The increasing prevalence of ultra-high-field magnetic resonance imaging (UHFMRI) in biomedical research and clinical settings will improve the resolution and diagnostic accuracy of MRI scans. However, better contrast agents are needed to achieve a satisfactory signal-to-noise ratio. Here, we report the synthesis of a bimodal contrast agent prepared by loading the internal cavity of tobacco mosaic virus (TMV) nanoparticles with a dysprosium (Dy3+) complex and the near-infrared fluorescence (NIRF) dye Cy7.5. The external surface of TMV was conjugated with an Asp-Gly-Glu-Ala (DGEA) peptide via a polyethylene glycol linker to target integrin α2β1. The resulting nanoparticle (Dy-Cy7.5-TMV-DGEA) was stable and achieved a high transverse relaxivity in ultra-high-strength magnetic fields (326 and 399 mM–1 s–1 at 7 and 9.4 T, respectively). The contrast agent was also biocompatible (low cytotoxicity) and targeted PC-3 prostate cancer cells and tumors in vitro and in vivo as confirmed by bimodal NIRF imaging and T2-mapping UHFMRI. Our results show that Dy-Cy7.5-TMV-DGEA is suitable for multiscale MRI scanning from the cellular level to the whole body, particularly in the context of UHFMRI applications.

Many human diseases are caused by an imbalance between energy production and demand.Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) provide the unique opportunity for in vivo assessment of several fundamental events in tissue metabolism without the use of ionizing radiation. Of particular interest, phosphate metabolites that are involved in ATP generation and utilization can be quantified noninvasively by phosphorous-31 ( 31 P) MRS/MRI. Furthermore, 31 P magnetization transfer (MT) techniques allow in vivo measurement of metabolic fluxes via creatine kinase (CK) and ATP synthase. However, a major impediment for the clinical applications of 31 P-MRS/MRI is the prohibitively long acquisition time and/or the low spatial resolution that are necessary to achieve adequate signal-to-noise ratio. P-MRS/MRI techniques. Applications of these techniques to the investigation of a specific physiology/pathology will be discussed without detailed description. Interested readers are referred to recent review articles on the applications of 31 P-MRS/MRI in metabolic characterization of skeletal muscle (10-12), heart (13), brain (14), and liver (11), as well as in diseases such as cancer (15), heart failure (16), and obesity and diabetes (17,18). Historical perspectiveThe use of 31 P-MRS for metabolic investigations dates back to 1960. Cohn and Hughes were the first to obtain a high-resolution 31 P spectrum of a solution of ATP (19). In addition, they also observed a dependence of the chemical shifts of the phosphorus nuclei of ATP on the pH of the solution. In parallel to the early development of MRI methods by Lauterbur (20), the entire 1970s also witnessed the rapid advance of 31 P-MRS in metabolic investigation of a broad range of biological systems. In 1973, Moon and Richards performed the first 31 P-MRS study that measured intracellular pH in human red blood cells (21). In the following year, Henderson and colleagues obtained the first 31 P spectrum of ATP from human red blood cells (22). At the same time, the Oxford team led by Radda performed the first experiment to acquire 31 P spectra from an intact organ, i.e., the excised and superfused muscle of rat hindlimb (23). The first in vivo 31 P-MRS study was performed on mouse brain by Chance et al. (24). Within the short span of one decade, organelles including mitochondria (25,26) and chromaffin granules (27), cells including Escherichia coli (28), yeast (29), and hepatocytes (30), and organs including skeletal muscle (31,32), heart (33-35), brain (36), kidney (37), and liver (38,39) have all been studied using 31 P-MRS.It is worth noting that most of these organ studies were performed on excised organs to avoid the need for spatial localization. Although Lauterbur has demonstrated the feasibility of imaging water protons (20), it was considered impractical for 31 P imaging of living systems because of the low sensitivity and difficulties with spectral resolution.The 1980s began with the publication of two important studies that aimed a...

One of the greatest challenges in nanomedicine is the low efficiency with which nanoparticles are delivered to lesions such as tumors in vivo. Here, we show that Physalis mottle virus (PhMV)-like nanoparticles can be developed as bimodal contrast agents to achieve long circulation, specific targeting capability, and efficient delivery to tumors in vivo. The self-assembling coat protein nanostructure offers various opportunities to modify the internal and external surfaces separately. After loading the internal cavity of the particles with the fluorescent dye Cy5.5 and paramagnetic Gd(III) complexes, we modified the outer surface by PEGylation and conjugation with targeting peptides. Using this combined approach, we were able to monitor a human prostate tumor model for up to 10 days by near-infrared fluorescence and magnetic resonance imaging, with up to 6% of the injection dose remaining. Our results show that PhMV-like nanoparticles provide a promising and innovative platform for the development of next-generation diagnostic and therapeutic agents.

Purpose To develop a rapid 31P-MRSI method with high spatiospectral resolution using low-rank tensor-based data acquisition and image reconstruction. Methods The multidimensional image function of 31P-MRSI is represented by a low-rank tensor to capture the spatial–spectral–temporal correlations of data. A hybrid data acquisition scheme is used for sparse sampling, which consists of a set of “training” data with limited k-space coverage to capture the subspace structure of the image function, and a set of sparsely sampled “imaging” data for high-resolution image reconstruction. An explicit subspace pursuit approach is used for image reconstruction, which estimates the bases of the subspace from the “training” data and then reconstructs a high-resolution image function from the “imaging” data. Results We have validated the feasibility of the proposed method using phantom and in vivo studies on a 3T whole-body scanner and a 9.4T preclinical scanner. The proposed method produced high-resolution static 31P-MRSI images (i.e., 6.9×6.9×10 mm3 nominal resolution in a 15-min acquisition at 3T) and high-resolution, high-frame-rate dynamic 31P-MRSI images (i.e., 1.5 × 1.5 × 1.6 mm3 nominal resolution, 30 s/frame at 9.4T). Conclusions Dynamic spatiospectral variations of 31P-MRSI signals can be efficiently represented by a low-rank tensor. Exploiting this mathematical structure for data acquisition and image reconstruction can lead to fast 31P-MRSI with high resolution, frame-rate, and SNR.

These results show that the RIPE-MRF method can provide effective motion artifact suppression with minimal impact on T and T accuracy for in vivo small animal MRI studies. Magn Reson Med 79:2176-2182, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Magnetic resonance fingerprinting provides the opportunity for dynamic quantification of contrast agent distribution in preclinical tumor models on high-field MRI scanners.

Purpose Quantitative T1 and T2 mapping in non‐human primates with whole‐brain coverage is challenged by the requirement of sub‐millimeter resolution and the inhomogeneity of the transmit magnetic field (B1+) covering a large field of view. The goal of the current study is to develop a magnetic resonance fingerprinting (MRF) method for simultaneous T1 and T2 mapping of the entire macaque brain within feasible scan time. Methods A three‐dimensional (3D) MRF sequence with both inversion‐ and T2‐preparation modules was developed and evaluated on a 9.4 T preclinical scanner. Data acquisition used a 3D stack‐of‐spirals trajectory, with undersampling along both the in‐plane and the through‐plane directions. The effect of B1+ inhomogeneity was accounted for by matching the acquired fingerprint to a dictionary simulated with the B1+ factors measured from a separate scan. In vitro and ex vivo studies were performed to evaluate the accuracy and the undersampling capacity of the MRF method. The application of the MRF method for in vivo, brain‐wide T1 and T2 mapping was demonstrated on macaques at 4, 6, and 12 years of age. Results The MRF method enabled highly repeatable T1 and T2 mapping at high spatial resolution (0.35 × 0.35 × 1 mm3) with an acceleration factor of 24. In vivo studies showed significant age‐related T2 reduction in deep gray nuclei including the globus pallidus, the putamen, and the caudate nucleus. Conclusions This study demonstrates the first MRF study for brain‐wide, multi‐parametric quantification in non‐human primates with sub‐millimeter resolution.

To enable non-invasive dynamic metabolic mapping in rodent model studies of mitochondrial function using 31 P-MR spectroscopic imaging (MRSI). Methods: We developed a novel method for high-resolution dynamic 31 P-MRSI. The method synergistically integrates physics-based models of spectral structures, biochemical modeling of molecular dynamics, and subspace learning to capture spatiospectral variations. Fast data acquisition was achieved using rapid spiral trajectories and sparse sampling of (k, t, T)-space; image reconstruction was accomplished using a low-rank tensor-based framework. Results: The proposed method provided high-resolution dynamic metabolic mapping in rat hindlimb at spatial and temporal resolutions of 4 × 4 × 2 mm 3 and 1.28 s, respectively. This allowed for in vivo mapping of the time-constant of phosphocreatine resynthesis, a well established index of mitochondrial oxidative capacity. Multiple rounds of in vivo experiments were performed to demonstrate reproducibility, and in vitro experiments were used to validate the accuracy of the estimated metabolite maps. Conclusions: A new model-based method is proposed to achieve high-resolution dynamic 31 P-MRSI. The proposed method's ability to delineate metabolic heterogeneity was demonstrated in rat hindlimb. Significance: Abnormal mitochondrial metabolism is a key cellular dysfunction in many prevalent diseases such as diabetes and heart disease; however, current understanding of mitochondrial function is mostly gained from studies on isolated mitochondria