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Aluminum-adjuvanted vaccines are freeze-sensitive products that require attentive cold chain adherence. Freeze/thaw events can be tested using "The World Health Organization Shake Test", a qualitative test whereby a vial from the batch suspected to have been frozen is checked to infer whether the whole batch has been frozen. In this paper, we present a noninvasive and quantitative method to detect whether a vial of liquid vaccine has experienced freeze/thaw using the water proton transverse relaxation rate by Nuclear Magnetic Resonance relaxometry (wNMR relaxometry). Importantly, wNMR relaxometry does not compromise the vial's integrity so the analyzed vial can be used for vaccination if it meets the quality specifications. Vial-to-vial variability in freezing susceptibility within a single carton of vaccine vials was also detected, both by visual observation and concurrently by wNMR relaxometry. This variability brings into question the practice of using one or a few vials in a batch of vaccines to infer about the quality of the whole batch.

For the construction of metal-free magnetic resonance imaging (MRI) contrast agents, radical-based nanoparticles (RNPs) are promising materials because they allow the water-proton longitudinal rela...

PURPOSE: To investigate the correlations between cortical bone microstructural properties and total water proton density (TWPD) obtained from three-dimensional ultrashort echo time Cones (3D-UTE-Cones) magnetic resonance imaging techniques. MATERIALS AND METHODS: 135 cortical bone samples were harvested from human tibial and femoral midshafts of 37 donors (61±24 years old). Samples were scanned using 3D-UTE-Cones sequences on a clinical 3T MRI and on a high-resolution micro-computed tomography (μCT) scanner. TWPD was measured using 3D-UTE-Cones MR images. Average bone porosity, pore size, and bone mineral density (BMD) were measured from μCT images at 9 μm voxel size. Pearson’s correlation coefficients between TWPD and μCT-based measures were calculated. RESULTS: TWPD showed significant moderate correlation with both average bone porosity (R=0.66, p

The present work reports an enabling novel technology for quantifying the gene content in adeno-associated viral capsids. The method is based on the water proton nuclear magnetic resonance (wNMR) technique. Instead of analyzing the capsid directly, it utilizes water molecules to distinguish empty and full capsids, as water interacts with them differently. The transverse relaxation rate of water protons, R2(1H2O), readily distinguishes empty and full capsids and is capable of quantifying the fraction of full capsids in a mixture of full and empty ones. It involves no sample preparation and no reagents. Measurement is rapid (data collection takes 1-2 min), noninvasive (the capsid sample can stay inside the original sealed and labeled container to be used in other studies or administered to a patient), and performed using a wide-bore benchtop NMR instrument. The method can be readily implemented at a production plant for product release as part of product quality control.

Background: There is a clear need to transition from batch-level to vial/syringe/pen-level quality control of biologic drugs, such as insulin. This could be achieved only by noninvasive and quantitative inspection technologies that maintain the integrity of the drug product. Methods: Four insulin products for patient self-injection presented as prefilled pens have been noninvasively and quantitatively inspected using the water proton NMR technology. The inspection output is the water proton relaxation rate R2(1H2O), a continuous numerical variable rather than binary pass/fail. Results: Ten pens of each product were inspected. R2(1H2O) displays insignificant variation among the 10 pens of each product, suggesting good insulin content uniformity in the inspected pens. It is also shown that transferring the insulin solution out of and then back into the insulin pen caused significant change in R2(1H2O), presumably due to exposure to O2 in air. Conclusions: Water proton NMR can noninvasively and quantitatively inspect insulin pens. wNMR can confirm product content uniformity, but not absolute content. Its sensitivity to sample transferring provides a way to detect drug product tampering. This opens the possibility of inspecting every pen/vial/syringe by manufacturers and end-users.

Summary The homeopathic medicine, Silicea has been used in biological, physico-chemical and clinical studies. In biology, Silicea increase the production of paf-acether by mouse peritoneal macrophages. The high dilutions of Silicea have been studied using nuclear magnetic resonance, with reproducible modifications of water proton relaxation times. It has been used in India for the treatment of tubercular lymphadenitis and could be included in the homeopathic treatment given in addition to the standard care in multi drug resistant pulmonary tuberculosis.

The conformational transition of a fluorinated amphiphilic dendrimer is monitored by the 1 H signal from water, alongside the 19 F signal from the dendrimer. High-field NMR data (chemical shift δ, self-diffusion coefficient D, longitudinal relaxation rate R1 , and transverse relaxation rate R2 ) for both dendrimer (19 F) and water (1 H) match each other in detecting the conformational transition. Among all parameters for both nuclei, the water proton transverse-relaxation rate R2 (1 H2 O) displays the highest relative scale of change upon conformational transition of the dendrimer. Hydrogen/deuterium-exchange mass spectrometry reveals that the compact form of the dendrimer has slower proton exchange with water than the extended form. This result suggests that the sensitivity of R2 (1 H2 O) toward dendrimer conformation originates, at least partially, from the difference in proton exchange efficiency between different dendrimer conformations. Finally, we also demonstrated that this conformational transition could be conveniently monitored using a low-field benchtop NMR spectrometer via R2 (1 H2 O). The 1 H2 O signal thus offers a simple way to monitor structural changes of macromolecules using benchtop time-domain NMR.

Water proton transverse relaxation rate R2(1H2O) measurements by NMR stand out as a powerful noninvasive tool to detect protein aggregates, including subvisible particles in biopharmaceutical formulations. To understand the applicability of water proton NMR (wNMR), we studied the response and sensitivity of wNMR to the aggregates of a monoclonal antibody (mAb) within a wide size range at different aggregate levels, for three different physical stresses: freeze–thaw cycling, heating, and agitation. We compared the sensitivity and response of wNMR with those observed by conventional techniques of size exclusion chromatography (SEC), microflow imaging (MFI), and dynamic light scattering (DLS). Our findings showed that wNMR detects mAb aggregates within wide aggregate levels and in a wide range of aggregate sizes. wNMR was sensitive to an increase in soluble protein aggregates in the range of

Unlike many known amphiphiles, the fluorinated amphiphilic dendrimer studied in this work demonstrated a concentration-dependent conformational transition rather than micellization or assembly. Hydrophobic and hydrophilic interactions with water were suggested as the most probable driving force of this transition. This assumption was consistent with the observed 19F chemical shift changes of the dendrimer compared to a known micelle-forming fluorinated amphiphile. Since water is an important factor in the process, trends of the concentration-dependent changes in water proton transverse relaxation rate served as an indicator of structural changes and/or supramolecular assembly. The conformational transition process was also confirmed by ion-mobility mass-spectrometry. We suggested that structural features, namely, steric hindrances, prevented the micellization/assembly of the dendrimer of this study. This conclusion might inform the approach to develop novel unconventional amphiphiles.

Objective To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature. Methods Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model. Results After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less. Discussion The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

Quantitative relaxometry mapping—the measurement of water proton relaxation with MRI—provides a valuable imaging tool to characterize tissue, particularly in the brain. This topic is presented in terms of two parts: i) models that relate transverse or longitudinal relaxation to the structure and composition of neural tissue, such as the volume fraction of myelin and concentration of iron, and 2) MRI methods that can provide quantitative relaxation measurements. The simplest models relate one or more tissue characteristic to a single mono-exponential relaxation rate, which allows efficient measurements but faces limits in specificity and accuracy. Multi-exponential models offer a more complete characterization of tissue at the cost of efficiency in measurement. For any application, the user should appreciate potential shortcomings of the model and the precision of the measured relaxation parameters.

International audience; Since the early eighties MRI has become the most powerful technic for in-vivo imaging particularly in the field of brain research. This non-invasive method allows acute anatomical observations of the living brain similar to post-mortem dissected tissues. However, one of the main limitation of MRI is that it does not make possible the neurochemical identification of the tissues conversely to positron emission tomography scanner which can provide a specific molecular characterization of tissue, in spite of poor anatomical definition. To gain neurochemical information using MRI, new categories of contrast agents were developed from the beginning of the 2000’s, particularly using the chemical-exchange saturation transfer (CEST) method. This method induces a significant change in the magnitude of the water proton signal and allows the detection of specific molecules within the tissues like sugars, amino acids, transmitters, and nucleosides. This short review presents several CEST contrast agents and their recent developments for in vivo detection of metabolites and neurotransmitters in the brain for research and clinical purposes.

Suspensions of solid particles find applications in many areas-mining, waste treatment, and in pharmaceutical formulations. Pharmaceutical suspensions include aluminum-adjuvanted vaccines are widely administered to millions of people worldwide annually. Hence, the stability parameters of such suspensions, for example, sedimentation rate and the compactness of the formed sediments, are of great interest to achieve the most optimal and stable formulations. Unlike currently used analytical techniques involving visual observations and/or monitoring of several optical properties using specialized glassware, water proton nuclear magnetic resonance (wNMR) used in this work allows one to analyze samples in their original sealed container regardless of its opacity and/or labeling. It was demonstrated that the water proton transverse relaxation rate could be used to monitor in real time the sedimentation process of two widely used aluminum adjuvants-Alhydrogel® and Adju-Phos®. Using wNMR, we obtained valuable information on the sedimentation rate, dynamics of the supernatant and sediment formation, and the sedimentation volume ratio (SVR) reflecting the compactness of the formed sediment. Results on SVR from wNMR were verified by caliper measurements. Verification of the sedimentation rate results from wNMR by other analytical techniques is challenging due to differences in the measured attributes and even units of the reported rate. Nonetheless, our results demonstrate the practical applicability of wNMR as an analytical tool to study pharmaceutical suspensions, for example, aluminum-adjuvanted vaccines, to provide higher quality and more efficient vaccines. Such analyses could be carried out in the original container of a suspension drug product to study its colloidal stability and to monitor its quality over time without compromising product integrity.

MRI relaxometry is sensitive to a variety of tissue characteristics in a complex manner, which makes it both attractive and challenging for characterizing tissue. This article reviews the most common water proton relaxometry measures, T(1), T(2), and [Formula: see text] , and reports on their development and current potential to probe the composition and microstructure of brain tissue. The development of these relaxometry measures is challenged by the need for suitably accurate tissue models, as well as robust acquisition and analysis methodologies. MRI relaxometry has been established as a tool for characterizing neural tissue, particular with respect to myelination, and the potential for further development exists.

Snowflakes and ordinary hexagonal ice were studied measuring water proton spin–lattice relaxation rate R1(ωI)-nuclear magnetic resonance dispersion (NMRD) profiles at proton Larmor frequencies ranging from 1 to 30 MHz and at different temperatures ranging from −2◦C to −10◦C. The spin–spin relaxation rate 1/ 1/T2(ωI) was determined at a single Larmor frequency of 16.3 MHz. The high-field wing of the proton R1(ωI)-NMRD profile was characterised by two parameters: a correlation time τc which described the dipole–dipole spectral density, and the relaxation rate at low fields R max real (0) which was determined from T 2 . The correlation time τc depended on the dynamic model used. A rotation diffusion model yield approximatively 3μs at −3◦C to about 5μs at 10◦C, whereas for a more realistic six-site discrete exchange model, the correlation times decreased slightly to about 80% for the same temperature interval. Proton dipole–dipole interactions were divided into intramolecular and intermolecular contributions where the intermolecular contribution was about 0.4–0.8 × the intramolecular contribution. It was not possible to discriminate between the dynamic models or to detect ice/water interface effects by comparing the NMRD data from snowflakes with ordinary hexagonal ice data.

Mechanical and microstructural evaluations of cortical bone using ultrashort echo time magnetic resonance imaging (UTE-MRI) have been performed increasingly in recent years. UTE-MRI acquires considerable signal from cortical bone and enables quantitative bone evaluations. Fitting bone apparent transverse magnetization (T2*) decay using a bicomponent model has been regularly performed to estimate bound water (BW) and pore water (PW) in the quantification of bone matrix and porosity, respectively. Human cortical bone possesses a considerable amount of fat, which appears as MRI T2* signal oscillation and can subsequently lead to BW overestimation when using a bicomponent model. Tricomponent T2* fitting model has been developed to improve BW and PW estimations by accounting for fat contribution in the MRI signal. This study aimed to investigate the correlations of microstructural and mechanical properties of human cortical bone with water pool fractions obtained from a tricomponent T2* model. 135 cortical bone strips (~4 × 2 × 40 mm3 ) from tibial and femoral midshafts of 37 donors (61 ± 24 years old) were scanned using ten sets of dual-echo 3D-UTE-Cones sequences (TE = 0.032-24.0 ms) on a 3 T MRI scanner for T2* fitting analyses. Average bone porosity and pore size were measured using microcomputed tomography (μCT) at 9 μm voxel size. Bone mechanical properties were measured using 4-point bending tests. Using a tricomponent model, bound water fraction (FracBW ) showed significant strong (R = 0.70, P < 0.01) and moderate (R = 0.58-0.62, P < 0.01) correlations with porosity and mechanical properties, respectively. Correlations of bone microstructural and mechanical properties with water pool fractions were higher for tricomponent model results compared with the bicomponent model. The tricomponent T2* fitting model is suggested as a useful technique for cortical bone evaluation where the MRI contribution of bone fat is accounted for.

Biopharmaceuticals and small-molecule drugs have different approval pathways but the same quality control (QC) paradigm, where the quality of released but untested units is inferred from that of tested but destroyed units. This inference-based QC will likely miss rare prerelease defects, and defects emerging after product release. The likelihood for such defects is heightened for biopharmaceuticals due to their complexity, which makes manufacturing errors more likely, and fragility, which makes postrelease damage more likely. To improve biopharmaceutical safety, we suggest transitioning their QC from inference- to verification-based practice by developing inspection technologies that can nondestructively verify the quality of every vial from the point of release to the point of care. One candidate, water proton NMR (wNMR), is briefly discussed.

Formulation stability is a critical attribute of any protein-based biopharmaceutical drug due to a protein’s inherent tendency to aggregate. Advanced analytical techniques currently used for characterization of protein aggregates are prone to a number of limitations and usually require additional manipulations with the sample, such as dilution, separation, labeling, and use of special cuvettes. In the present work, we compared conventional techniques for the analysis of protein aggregates with a novel approach that employs the water proton transverse relaxation rate R2(1H2O). We explored differences in the sensitivity of conventional techniques, size-exclusion chromatography (SEC), microflow imaging (MFI), and dynamic light scattering (DLS), and water NMR (wNMR) toward the presence of monoclonal antibody aggregates generated by different stresses. We demonstrate that wNMR outperformed SEC, DLS, and MFI in that it was most consistently sensitive to increases in both soluble and insoluble aggregates, includ...

Mixed Zn(II)/Gd(III) oxide nanoparticles (~8 mole%Zn) with d(avg) of 2.1 nm were synthesized. The D-glucuronic acid coated Zn(II)/Gd(III) oxide nanoparticles showed a longitudinal water proton relaxivity (r₁) of 12.3 s⁻¹mM⁻¹ with r₂/r₁ = 1.1, corresponding to an ideal condition for T₁ MRI contrast agent. We attribute this to reduced magnetization of the mixed nanoparticles owing to non-magnetic Zn in the nanoparticles. Their effectiveness as a T₁ MRI contrast agent was confirmed by acquiring In Vivo T₁ MR images of a mouse after intravenous injection.

Continuous manufacturing of biologics is one of the priorities of the biopharmaceutical industry. However, its widespread implementation is hampered by a lack of noninvasive/nondestructive process analytical technology (PAT) systems capable of real-time in-line monitoring of product flow parameters, such as concentration and/or aggregate content. We have previously demonstrated that, under nonflow conditions, the water proton transverse relaxation rate, R2(1H2O), is sensitive to protein concentration and aggregate content in biopharmaceutical formulations. In the present work, we explored the potential of water proton NMR under flow conditions (flow-wNMR) to use R2(1H2O) as a quantitative indicator of protein concentration variations and aggregate levels in the process flow. We show that, under flow conditions, R2(1H2O) is sensitive to rather small changes in protein concentration (

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R 1 , but evidence for between-site reproducibility of R 1 in small-animal MRI is lacking. Objective: To assess R 1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R 1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1–13 days. R 1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured. Results: CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R 1 -based MR biomarkers were found to be quite sensitive even to such small errors in R 1 , notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni 2+ in 2% agarose varied between 0.66 s −1 mM −1 at 3 T and 0.94 s −1 mM −1 at 11.7T. Interpretation: While several factors affect the reproducibility of R 1 -based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R 1 -reproducibility.

Ganglioside GM1 (GM1) micelles have been studied by means of water proton T1 NMRD experiment. The field dependent spin-lattice relaxation rates were measured for Larmor frequencies ranging from 0.1 ...

Purpose To quantify pure chemical exchange-dependent saturation transfer (CEST) related amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) signals in a rat glioma model and to investigate the mixed effects of water content and water T1 on APT and NOE imaging signals. Methods Eleven U87 tumor-bearing rats were scanned at 4.7 T. A relatively accurate mathematical approach, based on extrapolated semisolid magnetization-transfer reference signals, was used to remove the concurrent effects of direct water saturation and semisolid magnetization-transfer. Pure APT and NOE signals, in addition to the commonly used magnetization-transfer-ratio asymmetry at 3.5 ppm, MTRasym (3.5ppm), were assessed. Results The measured APT signal intensity of the tumor (11.06%, much larger than the value reported in the literature) was the major contributor (approximately 80.6%) to the MTRasym (3.5ppm) contrast between the tumor and the contralateral brain region. Both the water content ([water proton]) and water T1 (T1w ) were increased in the tumor, but there were no significant correlations among APT, NOE, or MTRasym (3.5ppm) signals and T1w /[water proton]. Conclusion The effect of increasing T1w on the CEST signal in the tumor was mostly eliminated by the effect of increasing water content, and the observed APT-weighted hyperintensity in the tumor should be dominated by the increased amide proton concentration. Magn Reson Med 77:855-863, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

The transverse relaxation rate of water protons R2(1H2O) is found to be sensitive to amide hydrolysis and diglycine dimerization. The results demonstrate the feasibility of using R2(1H2O) as a diagnostic tool to detect chemical changes in aqueous solutions. Potential applications include drug product formulation and inspection.

T2 MRI contrast agents cannot be synthesized by using molecules but nanoparticles because appreciable magnetic moments at room temperature are needed. Recently, some of lanthanide (Ln) oxide nanoparticles have shown decent magnetic moments at room temperature and even at ultrasmall particle diameters. In this study, we explored D-glucuronic acid coated Ln2O3 nanoparticles (Ln = Ho and Er) with ultrasmall particle diameters. They showed decent magnetic moments at room temperature and as a result, appreciable transverse water proton relaxivities (r2s) at 1.5 tesla MR field. Clear dose-dependent contrast enhancements in R2 map images were observed in both samples. These results showed that D-glucuronic acid coated Ln2O3 nanoparticles (Ln = Ho and Er) would be potential T2 MRI contrast agents at high MR fields.

In this mini review, magnetic resonance imaging (MRI) contrast agents based on lanthanideoxide (Ln2O3) nanoparticles are described. Ln2O3 (Ln = Gd, Dy, Ho, and Er) nanoparticles are paramagnetic, but show appreciable magnetic moments at room temperature and even at ultrasmall particle diameters. Among Ln2O3 nanoparticles, Gd2O3 nanoparticles show larger longitudinal water proton relaxivity (r1) values than Gd-chelates because of the large amount of Gd in the nanoparticle, and the other Ln2O3 nanoparticles (Ln = Dy, Ho, and Er) show appreciable transverse water proton relaxivity (r2) values. Therefore, Gd2O3 nanoparticles are potential T1 MRI contrast agents while the other Ln2O3 nanoparticles are potential T2 MRI contrast agents at high MR fields.

Chemical exchange saturation transfer (CEST) imaging of endogenous agents in vivo is influenced by direct water proton saturation (spillover) and semi-solid macromolecular magnetization transfer (MT). Lorentzian fit isolation and application of the inverse metric yields the pure CEST contrast AREX, which is less affected by these processes, but still depends on the measurement technique, in particular on the irradiation amplitude B1 of the saturation pulses. This study focuses on two well-known CEST effects in the slow exchange regime originating from amide and aliphatic protons resonating at 3.5 ppm or −3.5 ppm from water protons, respectively. A B1-correction of CEST contrasts is crucial for the evaluation of data obtained in clinical studies at high field strengths with strong B1-inhomogeneities. Herein two approaches for B1-inhomogeneity correction, based on either CEST contrasts or Z-spectra, are investigated. Both rely on multiple acquisitions with different B1-values. One volunteer was examined with eight different B1-values to optimize the saturation field strength and the correction algorithm. Histogram evaluation allowed quantification of the quality of the B1-correction. Finally, the correction was applied to CEST images of a patient with oligodendroglioma WHO grade 2, and showed improvement of the image quality compared with the non-corrected CEST images, especially in the tumor region. Copyright © 2015 John Wiley & Sons, Ltd.

Although radiofrequency ablation has become a worldwide accepted curative therapy for the treatment of cardiac arrhythmias, there is still a lack of lesion monitoring during ablation procedure. Magnetic Resonance (MR) thermometry based on the water proton frequency could give relevant information on local tissue temperature increase but requires dealing with motion and susceptibility artifacts due to the cardiac and respiratory motion. A real-time framework that overcomes these difficulties is described in this paper. The proposed approaches address both inter-scan and inplane motion using a rapid MR-acquisition sequence coupled with a robust optical-flow registration of all incoming images. The strategy was found to be robust and suitable to follow the temperature evolution in 10 healthy volunteers under free breathing conditions with a temperature standard deviation of 2.2 °C in the cardiac muscle at an update rate of approximately 1 Hz. Since local temperature rises due to RF ablation can lead to T1 and T2 relaxation time local variations, and thus to errors in the image-based registration process, we also analyze the performance of the algorithm during radiofrequency ablation applied under well controlled experimental conditions (no respiratory motion and cardiac triggered) using an ex vivo perfused pig heart. Contact electrophysiological signals were recorded simultaneously with magnetic resonance imaging by combining hardware and software filtering. A working heart setup, specifically designed for this project, provided a relevant model to assess the quality of cardiac MR-thermometry.

Gadofullerenols have received much attention due to their high relaxivities and low-toxicity as magnetic resonance imaging (MRI) contrast agents. However, the relaxivities of gadofullerenols vary in different reports. In this study, Gd@C-82(OH)(x)O-y with different hemiketal content were synthesized and the influence of this factor on water proton relaxation was investigated. The results show that Gd@C-82(OH)(x)O-y with more hemiketals exhibit much higher relaxivities than those with fewer hemiketals. The hemiketal structure is supposed to promote the formation of intermolecular hydrogen bonds, and finally lead to large aggregates. This is consistent with a previous report that the relaxivities of endohedral gadofullerene derivatives are strongly associated with the aggregate size. Hence, this work provides an important strategy for the manipulation of the relaxivities of gadofullerene based MRI contrast agents by controlling the quantity of hemiketals on the carbon cage.

Nanoparticles capable of accumulating in tumor tissues are promising materials for tumor imaging and therapy. In this study, two radical nanoparticles (RNPs), denoted as 1 and 2, composed of self-assembled ureabenzene derivatives possessing one or two amphiphilic side chains were demonstrated to be candidates for metal-free functional magnetic resonance imaging (MRI) contrast agents (CAs). Because of the self-assembly behavior of 1 and 2 in a saline solution, spherical RNPs of sizes ∼50–90 and ∼30–100 nm were detected. In a highly concentrated solution, RNP 1 showed considerably small water-proton relaxivity values (r1 and r2), whereas RNP 2 showed an r1 value that was around 5 times larger than that of RNP 1. These distinct r1 values might be caused by differences in the self-assembly behavior by a hydration or dehydration process. In vivo studies with RNP 2 demonstrated a slightly enhanced T1-weighted image in mice, suggesting that the RNPs can potentially be used as metal-free functional MRI CAs for T1...