon with saline or MM4. MPI data were acquired using a field of view of 37.3×37.3×18.6 mm3 and a frame rate of 46 volumes/sec. Analysis of the magnetic lacquer-marks on the devices were performed with electron microscopy, atomic absorption spectrometry and micro-computed tomography. RESULTS: Magnetic marks allowed for MPI/MRI guidance of interventional devices. Bimodal fiducial markers enable MPI/MRI image fusion for MRI based roadmapping. MRI roadmapping and the blood pool tracer approach facilitate MPI real time monitoring of in-vitro angioplasty. Successful angioplasty was verified with MPI and MRI. Magnetic marks consist of micrometer sized ferromagnetic plates mainly composed of iron and iron oxide. CONCLUSIONS: 4D real time MP imaging, tracking and guiding of endovascular instruments and in-vitro angioplasty is feasible. In addition to an approach that requires a blood pool tracer, MRI based roadmapping might emerge as a promising tool for radiation free 4D MPI-guided interventions.