Proton Relaxation Research Articles

Molecular miscibility of ASD blend components: an evaluation of (the added value of) solid state NMR spectroscopy and relaxometry.

In order to evaluate the stability of an amorphous solid dispersion (ASD) it is crucial to be able to accurately determine whether the ASD components are homogeneously mixed or not. Several solid-state analysis techniques are at the disposal of the formulation scientist, such as for example modulated differential scanning calorimetry (mDSC) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). ssNMR is a robust, versatile, and accurate analysis technique with a large number of application possibilities. Especially ssNMR relaxometry, which allows the measurement of the proton relaxation times T1H and T1ρH, is very useful for evaluating the miscibility of ASDs. In this paper, the miscibility of a model ASD, composed of indomethacin (IND) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), was assessed using mDSC and various ssNMR techniques, in order to compare the different techniques and to evaluate the advantages and disadvantages of each. It was found that measuring the relaxation times via the chemical shift selective carbon signals using 13C-cross-polarization magic angle spinning (13C-CPMAS) is still the golden standard to evaluate miscibility, even giving information about the miscibility at the nm scale. Although non-chemical shift selective 1H-wideline measurements are significantly faster than 13C-CPMAS measurements to determine the relaxation times, the results are often hard to interpret, especially with regard to the T1ρH relaxation times. 2D 1H-13C dipolar heteronuclear correlation (dipolar HETCOR) NMR is an additional technique that can be used, and which provides information about the special proximity of 1H and 13C nuclei with respect to each other and therefore about the miscibility of the components at the nm scale. Additionally, it often allows to acquire information regarding the intermolecular interactions and the functional groups involved. Nevertheless, optimalization of the experiments, data processing and interpretation of the results require some expertise. Compared to mDSC, the ssNMR techniques are more sensitive and robust and can often provide information about the miscibility at nm scale. However, mDSC is a very fast analysis technique that requires less optimalization. Therefore, it remains recommended to use mDSC always for a first screening and as a complementary analysis technique.

Zn(II)-Responsive MRI Probe Based on an Fe(III) Macrocyclic Complex.

The development of responsive MRI contrast agents to detect fluctuations in Zn(II) is a growing area of research. Here we describe a high-spin Fe(III) coordination complex, Fe(ADAPT), as one of the first examples of an Fe(III) MRI probe that is responsive to Zn(II). The six-coordinate Fe(ADAPT) contains a phenolate-appended 1,4,7-triazacyclononane (TACN) ligand framework, with the phenolate groups linked to a Zn(II) binding moiety. Fe(ADAPT) lacks an exchangeable inner-sphere water and thus relies on second- and outer-sphere water interactions for proton relaxation. Fe(ADAPT) is highly kinetically inert under physiological conditions at pH 7.4 and 37 °C and to excess Zn(II) over 72 h. In the presence of 2 equiv of Zn(II) with a 200 μM Fe(III) probe, an increase in relaxivity of ∼80% is observed. A ternary complex among Fe(ADAPT), Zn(II), and human serum albumin leads to a nearly 200% increase in relaxivity.

Structural Characterization and Hydration Dynamics of Cross-Linked Collagen and Hyaluronic Acid Scaffolds by Nuclear Magnetic Resonance.

Understanding a biomaterial's structural and hydration dynamics is essential for its development and applications in tissue regeneration. In this study, collagen-hyaluronic acid (HA) scaffolds were analyzed utilizing Nuclear Magnetic Resonance (NMR) techniques to elucidate how different cross-linking conditions influence the internal architecture and interaction with solvents in these scaffolds. The scaffolds were fabricated using 3D printing and cross-linked with 1,4-butanediol diglycidyl ether (BDDGE), a process known to impact their mechanical properties. We gained insights into the microstructural organization and hydration behavior within the scaffolds when exposed to water and ethanol by employing proton relaxation and diffusion measurements. To better understand the system's performance, static and dynamic experiments were performed. Our results indicate that the degree of cross-linking affects the scaffold's ability to retain water, with higher cross-linking leading to more rigid structures. This also altered the hydration dynamics mainly due to a difference in the diffusion of water within the scaffold. In addition, the anisotropy of the collagen fibers also decreases with the cross-linking. Ethanol, a less polar solvent, provided a contrasting environment that further revealed the structural dependencies on the cross-linking density. The study's findings contribute to a deeper understanding of how the structure and morphology affect the functionality of collagen-HA scaffolds, offering critical information for optimizing their design for specific biomedical applications, such as soft tissue regeneration. Our experiments show how NMR is a valuable tool to provide information on dynamic processes not only in collagen-HA scaffolds but also in many biocompatible polymeric samples. The outcomes of this research provide a foundation for future work aimed at tailoring scaffold properties to enhance their performance in clinical settings, ultimately advancing the field of tissue engineering.

Size dependent properties of Gd3+-free versus Gd3+-doped carbon dots for bioimaging application

Gd3+- free carbon dots (CDs) were synthesized by one-step solvothermal method using urea, citric acid and 3-(trifluoromethyl)aniline as precursors. Additionally, Gd3+-doped CDs were prepared by incorporating gadolinium chloride (Gd3+ ions) into the synthesis. Size selection of the purified CDs was achieved through filter membranes ranging from 3 kDa to 100 kDa. The chemical composition and optical properties of the obtained samples were characterized by Energy dispersive X-ray (EDX), Fourier-transform infrared spectroscopy (FTIR), Dynamic Light Scattering (DLS), proton relaxation time measurements, Ultraviolet–visible (UV-vis) and fluorescence spectroscopies. A comparative analysis revealed a strong size-dependent behavior in the optical properties of both Gd3+-doped and Gd3+-free CDs. Furthermore, in vitro tests confirmed the non-cytotoxicity of Gd3+-doped CDs, indicating their potential applicability in biomedicine for magnetic resonance imaging (MRI) and red fluorescence-based cell and tissue imaging.

Investigation of magnetic resonance contrast properties of PEG-coated gadolinium oxide nanoparticles in various biological environments

Abstract Magnetic nanoparticles (MNPs) are promising tools for biomedical applications, particularly in molecular imaging using magnetic resonance imaging (MRI). The unique magnetic properties of MNPs, combined with their similarity in size to biological objects, make them ideal candidates for in situ imaging probes. The present study explores the use of magnetic nanoparticles (MNPs) as contrast agents in magnetic resonance imaging (MRI) for improved diagnostic accuracy. Specifically, the study investigates the MR contrast properties of polyethylene glycol-coated gadolinium oxide nanoparticles (PEG@GONPs) in five different biological fluids. The nanoparticles were synthesized using the polyol route and their size, shape, and morphology were characterized using TEM, SEM, and FT-IR spectroscopy. The magnetic resonance (MR) relaxivity of PEG@GONPs was studied in different biologically relevant media, and results revealed highest relaxivity in plasma as compared to other media. In addition, comparative analysis of proton relaxivity of the synthesized nanoparticles was carried out with a well-known gadolinium-based contrast agent, Omniscan, in various medium. The present findings revealed that PEG@GONPs can serve as an effective contrast agent for MRI imaging in biological fluids such as plasma, which is crucial for preclinical diagnosis of specific diseases and lesions. The high relaxivity observed in plasma could be attributed to the interaction of the nanoparticles with plasma proteins, amplifying their magnetic properties which further improve their ability to produce contrast in MR images.

High-performance PVdF-HFP/PEG-IL composites: The combined effects of PEG and ionic liquid on proton conductivity and dielectric characteristics

This study explores the influence of varying polyethylene glycol (PEG) concentrations on the properties of PVdF-HFP/PEG-IL polymer composites through comprehensive characterization techniques, including FTIR, SEM, TGA, DMA, XRD and the detailed assessments of proton conductivity, dielectric properties, and relaxation dynamics. In terms of conductivity, the addition of PEG markedly improves proton conductivity. The PVdF-HFP/PEG40-IL composite exhibits the highest conductivity, reaching 1.96 × 10⁻2 S/m at 1 MHz and 300 K, and increasing to 4.27 × 10⁻2 S/m at 420 K. Dielectric properties show that the dielectric constant (ε′) increases with PEG content at low frequencies but decreases at higher frequencies due to reduced ionic polarization. Notably, PVdF-HFP/PEG40-IL achieves a dielectric constant of 3.39 × 106 at 20 Hz, which decreases to 30.34 at 1 MHz. Dielectric loss (ε'') also rises with temperature, with PVdF-HFP/PEG40-IL demonstrating the highest dielectric loss, indicative of superior proton conduction and polarization capabilities. Relaxation dynamics, as evidenced by tanδ, reveal that relaxation time significantly decreases with both increased PEG content and temperature, dropping from 1.06 × 10⁻4 s to 2 × 10⁻6 s as PEG concentration increases from 10 % to 40 %. This reduction in relaxation time correlates with enhanced proton conductivity and faster dipole relaxation, indicating PEG effect as a plasticizer that reduces polymer viscosity and improves ion transport. In conclusion, incorporating PEG into PVdF-HFP-IL composites leads to substantial improvements in proton conductivity, dielectric properties, and relaxation dynamics. The results highlight the crucial role of PEG in optimizing the performance of polymer electrolyte composites, making them effective candidates for advanced energy storage and conversion applications.

Pathological tissue changes in brain tumors affect the pH-sensitivity of the T1-corrected apparent exchange dependent relaxation (AREX) of the amide protons.

Measuring the intracellular pH (pHi) is of interest for brain tumor diagnostics. Common metrics of CEST imaging like the amide proton transfer-weighted (APTw) MTRasym are pHi sensitive and allow differentiating malignant tumor from healthy tissue. Yet, the image contrast also depends on additional magnetization transfer effects and T1. In contrast, the apparent exchange-dependent relaxation (AREX) provides a T1 corrected exchange rate of the amide protons. As AREX still depends on amide proton density, its pHi sensitivity remains ambiguous. Hence, we conducted this study to assess the influence of pathologic tissue changes on the pHi sensitivity of AREX in vivo. Patients with newly diagnosed intra-axial brain tumors were prospectively recruited and underwent conventional MRI, quantitative T1 relaxometry, APT-CEST and 31P-MRS on a 3T MRI scanner. Tumors were segmented into contrast-enhancing tumor (CE), surrounding T2 hyperintensity (T2-H) and contralateral normal appearing white matter (CNAWM). T1 mapping and APT-CEST metrics were correlated with 31P-MRS-derived pHi maps (Pearson's correlation). Without differentiating tissue subtypes, pHi did not only correlate significantly with MTRasym (r= 0.46) but also with T1 (r= 0.49). Conversely, AREX only correlated poorly with pHi (r= 0.17). Analyzing different tissue subtypes separately revealed a tissue dependency of the pHi sensitivity of AREX with a significant correlation (r= 0.6) in CNAWM and no correlation in T2-H or CE (r= -0.11/-0.24). CE showed significantly increased MTRasym, pHi, and T1 compared with CNAWM (p< 0.001). In our study, the pHi sensitivity of AREX was limited to CNAWM. The lack of sensitivity in CE and T2-H is probably attributable to altered amide and water proton concentrations in these tissues. Conversely, the correlation of pHi with MTRasym may be explained by the coincidental contrast increase through increased T1 and amide proton density. Therefore, limited structural deviations from CNAWM might be a perquisite for the use of CEST contrasts as pHi-marker.

Effect of the Dispersion Medium on NMR Relaxation Properties of Superparamagnetic Iron Oxide Nanoparticles between 0.24 mT and 14.1 T.

Due to weak exchange interactions, magnetite particles at a critical diameter of about 20 nm are considered monodomain. At this size, they exhibit a phenomenological magnetic property called superparamagnetism, making them useful as magnetic resonance imaging contrast agents, or MRI CAs. However, questions persist regarding the impact of using different physiological solvents and varying the environment in which these particles are dispersed on their performance, determined by their relaxivity. A colloidal suspension of superparamagnetic iron oxide nanoparticles (SPIONs) electrostatically stabilized by citrate ligand was synthesized using a fast, reliable, and reproducible developed microwave approach, ensuring high stability over time at pH 7. We studied the effects of three physiological media on these MRI CAs. Ultrapure water was used for the synthesis, while phosphate-buffered saline and physiological liquid were used to disperse the nanoparticles, as these media contain essential electrolytes for the functioning of the human body. The SPIONs underwent systematic characterizations to determine their physicochemical and magnetic properties. This study reports the longitudinal relaxivities of SPIONs at medically relevant magnetic field strengths. Field dependence of their relaxivity (efficacy) was evaluated using a nuclear magnetic resonance dispersion (NMRD) profile measured over a wide range of proton resonance frequencies between 5 kHz and 600 MHz. The Roch et al. model (Roch, A.; et al. J. Chem. Phys., 1999, 110, 5403-5411) was used to analyze the NMRD profile and evaluate the impact of SPIONs on water proton relaxation in the different redispersion media. It was observed in this study that the dynamics of water protons are not influenced by the redispersion media of these citrate-coated SPIONs. However, the presence of salt ions notably reduces their relaxivities by lowering the saturation magnetization of SPIONs.

Gadopiclenol: A q = 2 Gadolinium-Based MRI Contrast Agent Combining High Stability and Efficacy.

Gadopiclenol is a q = 2 pyclen gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration, European Medicines Agency, and other European countries. The aim of this report is to demonstrate its stability in multiple stressed in vitro conditions and in vivo, in rat kidney, while maintaining its higher relaxivity compared with conventional GBCAs on the market. Both gadopiclenol and its chemical precursor Pi828-Gd were characterized and compared with q = 1 gadolinium (Gd) complexes. The number of water molecules coordinated to the Gd (the hydration number, q) was determined by luminescence. 17O NMR (Nuclear Magnetic Resonance) measurements gave access to the water residence time τM. These parameters were used for the fitting of the nuclear magnetic relaxation dispersion profiles in water. Proton relaxivities of the complexes were determined in different media at 60 MHz (1.4 T), at different pH and temperature. The kinetic inertness was investigated in human serum, acidic media, under zinc competition in the presence of phosphate, and under ligand competition. The in vivo stability was evaluated in rat kidneys 12 months after repeated injections. The presence of 2 inner-sphere water molecules per Gd complex was confirmed for both pyclen derivatives. The high relaxivity of the complexes in water is maintained under physiological conditions, even under stressed conditions (ionic media, extreme pH, and temperature), which guarantees their efficiency in a large range of in vivo situations. Gd release from the q = 2 complexes was investigated in different potentially destabilizing conditions. Either no Gd release or a slower one than with "q = 1" stable macrocyclic GBCA (acidic conditions) was observed. Their kinetic inertness was demonstrated in physiological conditions, and the Gd release was below the lower limit of quantification of 0.1 μM after 12 days at 37°C in human serum. It was also demonstrated that gadopiclenol is stable in vivo in rat kidney 12 months after repeated injections. Thanks to its optimized structural design, gadopiclenol is a highly stable and effective macrocyclic q = 2 GBCA.

Synthesis of an Ethylenediaminetetraacetic Acid-like Ligand Based on Sucrose Scaffold and Complexation and Proton Relaxivity Studies of Its Gadolinium(III) Complex in Solution.

Sucrose constitutes a non-toxic, biodegradable, low-cost and readily available natural product. To expand its utility, we developed total synthesis for a ligand based on a sucrose scaffold for potential use as a metal chelation agent. The designed target (compound 2) has a metal-chelating functionality at both the C-6 and C-6' positions, which can provide a first coordination sphere of eight valencies. The designed total synthesis was highly efficient. To demonstrate the utility of the ligand, we studied its complexation with Gd(III). Using potentiometric titration and high-resolution mass spectrometry, we confirmed the formation of a 1:1 complex with Gd(III), which has a respectable formation constant of ~1013.4. Further NMR relaxivity studies show that the Gd(III) complex has a relaxivity (r1) of 7.6958 mmol-1 s-1.

Myo-regressor Deep Informed Neural NetwOrk (Myo-DINO) for fast MR parameters mapping in neuromuscular disorders

Magnetic Resonance (MR) parameters mapping in muscle Magnetic Resonance Imaging (mMRI) is predominantly performed using pattern recognition-based algorithms, which are characterised by high computational costs and scalability issues in the context of multi-parametric mapping.Deep Learning (DL) has been demonstrated to be a robust and efficient method for rapid MR parameters mapping. However, its application in mMRI domain to investigate Neuromuscular Disorders (NMDs) has not yet been explored. In addition, data-driven DL models suffered in interpretation and explainability of the learning process. We developed a Physics Informed Neural Network called Myo-Regressor Deep Informed Neural NetwOrk (Myo-DINO) for efficient and explainable Fat Fraction (FF), water-T2 (wT2) and B1 mapping from a cohort of NMDs.A total of 2165 slices (232 subjects) from Multi-Echo Spin Echo (MESE) images were selected as the input dataset for which FF, wT2,B1 ground truth maps were computed using the MyoQMRI toolbox. This toolbox exploits the Extended Phase Graph (EPG) theory with a two-component model (water and fat signal) and slice profile to simulate the signal evolution in the MESE framework. A customized U-Net architecture was implemented as the Myo-DINO architecture. The squared L2 norm loss was complemented by two distinct physics models to define two ‘Physics-Informed’ loss functions: Cycling Loss 1 embedded a mono-exponential model to describe the relaxation of water protons, while Cycling Loss 2 incorporated the EPG theory with slice profile to model the magnetization dephasing under the effect of gradients and RF pulses. The Myo-DINO was trained with the hyperparameter value of the 'Physics-Informed' component held constant, i.e. λmodel = 1, while different hyperparameter values (λcnn) were applied to the squared L2 norm component in both the cycling loss. In particular, hard (λcnn=10), normal (λcnn=1) and self-supervised (λcnn=0) constraints were applied to gradually decrease the impact of the squared L2 norm component on the ‘Physics Informed’ term during the Myo-DINO training process.Myo-DINO achieved higher performance with Cycling Loss 2 for FF, wT2 and B1 prediction. In particular, high reconstruction similarity and quality (Structural Similarity Index > 0.92, Peak Signal to Noise ratio > 30.0 db) and small reconstruction error (Normalized Root Mean Squared Error < 0.038) to the reference maps were shown with self-supervised weighting of the Cycling Loss 2. In addition muscle-wise FF, wT2 and B1 predicted values showed good agreement with the reference values. The Myo-DINO has been demonstrated to be a robust and efficient workflow for MR parameters mapping in the context of mMRI. This provides preliminary evidence that it can be an effective alternative to the reference post-processing algorithm. In addition, our results demonstrate that Cycling Loss 2, which incorporates the Extended Phase Graph (EPG) model, provides the most robust and relevant physical constraints for Myo-DINO in this multi-parameter regression task. The use of Cycling Loss 2 with self-supervised constraint improved the explainability of the learning process because the network acquired domain knowledge solely in accordance with the assumptions of the EPG model.

Bimodal Magneto‐Luminescent Response of Lanthanide Metallopolymers for Distinguishing of Phosphates in Aqueous Solutions

AbstractLinear N‐substituted polyacrylamides bearing tricarboxylic moieties pendant to the backbone are synthesized, and coordinative binding approach is developed to convert them into Gd3+/Eu3+‐metallopolymers. Inner‐sphere coordination of the lanthanide ions with the pendant chelating moieties, together with their outer‐sphere stabilization by the randomly coiled backbone, are the reasons for peculiar water proton relaxation and luminescence properties of the metallopolymers obtained. Indeed, for Gd3+‐metallopolymer, the values of longitudinal and transverse relaxivity (r1 and r2) are 50 and 60 mm−1·s−1, respectively, while for the Eu3+‐counterpart, Eu3+‐centered luminescence is significantly raised compared to Eu3+ aquaions. Coil‐like conformation of the metallopolymer molecules undergoes a swelling at pH values above 5.0 as evidenced by transmission electron microscopy TEM and dynamic light scattering (DLS) data, which is followed by the changes in the Eu3+‐centered luminescence and r1(2)‐values of Gd3+/Eu3+‐metallopolymers. The phosphates additives (adenosine monophosphoric acid (AMP), adenosine diphosphoric acid (ADP), HPO42− and adenosine triphosphoric acid (ATP) induce well detectable changes in both water proton relaxation and luminescence of Gd3+/Eu3+‐metallopolymers. The luminescent changes distinguish AMP from the other phosphates, while the changes in water proton relaxation are greater for HPO42− and ATP compared to AMP and ADP. This study explains this by interplay of the effects associated with the formation of ternary phosphate‐lanthanide‐polymer complexes and stripping of lanthanide ions from the polymer molecules.

Development of Myelin Growth Charts of the White Matter Using T1 Relaxometry.

Myelin maturation occurs in late fetal life to early adulthood, with the most rapid changes observed in the first few years of infancy. To quantify the degree of myelination, a specific MR imaging sequence is required to measure the changes in tissue proton relaxivity (R1). R1 positively correlates with the degree of myelination maturation at a given age. Similar to head circumference charts, these data can be used to develop normal growth charts for specific white matter tracts to detect pathologies involving abnormal myelination. This is a cross-sectional study using normal clinical pediatric brain MR images with the MP2RAGE sequence to generate T1 maps. The T1 maps were segmented to 75 brain regions from a brain atlas (white matter and gyri). Statistical modeling for all subjects across regions and the age range was computed, and estimates of population-level percentile ranking were computed to describe the effective myelination rate as a function of age. Test-retest analysis was performed to assess reproducibility. Logistic trendline and regression were performed for selected white matter regions and plotted for growth charts. After exclusion for abnormal MR imaging or diseases affecting myelination from the electronic medical record, 103 subject MR images were included, ranging from birth to 17 years of age. Test-retest analysis resulted in a high correlation for white matter (r = 0.88) and gyri (r = 0.95). All white matter regions from the atlas had significant P values for logistic regression with R 2 values ranging from 0.41 to 0.99. These data can serve as a myelination growth chart to permit patient comparisons with normal levels with respect to age and brain regions, thus improving detection of developmental disorders affecting myelin.

Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues

Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solid-state nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1H–13C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs.

Solid-State NMR Characterization of Mefloquine Resinate Complexes Designed for Taste-Masking Pediatric Formulations.

Mefloquine (MQ) is an antimalarial medication prescribed to treat or malaria prevention.. When taken by children, vomiting usually occurs, and new doses of medication frequently need to be taken. So, developing pediatric medicines using taste-masked antimalarial drug complexes is mandatory for the success of mefloquine administration. The hypothesis that binding mefloquine to an ion-exchange resin (R) could circumvent the drug's bitter taste problem was proposed, and solid-state 13C cross-polarization magic angle spinning (CPMAS) NMR was able to follow MQ-R mixtures through chemical shift and relaxation measurements. The nature of MQ-R complex formation could then be determined. Impedimetric electronic tongue equipment also verified the resinate taste-masking efficiency in vitro. Variations in chemical shifts and structure dynamics measured by proton relaxation properties (e.g., T1ρH) were used as probes to follow the extension of mixing and specific interactions that would be present in MQ-R. A significant decrease in T1ρH values was observed for MQ carbons in MQ-R complexes, compared to the ones in MQ (from 100-200 ms in MQ to 20-50 ms in an MQ-R complex). The results evidenced that the cationic resin interacts strongly with mefloquine molecules in the formulation of a 1:1 ratio complex. Thus, 13C CPMAS NMR allowed the confirmation of the presence of a binding between mefloquine and polacrilin in the MQ-R formulation studied.

Boundary of the Distribution of Solar Wind Proton Beta versus Temperature Anisotropy

The frequency distribution of solar wind protons, measured in the vicinity of Earth’s orbit, is customarily plotted in (β ∥, T ⊥/T ∥) phase space. Here, T ⊥/T ∥ is the ratio of perpendicular and parallel temperatures, and β ∥ = 8π nT ∥/B 2 is the ratio of parallel thermal energy to background magnetic field energy, the so-called “parallel beta,” with ⊥ and ∥ denoting directions with respect to the ambient magnetic field. Such a frequency distribution, plotted as a two-dimensional histogram, forms a peculiar rhombic shape defined with an outer boundary in the said phase space. Past studies reveal that the threshold conditions for temperature anisotropy–driven plasma instability partially account for the boundary on the high-β ∥ side. The low-β ∥ side remains largely unexplained despite some efforts. Work by Vafin et al. recently showed that certain contours of collisional relaxation frequency, ν pp, when parameterized by T ⊥/T ∥ and β ∥, could match the overall shape of the left-hand boundary, thus suggesting that the collisional relaxation process might be closely related to the formation of the left-hand boundary. The present paper extends the analysis by Vafin et al. and carries out the dynamical computation of the collisional relaxation process for an ensemble of initial proton states with varying degrees of anisotropic temperatures. The final states of the relaxed protons are shown to closely match the observed boundary to the left of the (β ∥, T ⊥/T ∥) phase space. When coupled with a similar set of calculations for the ensemble in the collective instability regime, it is found that the combined collisional/collective effects provide the baseline explanation for the observation.

Anisotropic longitudinal water proton relaxation in white matter investigated ex vivo in porcine spinal cord with sample rotation

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Interaction of MRI Contrast Agent [Gd(DOTA)]- with Lipid Membranes: A Molecular Dynamics Study.

Contrast agents are important imaging probes in clinical MRI, allowing the identification of anatomic changes that otherwise would not be possible. Intensive research on the development of new contrast agents is being made to image specific pathological markers or sense local biochemical changes. The most widely used MRI contrast agents are based on gadolinium(III) complexes. Due to their very high charge density, they have low permeability through tight biological barriers such as the blood-brain barrier, hampering their application in the diagnosis of neurological disorders. In this study, we explore the interaction between the widely used contrast agent [Gd(DOTA)]- (Dotarem) and POPC lipid bilayers by means of molecular dynamics simulations. This metal complex is a standard reference where several chemical modifications have been introduced to improve key properties such as bioavailability and targeting. The simulations unveil detailed insights into the agent's interaction with the lipid bilayer, offering perspectives beyond experimental methods. Various properties, including the impact on global and local bilayer properties, were analyzed. As expected, the results indicate a low partition coefficient (KP) and high permeation barrier for this reference compound. Nevertheless, favorable interactions are established with the membrane leading to moderately long residence times. While coordination of one inner-sphere water molecule is maintained for the membrane-associated chelate, the physical-chemical attributes of [Gd(DOTA)]- as a MRI contrast agent are affected. Namely, increases in the rotational correlation times and in the residence time of the inner-sphere water are observed, with the former expected to significantly increase the water proton relaxivity. This work establishes a reference framework for the use of simulations to guide the rational design of new contrast agents with improved relaxivity and bioavailability and for the development of liposome-based formulations for use as imaging probes or theranostic agents.

Fibronectin-Targeting Dual-Modal MR/NIRF Imaging Contrast Agents for Diagnosis of Gastric Cancer and Peritoneal Metastasis.

The prevalence and fatality rates of gastric cancer (GC) remain elevated, with advanced stages presenting a grim prognosis. Noninvasive diagnosis of GC cancer often proves challenging until the disease has progressed to an advanced stage or metastasized. Initially, the level of fibronectin (FN) in cancer-associated fibroblasts (CAFs) of GC was at least 3.7 times higher than that in normal fibroblasts. Herein, two FN-targeting magnetic resonance/near-infrared fluorescence (MR/NIRF) imaging contrast agents were developed to detect GC and peritoneal metastasis noninvasively. The probes CREKA-Cy7-(Gd-DOTA) and CREKA-Cy7-(Gd-DOTA)3 demonstrated significant FN-targeting capability (with dissociation constants of 1.0 and 2.1 mM) and effective MR imaging performance (with proton relaxivity values of 9.66 and 27.44 mM-1 s-1 at 9.4 T, 37 °C). In vivo imaging revealed a high signal-to-noise ratio and successful visualization of GC metastasis using NIRF imaging as well as successful tumor detection in MR imaging. Therefore, this study highlights the potential of FN-targeting probes for GC diagnosis and aids in the advancement of new diagnostic strategies for the clinical detection of GC.

Magnetic Field-Optimized Paramagnetic Nanoprobe for T2/T1 Switchable Histopathological-Level MRI.

Traditional magnetic resonance imaging (MRI) contrast agents (CAs) are a type of "always on" system that accelerates proton relaxation regardless of their enrichment region. This "always on" feature leads to a decrease in signal differences between lesions and normal tissues, hampering their applications in accurate and early diagnosis. Herein, we report a strategy to fabricate glutathione (GSH)-responsive one-dimensional (1-D) manganese oxide nanoparticles (MONPs) with improved T2 relaxivities and achieve effective T2/T1 switchable MRI imaging of tumors. Compared to traditional contrast agents with high saturation magnetization to enhance T2 relaxivities, 1-D MONPs with weak Ms effectively increase the inhomogeneity of the local magnetic field and exhibit obvious T2 contrast. The inhomogeneity of the local magnetic field of 1-D MONPs is highly dependent on their number of primary particles and surface roughness according to Landau-Lifshitz-Gilbert simulations and thus eventually determines their T2 relaxivities. Furthermore, the GSH responsiveness ensures 1-D MONPs with sensitive switching from the T2 to T1 mode in vitro and subcutaneous tumors to clearly delineate the boundary of glioma and metastasis margins, achieving precise histopathological-level MRI. This study provides a strategy to improve T2 relaxivity of magnetic nanoparticles and construct switchable MRI CAs, offering high tumor-to-normal tissue contrast signal for early and accurate diagnosis.