Potential Contrast Research Articles

Fe3O4@SiO2-NH2 Functionalized Nanoparticles as a Potential Contrast Agent in Magnetic Resonance

The present work proposes a method for the synthesis of a nanoparticle with a superparamagnetic Fe3O4 core coated with SiO2-NH2 by ultrasound-assisted coprecipitation. Additionally, the nanoparticle is functionalized with a microinflammation biomarker peptide, and its effects on the viability of monkey kidney endothelial cells and the Vero cell line were evaluated. The main physicochemical properties of the nanoparticles were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), a vibrating sample magnetometer (VSM), a field emission scanning electron, Scanning Electron Microscopy (SEM), and High-Resolution Transmission Electron Microscopy (HR-TEM). The results showed that the nanoparticles are spherical, with sizes smaller than 10 nm, with high thermal stability and superparamagnetic properties. They also demonstrated cell viability rates exceeding 85% through Magnetic Resonance Imaging (MRI). The results indicate the potential of these nanoparticles to be used as a contrast agent in magnetic resonance to detect mild brain lesions.

Advancements in Tumor Diagnostics through Carbon Dot‐Assisted Photoacoustic Imaging

AbstractSerendipitously discovered, carbon dots (CDs) have attracted significant attention as a potential contrast agent for photoacoustic imaging (PAI) in the biomedical sector. CDs play an essential role in PAI, contributing significantly to the early detection of diseases and monitoring treatment progress, particularly in tumor imaging. This review emphasizes the role of CDs in the domain of PAI, highlighting their characteristics like biocompatibility, enhanced spatial resolution, optical absorption in the NIR region, and facile surface functionalization for tumor‐ targeted imaging. The study explores the use of CDs for enhancing spatial resolution in PAI for improved detection and visualization of tumors in organs such as the breast, cervical, liver, gastrointestinal, skin, cardiovascular system, nervous system, and others. Challenges associated with PAI, such as optimizing the signal‐to‐noise ratio and ensuring stability under physiological conditions, have also been discussed.

Cell membrane-functionalized bismuth oxyiodide nanodots as potential contrast agent for gastrointestinal tract imaging

Various noninvasive imaging modalities, including X-ray and computed tomography (CT) imaging, have provided significant advantages in accurately assessing the conditions of the gastrointestinal (GI) tract. The corresponding contrast agent with high resolution and biosafety is one of the most crucial focuses in the diagnosis of GI diseases. In this study, considering the requirements of good biocompatibility and biosafety, a novel imaging platform composed of the high-performance contrast agent based on macrophage membrane-coated BiOI nanodots (BiOI@M) was designed via a facile approach. The BiOI@M exhibited outstanding long-term stability and low toxicity. Significantly, BiOI@M demonstrated superior imaging ability compared to clinical barium sulfate. Higher CT values of BiOI@M were observed at equivalent concentrations to barium sulfate, thereby clearly outlining the stomach, small intestine, caecum, and colon after the oral administration of BiOI@M solutions in X-ray and CT imaging. Taken together, BiOI@M could serve as a novel efficient contrast agent in X-ray/CT imaging of the GI tract and diagnosis of GI diseases.

Microglial activation-sensitive gadolinium complex as a potential MRI contrast agent for Alzheimer’s disease diagnosis

Numerous studies have developed gadolinium (Gd)-based contrast agents (GBCAs) for in-vivo magnetic resonance imaging (MRI) with the aim of diagnosing Alzheimer’s disease (AD). Nevertheless, GBCAs that are capable of identifying microglial activation, a critical early indicator of AD pathology, for in-vivo diagnosis remain scarce. In response to this, we synthesized a novel GBCA, Gd-DO3A-Va, designed specifically to detect microglial activation using MRI. This innovative GBCA, which was conjugated with vanillic acid, demonstrated a high selectivity for microglial activation by targeting Toll-like receptor 4 (TLR4). The use of Gd-DO3A-Va in in-vivo imaging successfully highlighted microglial activation in a transgenic AD mouse model. In particular, the use of Gd-DO3A-Va for contrast-enhanced T1-weighted MRI enabled the detection of microglial activation within the hippocampus and cortex, regions notably affected by AD. The observed enhancements in the MR contrast correlated well with immunohistological evidence of microglial activation. Consequently, Gd-DO3A-Va represents a highly promising GBCA for the identification of microglial activation, providing a novel pathway for the molecular diagnosis of AD.

Rigid Fe(III) Chelate with Phosphonate Pendants: A Stable and Effective Extracellular MRI Contrast Agent.

A novel Fe(III) complex, Fe-tBPCDTA, was synthesized and explored as a potential contrast agent for MRI. Compared to established agents like Fe-EDTA and Fe-tCDTA, Fe-tBPCDTA exhibited moderate relaxivity (r1 = 1.17 s-1·mmol-1) due to its enhanced second-sphere mechanism. It also displayed improved kinetic inertness, lower cytotoxicity, and enhanced redox stability. In vivo studies demonstrated its function as an extracellular fluid agent, providing tumor contrast comparable to that of Gd-DTPA at a higher dosage. Complete renal clearance occurred within 24 h. These findings suggest Fe-tBPCDTA as a promising candidate for further development as a safe and effective extracellular MRI contrast agent.

Noninvasive Diagnosis of Kidney Dysfunction Using a Small-Molecule Manganese-Based Magnetic Resonance Imaging Probe.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a promising approach for the diagnosis of kidney diseases. However, safety concerns, including nephrogenic systemic fibrosis, limit the administration of gadolinium (Gd)-based contrast agents (GBCAs) in patients who suffer from renal impairment. Meanwhile, nanomaterials meet biosafety concerns because of their long-term retention in the body. Herein, we propose a small-molecule manganese-based imaging probe Mn-PhDTA as an alternative to GBCAs to assess renal insufficiency for the first time. Mn-PhDTA was synthesized via a simple three-step reaction with a total yield of up to 33.6%, and a gram-scale synthesis can be realized. Mn-PhDTA has an r1 relaxivity of 2.72 mM-1 s-1 at 3.0 T and superior kinetic inertness over Gd-DTPA and Mn-EDTA with a dissociation time of 60 min in the presence of excess Zn2+. In vivo and in vitro experiments demonstrate their good stability and biocompatibility. In the unilateral ureteral obstruction rats, Mn-PhDTA provided significant MR signal enhancement, enabled distinguishing structure changes between the normal and damaged kidneys, and evaluated the renal function at different injured stages. Mn-PhDTA could act as a potential MRI contrast agent candidate for the replacement of GBCAs in the early detection of kidney dysfunction and analysis of kidney disease progression.

A Gadolinium(III) Complex Based on Pyridoxine Molecule with Single-Ion Magnet and Magnetic Resonance Imaging Properties.

Pyridoxine (pyr) is a versatile molecule that forms part of the family of B vitamins. It is used to treat and prevent vitamin B6 deficiency and certain types of metabolic disorders. Moreover, the pyridoxine molecule has been investigated as a suitable ligand toward metal ions. Nevertheless, the study of the magnetic properties of metal complexes containing lanthanide(III) ions and this biomolecule is unexplored. We have synthesized and characterized a novel pyridoxine-based GdIII complex of formula [GdIII(pyr)2(H2O)4]Cl3 · 2 H2O (1) [pyr = pyridoxine]. 1 crystallizes in the triclinic system and space group Pī. In its crystal packing, cationic [Gd(pyr)2(H2O)4]3+ entities are connected through H-bonding interactions involving non-coordinating water molecules and chloride anions. In addition, Hirshfeld surfaces of 1 were calculated to further investigate their intermolecular interactions in the crystal lattice. Our investigation of the magnetic properties of 1, through ac magnetic susceptibility measurements, reveals the occurrence of a slow relaxation in magnetization in this mononuclear GdIII complex, indicating an unusual single-ion magnet (SIM) behavior for this pseudo-isotropic metal ion at very low temperatures. We also studied the relaxometric properties of 1, as a potential contrast agent for high-field magnetic resonance imaging (MRI), from solutions of 1 prepared in physiological serum (0.0-3.2 mM range) and measured at 3 T on a clinical MRI scanner. The values of relaxivity obtained for 1 are larger than those of some commercial MRI contrast agents based on mononuclear GdIII systems.

Optimization and chemical free fabrication of green synthesized iron nanoparticles as potential MRI contrast agent.

The current research article has investigated the synthesis and characterization of novel iron nanoparticles (INPs) from neem and betel leaves extract combination using response surface methodology-central composite design and coated with chitosan-curcumin (CCINPs) as a biocompatible and contrast agent for magnetic resonance imaging (MRI). The coating of INPs with chitosan and curcumin (CCINPs) was carried out using a simple, easy, chemical-free ultrasonication method and characteristics were confirmed by UV-visible (Vis) spectrophotometer (UV-Vis), Fourier-transform infrared spectroscopy, X-ray diffraction, scanning electron microscope, atomic force microscopy, and vibrating sample magnetometer. The biocompatibility of the particles was ensured by conducting hemolytic and cell viability assays. The nanoparticle was found to be nonhemolytic (<5%) up to 150μg/mL for both INPs and CCINPs. The cell viability was stable (peripheral blood mononuclear cells-PBMCs) till 48h at 150μg/mL of INPs and CCINPs. Both the test results produced were found to be biocompatible and additionally, an in vitro MRI study of INPs and CCINPs demonstrated the efficiency of the nanoparticle as a negative contrast agent with enhanced contrast nature in CCINPs. Thus, overall results indicate that the green synthesized chemical-free novel CCINPs could be a potential candidate for a wide range of applications such as MRI, drug delivery, and in magnetic fluid hyperthermia.

T1-weighted MRI of targeting atherosclerotic plaque based on CD40 expression on engulfed USPIO’s cell surface

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a zeta potential of −47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10–100 μg ml−1, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentrations exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 μg ml−1 USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). In order to substantiate our hypothesis that CD40 protein on the cell surface facilitates migration towards inflammatory cells, we utilized AuNPs-PEI (gold nanoparticles-polyethylenimine) carrying siRNACD40 to knockout CD40 expression in MAECs. It has been documented that gold nanoparticle-oligonucleotide complexes could be employed as intracellular gene regulation agents for the control of protein level in cells. Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC (control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40 (reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone). In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue and in vivo level, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.

A Gd(III)-labelled self-assembling peptide as a potential pH-responsive MRI contrast agent.

A marine-derived peptide labelled with a Gd(III)-chelate was found to self-assemble depending on the solution pH, accompanied by changes in T1-relaxivity (r1) values when in the dispersed or self-assembled form. Such pH-responsive behavior can be advantageous in the development of macromolecular magnetic resonance imaging (MRI) contrast agents which monitor the tissue physiology.

Transition metal complexes of the (2,2,2-trifluoroethyl)phosphinate NOTA analogue as potential contrast agents for 19F magnetic resonance imaging.

A new hexadentate 1,4,7-triazacyclononane-based ligand bearing three coordinating methylene-(2,2,2-trifluoroethyl)phosphinate pendant arms was synthesized and its coordination behaviour towards selected divalent (Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+) and trivalent (Cr3+, Fe3+, Co3+) transition metal ions was studied. The ligand forms stable complexes with late divalent transition metal ions (from Co2+ to Zn2+) and the complexes of these metal ions are formed above pH ∼3. A number of complexes with divalent metal ions were structurally characterized by means of single-crystal X-ray diffraction. The complex of the larger Mn2+ ion adopts a twisted trigonally antiprismatic geometry with a larger coordination cavity and smaller torsion of the pendant arms, whereas the smaller ions Ni2+, Cu2+ and Zn2+ form octahedral species with a smaller cavity and larger pendant arm torsion. In the case of the Co2+ complexes, both coordination arrangements were observed. The complexes with paramagnetic metal ions were studied from the point of view of potential utilization in 19F magnetic resonance imaging. A significant shortening of the 19F NMR longitudinal relaxation times was observed: a sub-millisecond range for complexes of Cr3+, Mn2+ and Fe3+ with symmetric electronic states (t2g3 and HS-d5), the millisecond range for the Ni2+ and Cu2+ complexes and tens of milliseconds for the Co2+ complex. Such short relaxation times are consistent with a short distance between the paramagnetic metal ion and the fluorine atoms (∼5.5-6.5 Å). Among the redox-active complexes (Mn3+/Mn2+, Fe3+/Fe2+, Co3+/Co2+, Cu2+/Cu+), the cobalt complexes show sufficient stability and a paramagnetic-diamagnetic changeover with the redox potential lying in a physiologically relevant range. Thus, the Co3+/Co2+ complex pair can be potentially used as a smart redox-responsive contrast agent for 19F MRI.

MD Simulations to Calculate NMR Relaxation Parameters of Vanadium(IV) Complexes: A Promising Diagnostic Tool for Cancer and Alzheimer's Disease.

Early phase diagnosis of human diseases has still been a challenge in the medicinal field, and one of the efficient non-invasive techniques that is vastly used for this purpose is magnetic resonance imaging (MRI). MRI is able to detect a wide range of diseases and conditions, including nervous system disorders and cancer, and uses the principles of NMR relaxation to generate detailed internal images of the body. For such investigation, different metal complexes have been studied as potential MRI contrast agents. With this in mind, this work aims to investigate two systems containing the vanadium complexes [VO(metf)2]·H2O (VC1) and [VO(bpy)2Cl]+ (VC2), being metformin and bipyridine ligands of the respective complexes, with the biological targets AMPK and ULK1. These biomolecules are involved in the progression of Alzheimer's disease and triple-negative breast cancer, respectively, and may act as promising spectroscopic probes for detection of these diseases. To initially evaluate the behavior of the studied ligands within the aforementioned protein active sites and aqueous environment, four classical molecular dynamics (MD) simulations including VC1 + H2O (1), VC2 + H2O (2), VC1 + AMPK + H2O (3), and VC2 + ULK1 + H2O (4) were performed. From this, it was obtained that for both systems containing VCs and water only, the theoretical calculations implied a higher efficiency when compared with DOTAREM, a famous commercially available contrast agent for MRI. This result is maintained when evaluating the system containing VC1 + AMPK + H2O. Nevertheless, for the system VC2 + ULK1 + H2O, there was observed a decrease in the vanadium complex efficiency due to the presence of a relevant steric hindrance. Despite that, due to the nature of the interaction between VC2 and ULK1, and the nature of its ligands, the study gives an insight that some modifications on VC2 structure might improve its efficiency as an MRI probe.

Gadolinium(III) complex formation with a β-cyclodextrin ligand: an XAS study of a potential MRI contrast agent.

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L3-edge EXAFS spectrum revealed 5 Gd-O (4 COO- and 1 H2O) and 4 Gd-N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd-N distance is shorter in the Gd(III): β-CD(A) (1:1) complex, indicating stronger Gd-N bonding and stronger Gd(III) complex formation than with the DOTA4- ligand. This is consistent with the lower free Gd3+ concentration found previously for the Gd(III): β-CD(A) (1:1) complex than for the [Gd(DOTA)(H2O)]- complex, and shows its potential as an MRI probe. EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH4)]7-, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)].

Heterobimetallic lanthanide tetrahedral cages: Synthesis, design and application for potential multimodal imaging contrast agent

The construction and functionalization of lanthanide-organic cages have been a research hotspot in coordination chemistry. Benefiting from the unique luminescent and magnetic properties of lanthanide ions, the potential applications of lanthanide-organic cages in biological imaging applications are promising, but only a few corresponding explorations have been reported. Herein, we introduced a series of lanthanide tetrahedral cages, (EunGd4–nL4) (sol)8 (n = 0, 1, 2, 3 and 4, where L = (4,4′,4″-tris(4,4,4-trifluoro-1,3-dioxobutyl)-triphenylamine, and sol = dimethyl sulfoxide and methanol), with potential applications in biological imaging. Given the good luminescent and magnetic properties of Eu3+ and Gd3+ ions, Eu4L4 and Gd4L4 complexes show a high luminescence quantum yield of 29% in DMSO and large longitudinal relaxivity (r1) of 11.4 (mmol/L)−1/s at 0.5 T in water containing 1 vol% DMSO, respectively. The heterobimetallic Eu–Gd complexes achieve a dual imaging mode by combining luminescent and magnetic centers in one cage. When the Gd:Eu ratio increases from 1:3 to 3:1, the r1 values increases from 5.33 to 8.64 (mmol/L)−1/s, higher than that of commercial contrast agent Gd-DOTA (3.23 (mmol/L)−1/s). Owing to their low toxicity and good cell imaging ability toward ECA 109 cells, the self-assembled Eu–Gd heterobimetallic tetrahedral cages could be potential candidates for the multimodal imaging contrast agent.

Yb-Gd Codoped Hydroxyapatite as a Potential Contrast Agent for Tumor-Targeted Biomedical Applications.

Recently, various nanomaterials based on hydroxyapatite (HAp) have been developed for bioimaging applications. In particular, HAp doped with rare-earth elements has attracted significant attention, owing to its enhanced bioactivity and imaging properties. In this study, the wet precipitation method was used to synthesize HAp codoped with Yb and Gd. The synthesized Ybx-Gdx-HAp nanoparticles (NPs) were characterized via various techniques to analyze the crystal phase, functional groups, thermal characteristics, and particularly, the larger surface area. The IR783 fluorescence dye and a folic acid (FA) receptor were conjugated with the synthesized Ybx-Gdx-HAp NPs to develop an effective imaging contrast agent. The developed FA/IR783/Yb-Gd-HAp nanomaterial exhibited improved contrast, sensitivity, and tumor-specific properties, as demonstrated by using the customized LUX 4.0 fluorescence imaging system. An in vitro cytotoxicity study was performed to verify the biocompatibility of the synthesized NPs using MTT assay and fluorescence staining. Photodynamic therapy (PDT) was also applied to determine the photosensitizer properties of the synthesized Ybx-Gdx-HAp NPs. Further, reactive oxygen species generation was confirmed by Prussian blue decay and a 2',7'-dichlorofluorescin diacetate study. Moreover, MDA-MB-231 breast cancer cells were used to evaluate the efficiency of Ybx-Gdx-HAp NP-supported PDT.

Evaluation of methemoglobin as an intravascular contrast agent: T1 relaxation time effect in a rabbit model

ObjectiveAlternative contrast agents for MRI are needed for individuals who may respond adversely to gadolinium, and need an intravascular agent for specific indications. One potential contrast agent is intracellular methemoglobin, a paramagnetic molecule that is normally present in small amounts in red blood cells. An animal model was used to determine whether methemoglobin modulation with intravenous sodium nitrite transiently changes the T1 relaxation of blood. MethodsFour adult New Zealand white rabbits were treated with 30 mg intravenous sodium nitrite. 3D TOF and 3D MPRAGE images were acquired before (baseline) and after methemoglobin modulation. T1 of blood was measured with 2D ss EPl acquisitions with inversion recovery preparation performed at two-minute intervals up to 30 min. T1 maps were calculated by fitting the signal recovery curve within major blood vessels. ResultsBaseline T1 was 1758 ± 53 ms in carotid arteries and 1716 ± 41 ms in jugular veins. Sodium nitrite significantly changed intravascular T1 relaxation. The mean minimum value of T1 was 1126 ± 28 ms in carotid arteries 8 to 10 min after the injection of sodium nitrite. The mean minimum value of T1 was 1171 ± 52 ms in jugular veins 10 to 14 min after the injection of sodium nitrite. Arterial and venous T1 recovered to baseline after a period of 30 min. ConclusionMethemoglobin modulation produces intravascular contrast on T1-weighted MRI in vivo. Additional studies are needed to safely optimize methemoglobin modulation and sequence parameters for maximal tissue contrast.

A unified hybrid transformer for joint MRI sequences super-resolution and missing data imputation

Objective. High-resolution multi-modal magnetic resonance imaging (MRI) is crucial in clinical practice for accurate diagnosis and treatment. However, challenges such as budget constraints, potential contrast agent deposition, and image corruption often limit the acquisition of multiple sequences from a single patient. Therefore, the development of novel methods to reconstruct under-sampled images and synthesize missing sequences is crucial for clinical and research applications. Approach. In this paper, we propose a unified hybrid framework called SIFormer, which utilizes any available low-resolution MRI contrast configurations to complete super-resolution (SR) of poor-quality MR images and impute missing sequences simultaneously in one forward process. SIFormer consists of a hybrid generator and a convolution-based discriminator. The generator incorporates two key blocks. First, the dual branch attention block combines the long-range dependency building capability of the transformer with the high-frequency local information capture capability of the convolutional neural network in a channel-wise split manner. Second, we introduce a learnable gating adaptation multi-layer perception in the feed-forward block to optimize information transmission efficiently. Main results. Comparative evaluations against six state-of-the-art methods demonstrate that SIFormer achieves enhanced quantitative performance and produces more visually pleasing results for image SR and synthesis tasks across multiple datasets. Significance. Extensive experiments conducted on multi-center multi-contrast MRI datasets, including both healthy individuals and brain tumor patients, highlight the potential of our proposed method to serve as a valuable supplement to MRI sequence acquisition in clinical and research settings.

Development of Positively Charged Poly-L-Lysine Magnetic Nanoparticles as Potential MRI Contrast Agent.

A colloidal solution of magnetic nanoparticles (MNPs) modified with biocompatible positively charged poly-L-lysine (PLL) with an oleate (OL) layer employed as an initial coating was produced as a potential MRI contrast agent. The effect of various PLL/MNPs' mass ratios on the samples' hydrodynamic diameter, zeta potential, and isoelectric point (IEP) was studied by the dynamic light-scattering method. The optimal mass ratio for MNPs' surface coating was 0.5 (sample PLL0.5-OL-MNPs). The average hydrodynamic particle size in the sample of PLL0.5-OL-MNPs was 124.4 ± 1.4 nm, and in the PLL-unmodified nanoparticles, it was 60.9 ± 0.2 nm, indicating that the OL-MNPs' surface became covered by PLL. Next, the typical characteristics of the superparamagnetic behavior were observed in all samples. In addition, the decrease in saturation magnetizations from 66.9 Am2/kg for MNPs to 35.9 and 31.6 Am2/kg for sample OL-MNPs and PLL0.5-OL-MNPs also confirmed successful PLL adsorption. Moreover, we show that both OL-MNPs and PLL0.5-OL-MNPs exhibit excellent MRI relaxivity properties and a very high r2(*)/r1 ratio, which is very desirable in biomedical applications with required MRI contrast enhancement. The PLL coating itself appears to be the crucial factor in enhancing the relaxivity of MNPs in MRI relaxometry.

Nitrogen-15 and Fluorine-19 Relaxation Dynamics and Spin-Relayed SABRE-SHEATH Hyperpolarization of Fluoro-[15N3]metronidazole.

Efficient 15N-hyperpolarization of [15N3]metronidazole was reported previously using the Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) technique. This hyperpolarized FDA-approved antibiotic is a potential contrast agent because it can be administered in a large dose and because previous studies revealed long-lasting HP states with exponential decay constant T1 values of up to 10 min. Possible hypoxia-sensing applications have been proposed using hyperpolarized [15N3]metronidazole. In this work, we report on the functionalization of [15N3]metronidazole with a fluorine-19 moiety via a one-step reaction to substitute the -OH group. SABRE-SHEATH hyperpolarization studies of fluoro-[15N3]metronidazole revealed efficient hyperpolarization of all three 15N sites with maximum %P15N values ranging from 4.2 to 6.2%, indicating efficient spin-relayed polarization transfer in microtesla fields via the network formed by 2J15N-15N. The corresponding 15N to 19F spin-relayed polarization transfer was found to be far less efficient with %P19F of 0.16%, i.e., more than an order of magnitude lower than that of 15N. Relaxation dynamics studies in microtesla fields support a spin-relayed polarization transfer mechanism because all 15N and 19F spins share the same T1 value of ca. 16-20 s and the same magnetic field profile for the SABRE-SHEATH polarization process. We envision the use of fluoro-[15N3]metronidazole as a potential hypoxia sensor. It is anticipated that under hypoxic conditions, the nitro group of fluoro-[15N3]metronidazole undergoes electronic stepwise reduction to an amino derivative. Ab initio calculations of 15N and 19F chemical shifts of fluoro-[15N3]metronidazole and its putative hypoxia-induced metabolites clearly indicate that the chemical shift dispersions of all three 15N sites and the 19F site are large enough to enable the envisioned hypoxia-sensing approaches.

Comparison of Methemoglobin, Deoxyhemoglobin, and Ferrous Nitrosyl Hemoglobin as Potential MRI Contrast Agents.

Gadolinium-based contrast agents (GBCAs) are in widespread use to enhance magnetic resonance imaging for evaluating vascular pathology. However, safety concerns and limitations regarding the use of GBCAs has led to an increased interest in alternative contrast agents. Previously, methemoglobin (metHb) and oxygen-free hemoglobin (HHb) have been shown to increase the T1-weighted signal intensity of blood, which is associated with a decrease in the T1 parameter and an enhanced contrast of the image. Thus, a lower T1 value compared to the baseline value is favorable for imaging. However, it is unknown as to whether metHb or HHb would be a stronger and more appropriate contrast agent and to what extent the T1-weighted signal is affected by concentration. This study evaluated T1-weighted images of blood samples over a range of metHb and HHb concentrations, as well as ferrous nitrosyl hemoglobin (HbIINO) concentrations. Comparison of T1 values from a baseline value of ~ 1500ms showed that metHb is the strongest contrast agent (T1 ~ 950ms at 20% metHb) and that HHb is a relatively weak contrast agent (T1 ~ 1450ms at 20% HHb). This study showed for the first time that HbIINO can provide a contrast effect, although not as strong as metHb but stronger than HHb (T1 estimated as 1250ms at 20% HbIINO). With metHb providing a viable contrast between 10 and 20%, metHb has the potential to be a safe and effective contrast agent since it can be naturally converted back to hemoglobin.