Search Results (23)

Brain tumors exhibit extensive metabolic reprogramming that supports proliferation, invasion, therapeutic resistance, and adaptation to dynamic microenvironmental conditions. These alterations provide opportunities for metabolic imaging approaches that extend beyond conventional anatomical neuroimaging. Hyperpolarized magnetic resonance imaging (hpMRI) has emerged as a novel metabolic imaging platform capable of non-invasively visualizing real-time cellular metabolism through dynamic nuclear polarization of carbon-13-labeled substrates. By dramatically enhancing magnetic resonance signal intensity, hpMRI enables interrogation of enzyme-specific metabolic pathways and provides unique insight into tumor energetics, metabolic heterogeneity, and treatment response. The distinct contribution of this review is an updated, brain tumor-specific, clinically oriented framework that integrates recent human evidence with longitudinal metabolic phenotyping, emerging pathway-specific probes, acquisition standardization, multimodal validation, and the remaining barriers to clinical implementation. Particular emphasis is placed on hyperpolarized [1-¹³C]pyruvate, which has demonstrated feasibility and safety in patients with gliomas and has enabled assessment of glycolytic metabolism, oxidative phosphorylation, tumor recurrence, and longitudinal treatment response. Serial changes in lactate and bicarbonate flux may also reflect evolution toward more glycolytic, heterogeneous, and treatment-resistant tumor phenotypes, supporting the potential prognostic value of hpMRI before conventional radiographic progression becomes evident. We also review emerging applications involving α-ketoglutarate metabolism, redox biology, glutathione cycling, perfusion imaging, and molecular characterization of clinically relevant alterations including IDH1, TERT, and c-MYC-associated metabolic programs. In addition, we discuss recent advances in acquisition methods, image standardization, and multimodal integration with conventional MRI and positron emission tomography. Although several technical and logistical challenges remain, hpMRI is an investigational, radiation-free metabolic imaging modality with potential applications in diagnosis, molecular stratification, and treatment monitoring; however, substantial technical, regulatory, logistical, and economic barriers currently limit routine clinical use, molecular stratification, therapeutic monitoring, and precision medicine approaches in neuro-oncology. Continued clinical translation and development of novel metabolic probes may further expand its role in brain tumors and other neurological diseases. Full article

Magnetic resonance techniques have evolved beyond conventional proton-based imaging, enabling access to a broader range of nuclei that provide complementary structural, functional, and molecular information. This review presents a comprehensive overview of multinuclear NMR and MRI in solid and soft materials as well as in biomedical applications, with particular emphasis on ¹H, ¹³C, ³¹P, ²³Na, and ¹⁹F nuclei. Proton-based methods remain the foundation of magnetic resonance due to their high sensitivity and widespread applicability, offering insights into molecular mobility, hydration, and microstructural heterogeneity. In contrast, heteronuclear approaches enable more specific characterization of chemical structure (¹³C), phosphorus-containing functional groups and membranes (³¹P), ionic homeostasis and transport (²³Na), and exogenous tracers with negligible biological background (¹⁹F). Together, these techniques extend magnetic resonance from primarily anatomical imaging toward functional, metabolic, and molecular-level analysis. The review further discusses key hardware aspects, including magnetic field strength and radiofrequency coil design, highlighting the trade-offs between low- and high-field systems and the growing importance of multinuclear coil architectures. For example, because ¹H, ²³Na, ³¹P, and ¹⁹F resonate at different Larmor frequencies, multinuclear experiments require dedicated or multi-tuned RF coils that balance sensitivity, field homogeneity, and decoupling between channels. Mechanisms of contrast generation are examined in detail, distinguishing between endogenous sources—such as water, ions, and metabolites—and exogenous contrast agents, including gadolinium-, manganese-, and fluorine-based compounds, as well as targeted and theranostic platforms. A comparative framework of endogenous and exogenous signals is presented, emphasizing their complementary roles in balancing safety, specificity, and sensitivity. Finally, the opportunities and challenges of multinuclear magnetic resonance are critically evaluated, including limitations in sensitivity, signal-to-noise ratio, data interpretation in heterogeneous systems, and technical complexity. Emerging directions such as ultrahigh-field imaging, advanced RF technologies, hyperpolarization, and artificial intelligence-assisted reconstruction are discussed as key drivers for future development. Overall, multinuclear NMR and MRI represent a powerful and expanding toolbox for probing complex material and biological systems, with the potential to significantly enhance diagnostic capabilities and deepen our understanding of structure–function relationships across multiple scales. Full article

Nuclear Magnetic Resonance (NMR) spectroscopy has long been a cornerstone in the structural elucidation of molecules, offering unique insights into atomic-level connectivity, conformation, and dynamics. Over the past decades, methodological and technological advances have significantly expanded its capabilities and applications. This manuscript charts the evolution of NMR from classical 1D/2D experiments to modern methods empowered by ultrahigh magnetic fields, cryogenic probes, non-uniform sampling, new methodologies, and hyperpolarization. We emphasize the growing synergy between experiment and computation, where automated analysis, quantum chemical calculations, and machine learning are dramatically enhancing the accuracy and efficiency of structure determination. We also highlight NMR’s broadening scope in areas ranging from complex mixtures and natural products to biomolecular and materials science. Full article

Breast cancer screening, while vital for reducing mortality, faces significant limitations in sensitivity and specificity, particularly in dense breasts. Current modalities primarily detect anatomical changes, often missing biologically aggressive tumors at their earliest stages. The altered metabolism of cancer cells establishes a characteristic inverted pH gradient that drives tumor invasion, metastasis, and treatment resistance. This makes tumor acidity a compelling, functional biomarker for early detection. This review synthesizes the emerging role of pH as a diagnostic biomarker and provides a critical evaluation of advanced imaging techniques for its non-invasive or minimal measurement. We detail the biological underpinnings of tumor acidosis, emphasizing its regulation through glycolytic reprogramming and dysregulated proton transport. Our analysis encompasses a broad spectrum of pH-sensitive imaging modalities, including magnetic resonance methods such as Chemical Exchange Saturation Transfer (CEST) MRI for extracellular pH mapping and multi-nuclear Magnetic Resonance Spectroscopy (MRS) using ¹H, ³¹P, and ¹⁹F nuclei to probe various cellular compartments. Furthermore, we examine hyperpolarized ¹³C MRI for real-time metabolic flux imaging, where metrics such as the lactate-to-pyruvate ratio demonstrate significant predictive value for treatment response. The review also assesses optical and photoacoustic imaging techniques, which offer high sensitivity but are often constrained to superficial tumors. Imaging tumor pH provides a powerful functional window into the earliest metabolic shifts in breast cancer, far preceding macroscopic anatomical changes. The ongoing development and evidence support the role of the pH-sensitive imaging techniques in diagnosis, lesion characterization, and therapy. Additionally, it holds promise for supplementing breast cancer screening by enabling earlier, more specific detection and personalized risk stratification, ultimately aiming to improve patient outcomes. Full article

In cancer diagnostics, magnetic resonance imaging (MRI) uses contrast agents to enhance the distinction between the target tissue and background. Several promising approaches have been developed to increase MRI sensitivity, one of which is Overhauser dynamic nuclear polarization (ODNP)-enhanced MRI (OMRI). In this study, a macromolecular construct based on human serum albumin and nitroxyl radicals (HSA-NIT) was developed using a new synthesis method that significantly increased the modification to 21 nitroxide residues per protein. This was confirmed by electron paramagnetic resonance (EPR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry. Gel electrophoresis and circular dichroism showed no significant changes in the structure of HSA-NITs, and no oligomers were formed during modification. The cytotoxicity of HSA-NITs was comparable to that of native albumin. HSA-NITs were evaluated as potential “metal-free” organic radical relaxation-based contrast agents for ¹H-MRI and as hyperpolarizing contrast agents for OMRI. Relaxivities (longitudinal and transversal relaxation rates r₁ and r₂) for HSA-NITs were measured at different magnetic field strengths (1.88, 3, 7, and 14 T). Phantoms were used to demonstrate the potential use of HSA-NIT as a T₁- and T₂-weighted relaxation-based contrast agent at 3 T and 14 T. The efficacy of ¹H Overhauser dynamic nuclear polarization (ODNP) in liquids at an ultralow magnetic field (ULF, B₀ = 92 ± 0.8 μT) was investigated for HSA-NIT conjugates. The HSA-NITs themselves did not show ODNP enhancement; however, under the proteolysis conditions simulating cancer tissue, HSA-NIT conjugates were cleaved into lower-molecular-weight (MW) protein fragments that activate ODNP capabilities, resulting in a maximum achievable enhancement |E_max| of 40–50 and a radiofrequency power required to achieve half of E_max, P_1/2, of 21–27 W. The HSA-NIT with a higher degree of modification released increased the number of spin probes upon biodegradation, which significantly enhanced the Overhauser effect. Thus, HSA-NITs may represent a new class of MRI relaxation-based contrast agents as well as novel cleavable conjugates for use as hyperpolarizing contrast agents (HCAs) in OMRI. Full article

The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20–tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry. The results indicate the hyperpolarizing effect of porphyrins in the concentration range of 0.5, 5, and 50 μM on the membrane of human U937 monocytic cells. Moreover, the tested porphyrins were shown to increase membrane anisotropy. Altogether, the results evidence the interaction of asymmetrical porphyrins with the membrane of U937 cells, with potential consequences on cellular homeostasis. Molecular docking simulations, and Molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) free energy of binding calculations, supported the hypothesis that the investigated porphyrinic compounds could potentially bind to membrane proteins, with a critical role in regulating the transmembrane potential. Thus, both the free base porphyrins and the metalloporphyrins could bind to the SERCA2b (sarco/endoplasmic reticulum ATPase isoform 2b) calcium pump, while the metal complexes may specifically interact and modulate calcium-dependent (large conductance calcium-activated potassium channel, Slo1/KCa1.1), and ATP-sensitive (K_ATP), potassium channels. Further studies are required to investigate these interactions and their impact on cellular homeostasis and functionality. Full article

G protein-coupled receptors can adopt many different conformational states, each of them exhibiting different restraints towards downstream signaling pathways. One promising strategy to identify and quantify this conformational landscape is to introduce a cysteine at a receptor site sensitive to different states and label this cysteine with a probe for detection. Here, the application of NMR of hyperpolarized ¹²⁹Xe for the detection of the conformational states of human neuropeptide Y2 receptor is introduced. The xenon trapping cage molecule cryptophane-A attached to a cysteine in extracellular loop 2 of the receptor facilitates chemical exchange saturation transfer experiments without and in the presence of native ligand neuropeptide Y. High-quality spectra indicative of structural states of the receptor–cage conjugate were obtained. Specifically, five signals could be assigned to the conjugate in the apo form. After the addition of NPY, one additional signal and subtle modifications in the persisting signals could be detected. The correlation of the spectroscopic signals and structural states was achieved with molecular dynamics simulations, suggesting frequent contact between the xenon trapping cage and the receptor surface but a preferred interaction with the bound ligand. Full article

Efficient ¹³C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-¹³C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous chemical exchange with an Ir-IMes-based hexacoordinate complex in CD₃OD. SABRE-SHEATH enables spontaneous polarization transfer from parahydrogen-derived hydrides to the ¹³C nucleus of transiently bound ketoisocaproate. ¹³C polarization values of up to 18% are achieved at the 1-¹³C site in 1 min in the liquid state at 30 mM substrate concentration. The efficient polarization build-up becomes possible due to favorable relaxation dynamics. Specifically, the exponential build-up time constant (14.3 ± 0.6 s) is substantially lower than the corresponding polarization decay time constant (22.8 ± 1.2 s) at the optimum polarization transfer field (0.4 microtesla) and temperature (10 °C). The experiments with natural abundance ketoisocaproate revealed polarization level on the ¹³C-2 site of less than 1%—i.e., one order of magnitude lower than that of the 1-¹³C site—which is only partially due to more-efficient relaxation dynamics in sub-microtesla fields. We rationalize the overall much lower ¹³C-2 polarization efficiency in part by less favorable catalyst-binding dynamics of the C-2 site. Pilot SABRE experiments at pH 4.0 (acidified sample) versus pH 6.1 (unaltered sodium [1-¹³C]ketoisocaproate) reveal substantial modulation of SABRE-SHEATH processes by pH, warranting future systematic pH titration studies of ketoisocaproate, as well as other structurally similar ketocarboxylate motifs including pyruvate and alpha-ketoglutarate, with the overarching goal of maximizing ¹³C polarization levels in these potent molecular probes. Finally, we also report on the pilot post-mortem use of HP [1-¹³C]ketoisocaproate in a euthanized mouse, demonstrating that SABRE-hyperpolarized ¹³C contrast agents hold promise for future metabolic studies. Full article

Parahydrogen-induced nuclear polarization offers a significant increase in the sensitivity of NMR spectroscopy to create new probes for medical diagnostics by magnetic resonance imaging. As precursors of the biocompatible hyperpolarized probes, unsaturated derivatives of phosphoric acid, propargyl and allyl phosphates, are proposed. The polarization transfer to ¹H and ³¹P nuclei of the products of their hydrogenation by parahydrogen under the ALTADENA and PASADENA conditions, and by the PH-ECHO-INEPT+ pulse sequence of NMR spectroscopy, resulted in a very high signal amplification, which is among the largest for parahydrogen-induced nuclear polarization transfer to the ³¹P nucleus. Full article

Abnormal metabolism is a hallmark of cancer cells. Accumulating evidence suggests that metabolic changes are likely to occur before other cellular responses in cancer cells upon drug treatment. Therefore, the metabolic activity or flux in cancer cells could be a potent biomarker for cancer detection and treatment monitoring. Magnetic resonance (MR)-based sensing technologies have been developed with hyperpolarized molecules for real-time flux analysis, but they still suffer from low sensitivity and throughput. To address this limitation, we have developed an innovative miniaturized MR coil, termed micro-slab MR coil, for simultaneous analysis of metabolic flux in multiple samples. Combining this approach with hyperpolarized probes, we were able to quantify the pyruvate-to-lactate flux in two different leukemic cell lines in a non-destructive manner, simultaneously. Further, we were able to rapidly assess flux changes with drug treatment in a single hyperpolarization experiment. This new multi-sample system has the potential to transform our ability to assess metabolic dynamics at scale. Full article

3D Single-breath Chemical Shift Imaging (3D-SBCSI) is a hybrid MR-spectroscopic imaging modality that uses hyperpolarized xenon-129 gas (Xe-129) to differentiate lung diseases by probing functional characteristics. This study tests the efficacy of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects—16 healthy, 11 idiopathic pulmonary fibrosis (IPF), 13 cystic fibrosis (CF), and 5 chronic obstructive pulmonary disease (COPD)—were given 1/3 forced vital capacity (FVC) of hyperpolarized Xe-129, inhaled for a ~7 s MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (R = −0.74). FEV1 predicted correlated well with RBC/Gas ratio (R = 0.67). COPD and IPF had significantly higher Tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated Tissue/RBC ratio, shorter Tissue T2* relaxation, and greater RBC chemical shift. 3D-SBCSI may be helpful in the detection and characterization of pulmonary disease, following treatment efficacy, and predicting disease outcomes. Full article

Chronic obstructive pulmonary disease (COPD) and emphysema are characterized by functional and structural damage which increases the spaces for gaseous diffusion and impairs oxygen exchange. Here we explore the potential for hyperpolarized (HP) ³He MRI to characterize lung structure and function in a large-scale population-based study. Participants (n = 54) from the Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study, a nested case-control study of COPD among participants with 10+ packyears underwent HP ³He MRI measuring p_AO₂, apparent diffusion coefficient (ADC), and ventilation. HP MRI measures were compared to full-lung CT and pulmonary function testing. High ADC values (>0.4 cm²/s) correlated with emphysema and heterogeneity in p_AO₂ measurements. Strong correlations were found between the heterogeneity of global p_AO₂ as summarized by its standard deviation (SD) (p < 0.0002) and non-physiologic p_AO₂ values (p < 0.0001) with percent emphysema on CT. A regional study revealed a strong association between p_AO₂ SD and visual emphysema severity (p < 0.003) and an association with the paraseptal emphysema subtype (p < 0.04) after adjustment for demographics and smoking status. HP noble gas p_AO₂ heterogeneity and the fraction of non-physiological p_AO₂ results increase in mild to moderate COPD. Measurements of p_AO₂ are sensitive to regional emphysematous damage detected by CT and may be used to probe pulmonary emphysema subtypes. HP noble gas lung MRI provides non-invasive information about COPD severity and lung function without ionizing radiation. Full article

Idiopathic pulmonary fibrosis, a pattern of interstitial lung disease, is often clinically unpredictable in its progression. This paper presents hyperpolarized Xenon-129 chemical shift imaging as a noninvasive, nonradioactive method of probing lung physiology as well as anatomy to monitor subtle changes in subjects with IPF. Twenty subjects, nine healthy and eleven IPF, underwent HP Xe-129 ventilation MRI and 3D-SBCSI. Spirometry was performed on all subjects before imaging, and DLCO and hematocrit were measured in IPF subjects after imaging. Images were post-processed in MATLAB and segmented using ANTs. IPF subjects exhibited, on average, higher Tissue/Gas ratios and lower RBC/Gas ratios compared with healthy subjects, and quantitative maps were more heterogeneous in IPF subjects. The higher ratios are likely due to fibrosis and thickening of the pulmonary interstitium. T2* relaxation was longer in IPF subjects and corresponded with hematocrit scores, although the mechanism is not well understood. A lower chemical shift in the red blood cell spectroscopic peak correlated well with a higher Tissue/RBC ratio and may be explained by reduced blood oxygenation. Tissue/RBC also correlated well, spatially, with areas of fibrosis in HRCT images. These results may help us understand the underlying mechanism behind gas exchange impairment and disease progression. Full article

Alterations in metabolism following radiotherapy affect therapeutic efficacy, although the mechanism underlying such alterations is unclear. A new imaging technique—named dynamic nuclear polarization (DNP) carbon-13 magnetic resonance imaging (MRI)—probes the glycolytic flux in a real-time, dynamic manner. The [1-¹³C]pyruvate is transported by the monocarboxylate transporter (MCT) into cells and converted into [1-¹³C]lactate by lactate dehydrogenase (LDH). To capture the early glycolytic alterations in the irradiated cancer and immune cells, we designed a preliminary DNP ¹³C-MRI study by using hyperpolarized [1-¹³C]pyruvate to study human FaDu squamous carcinoma cells, HMC3 microglial cells, and THP-1 monocytes before and after irradiation. The pyruvate-to-lactate conversion rate (k_PL [Pyr.]) calculated by kinetic modeling was used to evaluate the metabolic alterations. Western blotting was performed to assess the expressions of LDHA, LDHB, MCT1, and MCT4 proteins. Following irradiation, the pyruvate-to-lactate conversion rates on DNP ¹³C-MRI were significantly decreased in the FaDu and the HMC3 cells but increased in the THP-1 cells. Western blot analysis confirmed the similar trends in LDHA and LDHB expression levels. In conclusion, DNP ¹³C-MRI non-invasively captured the different glycolytic alterations among cancer and immune systems in response to irradiation, implying its potential for clinical use in the future. Full article

Type II diabetes and pre-diabetes are widely prevalent among adults. Elevated serum glucose levels are commonly treated by targeting hepatic gluconeogenesis for downregulation. However, direct measurement of hepatic gluconeogenic capacity is accomplished only via tracer metabolism approaches that rely on multiple assumptions, and are clinically intractable due to expense and time needed for the studies. We previously introduced hyperpolarized (HP) [2-¹³C]dihydroxyacetone (DHA) as a sensitive detector of gluconeogenic potential, and showed that feeding and fasting produced robust changes in the ratio of detected hexoses (6C) to trioses (3C) in the perfused liver. To confirm that this ratio is robust in the setting of treatment and hormonal control, we used ex vivo perfused mouse livers from BLKS mice (glucagon treated and metformin treated), and db/db mice. We confirm that the ratio of signal intensities of 6C to 3C in ¹³C nuclear magnetic resonance spectra post HP DHA administration is sensitive to hepatic gluconeogenic state. This method is directly applicable in vivo and can be implemented with existing technologies without the need for substantial modifications. Full article