A Nanoparticle Ink Allowing the High Precision Visualization of Tissue Engineered Scaffolds by MRI.

Hydrogels are widely used as cell scaffolds in several biomedical applications. Once implanted in vivo, cell scaffolds must often be visualized, and monitored overtime. However, cell scaffolds appear poorly contrasted in most biomedical imaging modalities such as magnetic resonance imaging (MRI). MRI is the imaging technique of choice for high-resolution visualization of low-density, water-rich tissues. Attempts to enhance hydrogel contrast in MRI are performed with "negative" contrast agents that produce several image artifacts impeding the delineation of the implant's contours. In this study, a magnetic ink based on ultra-small iron oxide nanoparticles (USPIONs; <5 nm diameter cores) is developed and integrated into biocompatible alginate hydrogel used in cell scaffolding applications. Relaxometric properties of the magnetic hydrogel are measured, as well as biocompatibility and MR-visibility (T1 -weighted mode; in vitro and in vivo). A 2-week MR follow-up study is performed in the mouse model, demonstrating no image artifacts, and the retention of "positive" contrast overtime, which allows very precise delineation of tissue grafts with MRI. Finally, a 3D-contouring procedure developed to facilitate graft delineation and geometrical conformity assessment is applied on an inverted template alginate pore network. This proof-of-concept establishes the possibility to reveal precisely engineered hydrogel structures using this USPIONs ink high-visibility approach.

Nuclear magnetic resonance relaxometry to monitor chromium (VI) reduction by hydrogen peroxide, ascorbic acid, and aluminum powder.

The reduction of K2 Cr2 O7 solutions by H2 O2 was studied by nuclear magnetic resonance (NMR) relaxometry and UV-vis spectroscopy in HCl/KCl buffer (pH 2), NaCl/glycine/HCl buffer (pH 3), and sodium acetate/acetic acid buffer (pH 4). Because of Cr(III) paramagnetism, 1/T1 and 1/T2 of the solutions increase during the reduction of diamagnetic Cr(VI). This increase is proportional to the produced Cr(III) concentration. Using different initial H2 O2 concentrations, partially reduced Cr(VI) samples were prepared and studied by T1 and T2 relaxometry and by UV-vis spectroscopy. The correlation between the relaxation rates and the concentration of Cr(VI) remaining in the sample, measured by spectroscopy, was excellent. It was possible, thanks to the measurement of T2 , to study the kinetics of the reduction of K2 Cr2 O7 by H2 O2 in the pH 3 and pH 4 buffers. The reduction of Cr(VI) by ascorbic acid was successfully monitored by NMR relaxometry in the pH 2 buffer. The presence of complexing molecules/ions was shown to drastically influence the nuclear magnetic relaxation dispersion profiles of reduced K2 Cr2 O7 solutions: Both relaxation rates are divided by ~5 when citrate or acetate ions are present and by ~3 in the presence of ascorbic acid. Therefore, the comparison of relaxation results obtained in different reaction mixtures must be done carefully. When all the solutions are set to pH 0, which prevents any complexation, the longitudinal and transverse relaxation rates of all samples become comparable. Finally, as a proof of concept for a turbid solution, the kinetics of the reduction of a K2 Cr2 O7 solution by aluminum powder in the pH 2 buffer was successfully monitored.

Ferritin Protein Regulates the Degradation of Iron Oxide Nanoparticles.

Proteins implicated in iron homeostasis are assumed to be also involved in the cellular processing of iron oxide nanoparticles. In this work, the role of an endogenous iron storage protein-namely the ferritin-is examined in the remediation and biodegradation of magnetic iron oxide nanoparticles. Previous in vivo studies suggest the intracellular transfer of the iron ions released during the degradation of nanoparticles to endogenous protein cages within lysosomal compartments. Here, the capacity of ferritin cages to accommodate and store the degradation products of nanoparticles is investigated in vitro in the physiological acidic environment of the lysosomes. Moreover, it is questioned whether ferritin proteins can play an active role in the degradation of the nanoparticles. The magnetic, colloidal, and structural follow-up of iron oxide nanoparticles and proteins in lysosome-like medium confirms the efficient remediation of potentially harmful iron ions generated by nanoparticles within ferritins. The presence of ferritins, however, delays the degradation of particles due to a complex colloidal behavior of the mixture in acidic medium. This study exemplifies the important implications of intracellular proteins in processes of degradation and metabolization of iron oxide nanoparticles.

Fluorinated Mesoporous Silica Nanoparticles for Binuclear Probes in 1H and 19F Magnetic Resonance Imaging.

The development of molecular and cellular magnetic resonance imaging (MRI) procedures has always represented a challenge because of the fact that conventional MRI contrast agents are not directly detected in vivo; in proton MRI (e.g., with the nucleus 1H), their local concentration is measured through the effect they exert on the signal of hydrogen protons present in their immediate vicinity. Because the contrast effects generated by conventional MRI probes superpose to and can often impede the anatomical information contained in 1H MRI images, new probes based on a nucleus other than 1H, are being developed. In this study, we report on the development of fluorinated mesoporous silica nanoparticles (MSNs), which could represent an interesting dual probe that allows two MRI modes: 1H for high-resolution anatomical information and 19F for the detection of MSNs used as drug delivery agents. MSNs were synthesized and covalently functionalized either with fluorosilane (FMSNs) or polyfluorosiloxane (polyFMSNs) to enable their detection in 19F MRI. Then, gadolinium chelates were grafted on the particles to enhance their detectability in 1H MRI. The physicochemical, textural, and relaxometric properties (1H and 19F relaxation times) of the nanoparticles were measured and compared. The 19F relaxation properties were found to be dependent on the concentration of fluorine; they were also highly sensitive to the presence of gadolinium. The shortest relaxation times were obtained with polyFMSNs. At clinical magnetic field strengths, high 1H relaxivities and low relaxometric ratios (r2/r1 = 1.45; 2.2 for nanoparticles entrapped in hydrogel) were found for both nanoparticle systems. Finally, the visibility of both systems was confirmed in 1H, and the detectability of polyFMSNs was confirmed in 19F MRI. This physicochemical and relaxometric study opens the door to the applications of fluorinated silica nanoparticles as theranostic materials allowing dual MRI (1H and 19F).

Sample Shuttling Relaxometry of Contrast Agents: NMRD Profiles above 1 T with a Single Device.

Nuclear magnetic relaxation dispersion (NMRD) profiles are essential tools to evaluate the efficiency and investigate the properties of magnetic compounds used as contrast agents for magnetic resonance imaging (MRI), namely gadolinium chelates and superparamagnetic iron oxide particles. These curves represent the evolution of proton relaxation rates with the magnetic field. NMRD profiles are unparalleled to probe extensively the spectral density function involved in the relaxation of water in the presence of the paramagnetic ion or the magnetic nanoparticles. This makes such profiles an excellent test of the adequacy of a theoretical relaxation model and allow for a predictive approach to the development and optimization of contrast agents. From a practical point of view they also allow to evaluate the efficiency of a contrast agent in a certain range of magnetic fields. Nowadays, these curves are recorded with commercial fast field cycling devices, often limited to a maximum Larmor frequency of 40 MHz (0.94 T). In this article, relaxation data were acquired on a wide range of magnetic fields, from 3.5 × 10-4 to 14 T, for a gadolinium-based contrast agent and for PEGylated iron oxide nanoparticles. We show that the low-field NMRD curves can be completed with high-field data obtained on a shuttle apparatus device using the superconductive magnet of a high-field spectrometer. This allows a better characterization of the contrast agents at relevant magnetic fields for clinical and preclinical MRI, but also refines the experimental data that could be used for the validation of relaxation models.

Biodegradation mechanisms of iron oxide monocrystalline nanoflowers and tunable shield effect of gold coating.

Understanding the relation between the structure and the reactivity of nanomaterials in the organism is a crucial step towards efficient and safe biomedical applications. The multi-scale approach reported here, allows following the magnetic and structural transformations of multicore maghemite nanoflowers in a medium mimicking intracellular lysosomal environment. By confronting atomic-scale and macroscopic information on the biodegradation of these complex nanostuctures, we can unravel the mechanisms involved in the critical alterations of their hyperthermic power and their Magnetic Resonance imaging T1 and T2 contrast effect. This transformation of multicore nanoparticles with outstanding magnetic properties into poorly magnetic single core clusters highlights the harmful influence of cellular medium on the therapeutic and diagnosis effectiveness of iron oxide-based nanomaterials. As biodegradation occurs through surface reactivity mechanism, we demonstrate that the inert activity of gold nanoshells can be exploited to protect iron oxide nanostructures. Such inorganic nanoshields could be a relevant strategy to modulate the degradability and ultimately the long term fate of nanomaterials in the organism.

Paramagnetic nanoparticles as potential MRI contrast agents: characterization, NMR relaxation, simulations and theory.

OBJECT: Paramagnetic nanoparticles, mainly rare earth oxides and hydroxides, have been produced these last few years for use as MRI contrast agents. They could become an interesting alternative to iron oxide particles. However, their relaxation properties are not well understood. MATERIALS AND METHODS: Magnetometry, (1)H and (2)H NMR relaxation results at different magnetic fields and electron paramagnetic resonance are used to investigate the relaxation induced by paramagnetic particles. When combined with computer simulations of transverse relaxation, they allow an accurate description of the relaxation induced by paramagnetic particles. RESULTS: For gadolinium hydroxide particles, both T(1) and T(2) relaxation are due to a chemical exchange of protons between the particle surface and bulk water, called inner sphere relaxation. The inner sphere is also responsible for T(1) relaxation of dysprosium, holmium, terbium and erbium containing particles. However, for these latter compounds, T(2) relaxation is caused by water diffusion in the field inhomogeneities created by the magnetic particle, the outer-sphere relaxation mechanism. The different relaxation behaviors are caused by different electron relaxation times (estimated by electron paramagnetic resonance). CONCLUSION: These findings may allow tailoring paramagnetic particles: ultrasmall gadolinium oxide and hydroxide particles for T(1) contrast agents, with shapes ensuring the highest surface-to-volume ratio. All the other compounds present interesting T(2) relaxation performance at high fields. These results are in agreement with computer simulations and theoretical predictions of the outer-sphere and static dephasing regime theories. The T(2) efficiency would be optimum for spherical particles of 40-50 nm radius.

Impact of agglomeration on the relaxometric properties of paramagnetic ultra-small gadolinium oxide nanoparticles.

Ultra-small gadolinium oxide nanoparticles (US-Gd(2)O(3)) are used to provide 'positive' contrast effects in magnetic resonance imaging (MRI), and are being considered for molecular and cellular imaging applications. However, these nanoparticles can aggregate over time in aqueous medium, as well as when internalized into cells. This study is aimed at measuring in vitro, in aqueous medium, the impact of aggregation on the relaxometric properties of paramagnetic US-Gd(2)O(3) particles. First, the nanoparticle core size as well as aggregation behaviour was assessed by HRTEM. DLS (hydrodynamic diameter) was used to measure the hydrodynamic diameter of nanoparticles and nanoaggregates. The relaxometric properties were measured by NMRD profiling, as well as with (1)H NMR relaxometers. Then, the positive contrast enhancement effect was assessed by using magnetic resonance scanners (at 1.5 and 7 T). At every magnetic field, the longitudinal relaxivity (r(1)) decreased upon agglomeration, while remaining high enough to provide positive contrast. On the other hand, the transverse relaxivity (r(2)) slightly decreased at 0.47 and 1.41 T, but it was enhanced at higher fields (7 and 11.7 T) upon agglomeration. All NMRD profiles revealed a characteristic relaxivity peak in the range 60-100 MHz, suggesting the possibility to use US-Gd(2)O(3) as an efficient 'positive-T(1)' contrast agent at clinical magnetic fields (1-3 T), in spite of aggregation.

Comparative analysis of the 1H NMR relaxation enhancement produced by iron oxide and core-shell iron-iron oxide nanoparticles.

Physicochemical and magnetorelaxometric characterization of the colloidal suspensions consisting of Fe-based nanoparticles coated with dextran have been carried out. Iron oxide and iron core/iron oxide shell nanoparticles were obtained by laser-induced pyrolysis of Fe(CO)5 vapours. Under different magnetic field strengths, the colloidal suspension formed by iron oxide nanoparticles showed longitudinal (R1) and transverse (R2) nuclear magnetic relaxation suspension (NMRD) profiles, similar to those previously reported for other commercial magnetic resonance imaging (MRI) contrast agents. However, colloidal suspension formed by ferromagnetic iron-core nanoparticles showed a strong increase of the R1 values at low applied magnetic fields and a strong increase of the R2 measured at high applied magnetic field. This behaviour was explained considering the larger magnetic aggregate size and saturation magnetization values measured for this sample, 92 nm and 31 emu/g Fe, respectively, with respect to those measured for the colloidal suspensions of iron oxide nanoparticles (61 nm and 23 emu/g Fe). This suspension can be used both as T1 and T2 contrast agent.

Magnetic resonance relaxation induced by superparamagnetic particles used as contrast agents in magnetic resonance imaging: a theoretical review.

Superparamagnetic nanoparticles are used as contrast agents in magnetic resonance imaging and allow, for example, the detection of tumors or the tracking of stem cells in vivo. By producing magnetic inhomogeneities, they influence the nuclear magnetic relaxation times, which results in a darkening, on the image, of the region containing these particles. A great number of studies have been devoted to their magnetic properties, to their synthesis and to their influence on nuclear magnetic relaxation. The theoretical and fundamental understanding of the behavior of these particles is a necessary step in predicting their efficiency as contrast agents, or to be able to experimentally obtain some of their properties from a nuclear magnetic resonance measurement. Many relaxation models have been published, and choosing one of them is not always easy, many parameters and conditions have to be taken into account. Relaxation induced by superparamagnetic particles is generally attributed to an outersphere relaxation mechanism. Each model can only be used under specific conditions (motional averaging regime, static regime, high magnetic field, etc.) or for a particular sequence (Carr-Purcell-Meiboom-Gill, spin echo, free-induction decay, nuclear magnetic relaxation dispersion profile, etc.). The parameters included in the equations must be carefully interpreted. In some more complex conditions, simulations are necessary to be able to predict the relaxation rates. A good agreement is usually observed between the theoretical predictions and the experimental results, although some data still cannot be fully understood, such as the dependence of the transverse relaxation on the magnetic field. WIREs Nanomed Nanobiotechnol 2017, 9:e1468. doi: 10.1002/wnan.1468 For further resources related to this article, please visit the WIREs website.

NMR relaxation properties of the synthetic malaria pigment ß-hematin.

200 million patients suffer from malaria, a parasitic disease caused by protozoans of the genus Plasmodium. Reliable diagnosis is crucial since it allows the early detection of the disease. The development of rapid, sensitive and low-cost diagnosis tools is an important research area. Different studies focused on the detection of hemozoin, a major by-product of hemoglobin detoxification by the parasite. Hemozoin and its synthetic analog, ß-hematin, form paramagnetic crystals. A new detection method of malaria takes advantage of the paramagnetism of hemozoin through the effect that such magnetic crystals have on Nuclear Magnetic Resonance (NMR) relaxation of water protons. Indeed, magnetic microparticles cause a shortening of the relaxation times. In this work, the magnetic properties of two types of ß-hematin are assessed at different temperatures and magnetic fields. The pure paramagnetism of ß-hematin is confirmed. The NMR relaxation of ß-hematin suspensions is also studied at different magnetic fields and for different echo-times. Our results help to identify the best conditions for ß-hematin detection by NMR: T 2 must be selected, at large magnetic fields and for long echo-times. However, the effect of ß-hematin on relaxation does not seem large enough to achieve accurate detection of malaria without any preliminary sample preparation, as microcentrifugation.

Physiological Remediation of Cobalt Ferrite Nanoparticles by Ferritin.

Metallic nanoparticles have been increasingly suggested as prospective therapeutic nanoplatforms, yet their long-term fate and cellular processing in the body is poorly understood. Here we examined the role of an endogenous iron storage protein - namely the ferritin - in the remediation of biodegradable cobalt ferrite magnetic nanoparticles. Structural and elemental analysis of ferritins close to exogenous nanoparticles within spleens and livers of mice injected in vivo with cobalt ferrite nanoparticles, suggests the intracellular transfer of degradation-derived cobalt and iron, entrapped within endogenous protein cages. In addition, the capacity of ferritin cages to accommodate and store the degradation products of cobalt ferrite nanoparticles was investigated in vitro in the acidic environment mimicking the physiological conditions that are present within the lysosomes. The magnetic, colloidal and structural follow-up of nanoparticles and proteins in the lysosome-like medium confirmed the efficient remediation of nanoparticle-released cobalt and iron ions by ferritins in solution. Metal transfer into ferritins could represent a quintessential process in which biomolecules and homeostasis regulate the local degradation of nanoparticles and recycle their by-products.

Relaxivities of human liver and spleen ferritin.

Ferritin, the iron-storing protein of mammals, is known to darken T2-weighted magnetic resonance images. This darkening can be used to noninvasively measure an organ's iron content. Significant discrepancies exist between T2 data obtained with ferritin-containing tissues and with aqueous solutions of horse spleen ferritin (HSF). The NMR properties of stable human ferritin have never been studied in aqueous solutions. Relaxometry results on human liver and spleen ferritin are reported here, showing that the relaxation induced in aqueous solutions by human ferritins is comparable to that induced by HSF. As a consequence, the differences between ferritin-containing human tissues and ferritin solutions cannot be attributed to different NMR properties of human and horse ferritins, but probably to a clustering of the protein in vivo.

Effect of magnetic field and iron content on NMR proton relaxation of liver, spleen and brain tissues.

Iron accumulation is observed in liver and spleen during hemochromatosis and important neurodegenerative diseases involve iron overload in brain. Storage of iron is ensured by ferritin, which contains a magnetic core. It causes a darkening on T2 -weighted MR images. This work aims at improving the understanding of the NMR relaxation of iron-loaded human tissues, which is necessary to develop protocols of iron content measurements by MRI. Relaxation times measurements on brain, liver and spleen samples were realized at different magnetic fields. Iron content was determined by atomic emission spectroscopy. For all samples, the longitudinal relaxation rate (1/T1 ) of tissue protons decreases with the magnetic field up to 1 T, independently of iron content, while their transverse relaxation rate (1/T2 ) strongly increases with the field, either linearly or quadratically, or a combination thereof. The extent of the inter-echo time dependence of 1/T2 also varies according to the sample. A combination of theoretical models is necessary to describe the relaxation of iron-containing tissues. This can be due to the presence, inside tissues, of ferritin clusters of different sizes and densities. When considering all samples, a correlation (r(2) = 0.6) between 1/T1 and iron concentration is observed at 7.0 T. In contrast the correlation between 1/T2 and iron content is poor, even at high field (r(2) = 0.14 at 7.0 T). Our results show that MRI methods based on T1 or T2 measurements will easily detect an iron overloading at high magnetic field, but will not provide an accurate quantification of tissue iron content at low iron concentrations.

Metal chelate grafting at the surface of mesoporous silica nanoparticles (MSNs): physico-chemical and biomedical imaging assessment.

Mesoporous silica nanoparticles (MSNs) are being developed as drug delivery vectors. Biomedical imaging (MRI and PET) enables their tracking in vivo, provided their surface is adequately grafted with imaging probes (metal chelates). However, MSNs are characterized by huge specific surfaces, and high-quality metal chelate anchoring procedures must be developed and validated, to demonstrate that their detection in vivo is associated to the presence of nanoparticles and not to detached metal chelates. MCM-48 nanospheres (M48SNs, 150 nm diam., 3-D pore geometry) were synthesized and functionalized with diethylenetriaminepentaacetic acid (DTPA). The strong grafting of DTPA was confirmed by 29Si MAS-NMR, XPS, FTIR and TGA. The particles were labeled with paramagnetic ions Gd3+ (for MRI) as well as radioactive ions 64Cu2+ (for PET; half-life: 12.7 h). Gd3+-DTPA-M48SNs formed a stable colloid in saline media for at least 6 months, without any sign of aggregation. The relaxometric properties were measured at various magnetic fields. The strength of DTPA binding at the surface of MSNs was also assessed in vivo, by injecting mice (i.v.) with Gd3+/64Cu2+-DTPA-M48SNs. Vascular retention and urinary clearance were monitored by MRI, whereas the PET modality provided dynamic and quantitative assessment of biodistribution and blood/organ clearance. No significant 64Cu activity was detectable in the bladder. The study confirmed the very limited detachment of DTPA from M48SNs cores once injected in vivo. The transit of MSNs through the liver and intestinal tract, does not lead to evidence of Gd3+/64Cu2+-DTPA in the urine. This physico-chemical and biodistribution study confirms the quality of DTPA attachment at the surface of the particles, necessary to allow further development of PET/MRI-assisted MSN-vectorized drug delivery procedures.

An evaluation of the contributions of diffusion and exchange in relaxation enhancement by MRI contrast agents.

Magnetic compounds are known to enhance water proton relaxation, either by diffusion or by proton exchange. An experimental procedure to distinguish both mechanisms is proposed and validated by relaxation measurements made in water-methanol solutions of Dy(3+), Ni(2+), Gd(3+), Tempo, and AMI-25. The test discriminates according to the character of the transverse relaxation in water-methanol solutions: a mono-exponential decay corresponds to diffusion, while a bi-exponential decay indicates the contribution of a proton exchange. The study of ferritin and akaganeite particle solutions confirms the occurrence of a proton exchange between protons belonging to hydroxyl groups of the particle surface and free water protons.

Cesium adsorption in hydrated iron oxide particles suspensions: an NMR study.

137Cs is an important component of nuclear waste which may pollute water. Its migration in natural environments is slowed down by adsorption on minerals. Cesium adsorption on akaganeite (beta-FeOOH) particles, dextran-coated ferrihydrite (5 Fe(2)O(3)-9H(2)O) particles, and ferritin in aqueous solutions is studied with (133)Cs nuclear magnetic resonance measurements. The longitudinal relaxation time (T(1)) of (133)Cs in the presence of such magnetic particles depends on whether the ions bind to the particle or not. T(1) of (133)Cs ions in aqueous solutions containing the same amount of magnetized particles will not depend on cesium concentration if relaxation is governed by diffusion (when cesium is not able to bind), but it will depend on cesium concentration if exchange governs relaxation (when cesium is able to bind). The method is successfully tested using TEMPO, a nitroxide stable free radical whose relaxation is due to diffusion. (133)Cs relaxation in solutions of ferritin, akaganeite, and dextran-coated ferrihydrite particles is found to result from a cationic exchange of cesium ions between particles surface and bulk ions, owing to adsorption. The effect of pH on (133)Cs relaxation in solutions of the particles is consistent with the adsorption properties of cations on hydrated iron oxides.

High relaxivities and strong vascular signal enhancement for NaGdF4 nanoparticles designed for dual MR/optical imaging.

Near-infrared (NIR)-to-NIR upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) paramagnetic nanoparticles (NPs) are efficiently detected by NIR imaging techniques. As they contain Gd(3+) ions, they also provide efficient "positive" contrast in magnetic resonance imaging (MRI). Water-dispersible small (≈25 nm, "S-") and ultrasmall (<5 nm diam., "US-") NaY(Gd)F4 :Tm(3+) ,Yb(3+) NPs are synthesized by thermal decomposition and capped with citrate. The surface of citrate-coated US-NPs shows sodium depletion and high Gd elemental ratios, as confirmed by a comparative X-ray photoelectron spectroscopy (XPS)/neutron absorption analysis study. US-NaGd0.745 F4 :Tm0.005 ,Yb0.25 NPs have hydrodynamic diameters close to that measured by TEM, with the lowest relaxometric ratios (r2 /r1 = 1.18) reported for NaGdF4 nanoparticle suspensions (r1 = 3.37 mM(-1) s(-1) at 1.4 T and 37 °C). Strong relaxivity peaks in the range of 20 (0.47 T) - 300 MHz (7.05 T) are revealed in nuclear magnetic resonance dispersion profiles, with high r2 /r1 ratios at increasing field strengths for S-NPs. This indicates the superiority of US-NPs over S-NPs for achieving high positive contrast at clinical MRI field strengths. I.-v. injected citrate-coated US-NPs evidence long blood retention times (>90 min) in mice. Biodistribution studies (48 h, 8 d) show elimination through the reticuloendothelial and urinary systems, similarly to other citrate-capped US-NP systems. In summary, upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) nanoparticles have promising luminescent, relaxometric and blood-retention properties for dual MRI/optical imaging.

Imaging: high relaxivities and strong vascular signal enhancement for NaGdF4 nanoparticles designed for dual MR/optical imaging (Adv. Healthcare Mater. 11/2013).

Tripositive gadolinium-ion doped NIR-to-NIR upconverting paramagnetic nanoparticles are efficiently detected are NIR imaging techniques but can also provide efficient "positive" contrast in MRI. On page 1478 John A. Capobianco, Marc-André Fortin, and co-workers show that citrate-coated nanoparticles present the lowest relaxometric ratios reported for NaGdF4 nanoparticle suspensions. IV-injected nanoparticles evidence long blood retention times in mice while biodistribution studies show elimination through the reticuloendothelial and urinary systems.