A Multifunctional Integrated Metal-Free MRI Agent for Early Diagnosis of Oxidative Stress in a Mouse Model of Diabetic Cardiomyopathy.

Reactive oxygen species (ROS) are closely associated with the progression of diabetic cardiomyopathy (DCM) and can be regarded as one of its early biomarkers. Magnetic resonance imaging (MRI) is emerging as a powerful tool for the detection of cardiac abnormalities, but the sensitive and direct ROS-response MRI probe remains to be developed. This restricts the early diagnosis of DCM and prevents timely clinical interventions, resulting in serious and irreversible pathophysiological abnormalities. Herein, a novel ROS-response contrast-enhanced MRI nanoprobe (RCMN) is developed by multi-functionalizing fluorinated carbon nanosheets (FCNs) with multi-hydroxyl and 2,2,6,6-tetramethylpiperidin-1-oxyl groups. RCMNs capture ROS and then gather in the heart provisionally, which triggers MRI signal changes to realize the in vivo detection of ROS. In contrast to the clinical MRI agents, the cardiac abnormalities of disease mice is detected 8 weeks in advance with the assistance of RCMNs, which greatly advances the diagnostic window of DCM. To the best of the knowledge, this is the first ROS-response metal-free T2 -weighted MRI probe for the early diagnosis of DCM mice model. Furthermore, RCMNs can timely scavenge excessively produced ROS to alleviate oxidative stress.

Targeted trapping of endogenous endothelial progenitor cells for myocardial ischemic injury repair through neutrophil-mediated SPIO nanoparticle-conjugated CD34 antibody delivery and imaging.

Endothelia progenitor cell (EPC)-based revascularization therapies have shown promise for the treatment of myocardial ischemic injury. However, applications and efficacy are limited by the relatively inefficient recruitment of endogenous EPCs to the ischemic area, while implantation of exogenous EPCs carries the risk of tumorigenicity. In this study, we developed a therapeutic protocol that relies on the capacity of neutrophils (NEs) to target lesions and release preloaded EPC-binding molecules for high efficiency capture. Neutrophils were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface marker CD34 (SPIO-antiCD34/NEs), and the therapeutic efficacy in ischemic mouse heart following SPIO-antiCD34/NEs injection was monitored by SPIO-enhanced magnetic resonance imaging (MRI). These SPIO-antiCD34/NEs exhibited unimpaired cell viability, superoxide generation, and chemotaxis in vitro as well as satisfactory biocompatibility in vivo. In a mouse model of acute myocardial infarction (MI), SPIO-antiCD34 accumulation could be observed 0.5 h after intravenous injection of SPIO-antiCD34/NEs. Moreover, the degree of CD133+ EPC accumulation at MI sites was three-fold higher than in control MI model mice, while ensuing microvessel density was roughly two-fold higher than controls and left ventricular ejection fraction was > 50%. Therapeutic cell biodistribution, MI site targeting, and treatment effects were confirmed by SPIO-enhanced MRI. This study offers a new strategy to improve the endogenous EPC-based myocardial ischemic injury repair through NEs mediated SPIO nanoparticle conjugated CD34 antibody delivery and imaging. STATEMENT OF SIGNIFICANCE: The efficacy of endogenous endothelial progenitor cell (EPC)-based cardiovascular repair therapy for ischemic heart damage is limited by relatively low EPC accumulation at the target site. We have developed a method to improve EPC capture by exploiting the strong targeting ability of neutrophils (NEs) to ischemic inflammatory foci and the capacity of these treated cells to release of preloaded cargo with EPC-binding affinity. Briefly, NEs were loaded with superparamagnetic iron oxide nanoparticles conjugated to an antibody against the EPC surface protein CD34 (SPIO-antiCD34). Thus, we explored sites targeting with nanocomposites cargo for non-invasive EPCs interception and therapy tracking. We demonstrate that SPIO-antiCD34 released from NEs can effectively capture endogenous EPCs and thereby promote heart revascularization and functional recovery in mice. Moreover, the entire process can be monitored by SPIO-enhanced magnetic resonance imaging including therapeutic cell biodistribution, myocardial infarction site targeting, and tissue repair.

GlyCEST: Magnetic Resonance Imaging of Glycine-Distribution in the Normal Murine Brain and Alterations in 5xFAD Mice.

The glycine level in the brain is known to be altered in neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease (AD). Several studies have reported the in vivo measurement of glycine concentrations in the brain using proton magnetic resonance spectroscopy (1H-MRS), but 1H-MRS is not capable of imaging the distribution of glycine concentration with high spatial resolution. Chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) is a new technology that can detect specific molecules, including amino acids, in tissues. To validate the measurements of glycine concentrations in living tissues using CEST from glycine to water (GlyCEST), we extracted the brain tissues from mice and performed biochemical tests. In wild-type C57BL/6 mice, GlyCEST effects were found to be higher in the thalamus than in the cerebral cortex (P < 0.0001, paired t-test), and this result was in good agreement with the biochemical results. In 5xFAD mice, an animal model of AD, GlyCEST measurements demonstrated that glycine concentrations in the cerebral cortex (P < 0.05, unpaired t-test) and thalamus (P < 0.0001, unpaired t-test), but not in the hippocampus, were decreased compared to those in wild-type mice. These findings suggest that we have successfully applied the CEST-MRI technique to map the distribution of glycine concentrations in the murine brain. The present method also captured the changes in cerebral glycine concentrations in mice with AD. Imaging the distribution of glycine concentrations in the brain can be useful in investigating and elucidating the pathological mechanisms of neuropsychiatric disorders.

Extremely low frequency alternating magnetic field-triggered and MRI-traced drug delivery by optimized magnetic zeolitic imidazolate framework-90 nanoparticles.

An extremely low frequency alternating magnetic field (ELF-AMF) was demonstrated to be able to effectively trigger drug release from carefully engineered magnetic ZIF-90 nanoparticles. The embedded Fe3O4 nanoparticles or alternatively Gd2O3 nanoparticles serve as effective MRI tracers for potential visualization of drug delivery to ensure drug delivery accuracy.

Engineered water-soluble two-dimensional magnetic nanocomposites: towards highly magnetic relaxometric properties.

Water dispersible two-dimensional magnetic nanocomposites are formed by phase-transferring hydrophobic manganese-doped ferrite nanoparticles (MFPs) into aqueous solvent using a one-step simple approach involving only graphene oxide (GO) as the phase transfer agent. The resultant hydrophilic magnetic nanocomposites (MFNs) are surprisingly stable in the aqueous phase despite its large hydrodynamic size (dhyd). Because of its unique construct that promotes water accessibility towards the MFP core, large MFNs loaded with an 18 nm MFP core (MFN-18; dhyd = 577.9 nm) exhibits transverse relaxivity (r2) up to ∼6.8 times (r2 = 800.8 mM [Mn + Fe](-1) s(-1)) higher than the typical individually coated MFP-18 with amphiphilic brush copolymers (r2 = 117.3 mM [Mn + Fe](-1) s(-1)). Meanwhile, the overall nanocomposites dhyd can be further reduced by employing a smaller pre-sonicated GO sheet phase transfer agent. As a result of using small GO sheets with enhanced hydrophilicity, the r2 of small MFN-18* nanocomposites (dhyd = 224.9 nm) increases by approximately 37% (r2 = 1097.4 mM [Mn + Fe](-1) s(-1)) as compared to larger MFN-18. From a simple comparative study among various magnetic nanocomposites involving a MFP-18 core, the high MFN-18 r2 relaxivity value can be attributed to enhanced water diffusion and exchange due to the GO sheet, allowing better interaction between magnetic the MFP core and water protons. The proposed method can be readily extended to convert other types of hydrophobic nanoparticles into water-dispersible nanocomposites.

Tailoring a two-dimensional graphene oxide surface: dual T1 and T2 MRI contrast agent materials.

A generalized strategy for developing a hybrid two-dimensional nanostructured dual T1-T2 MRI contrast agent (CA), by co-loading graphene oxide with both Mn-doped Fe3O4 (T2 agent) and MnO (T1 agent) magnetic nanoparticles, is reported. Typical T1/T2 signal quenching, due to magnetic coupling, was not observed because of the fair T1 CA separation distance from the T2 CA on the graphene oxide. The resultant two-dimensional nanostructured MRI CA complements the existing dual T1-T2 MRI CA libraries.

High-sensitivity cerebral perfusion mapping in mice by kbGRASE-FAIR at 9.4 T.

The combination of flow-sensitive alternating inversion recovery (FAIR) and single-shot k-space-banded gradient- and spin-echo (kbGRASE) is proposed here to measure perfusion in the mouse brain with high sensitivity and stability. Signal-to-noise ratio (SNR) analysis showed that kbGRASE-FAIR boosts image and temporal SNRs by 2.01 ± 0.08 and 2.50 ± 0.07 times, respectively, when compared with standard single-shot echo planar imaging (EPI)-FAIR implemented in our experimental systems, although the practically achievable spatial resolution was slightly reduced. The effects of varying physiological parameters on the precision and reproducibility of cerebral blood flow (CBF) measurements were studied following changes in anesthesia regime, capnia and body temperature. The functional MRI time courses with kbGRASE-FAIR showed a more stable response to 5% CO(2) than did those with EPI-FAIR. The results establish kbGRASE-FAIR as a practical and robust protocol for quantitative CBF measurements in mice at 9.4 T.

iDQC MRI weighted by longitudinal relaxation in the rotating frame.

A long-duration, low-power, off-resonance spin-locking pulse was incorporated into the COSY revamped by asymmetric z gradient-echo detection (CRAZED) pulse sequence in order to evaluate the effects of intermolecular double-quantum longitudinal relaxation in the tilted rotating frame (T1rho,DQ(eff)). This modified CRAZED sequence was followed by a standard fast spin-echo imaging sequence to form images with T1rho,DQ(eff)-weighted contrast. Imaging experiments were performed on an agarose-gel phantom and mouse-tail tissue at 600 MHz. Experimental results demonstrated the feasibility of imaging applications based on T1rho,DQ(eff) as a novel contrast mechanism, and showed that iDQC off-resonance longitudinal relaxation in the rotating frame T1rho,DQ(eff) is sensitive to the tilt angle theta and the effective spin-locking field omegae. Imaging based on T1rho,DQ(eff)) has reduced RF power deposition compared to on-resonance spin-locking, which is advantageous for human applications.

Theoretical formalism and experimental verification of line shapes of NMR intermolecular multiple-quantum coherence spectra.

Although the theories and potential applications of intermolecular multiple-quantum coherences (iMQCs) have been under active investigations for over a decade, discussion of iMQC NMR signal formation was mainly confined in the time domain. In this paper, a full line-shape theory was developed to describe iMQC signals in the frequency domain. Relevant features of the line shape, such as peak height, linewidth, and phase, were investigated in detail. Predictions based on the theory agree well with experimental and simulated results. Since radiation-damping effects always couple with iMQCs in highly polarized liquid-state NMR systems, and strongly radiation-damped signals have many spectral characteristics similar to those of iMQCs, a detailed comparison was also made between them from different spectral aspects. With detailed comparison of peak height, linewidth, and phase, this work demonstrates that the iMQC and radiation-damping phenomena result from two completely different physical mechanisms despite that both present similar signal features and coexist in highly polarized liquid-state NMR systems.

Rotating-frame intermolecular double-quantum spin-lattice relaxation T1rho, DQC-weighted magnetic resonance imaging.

In this study, spin-locking techniques were added as a part of intermolecular multiple-quantum experiments, thereby introducing the concept of rotating-frame intermolecular double-quantum spin-lattice relaxation, T(1rho, DQC). A novel magnetic resonance imaging methodology based on intermolecular multiple-quantum coherences is demonstrated on a 7.05-T microimaging scanner. The results clearly reveal that the intermolecular double-quantum coherence T(1rho, DQC)-weighted imaging technique provides an alternative contrast mechanism to conventional imaging.