T1 MRI Contrast Agents Research Articles

Citrate stabilized maghemite hydrosol with controllable MRI contrast: Key role of nanoparticle size

In this study, we have synthetized a series of citric acid stabilized superparamagnetic iron oxide nanoparticles (CA-SPIONs) with different core sizes in an automated chemical reactor with high repeatability of the nanoparticle size and chemical composition. The prepared CA-SPIONs are highly crystalline spherical-shaped particles with the diameters of 3.5 ± 0.7, 6 ± 1, 9 ± 1, and 12 ± 2 nm. The valent state of iron oxide was determined by a combination of X-ray photoelectron spectroscopy, UV–Vis spectroscopy, and Mössbauer studies, which confirmed predominantly maghemite formation. Under normal conditions, these nanoparticles exhibit no coercive force and no hysteresis, while saturation magnetization increases from 2 to 61 emu/g along with the increasing core size. Both longitudinal (r1) and transverse (r2) relaxivities of maghemite hydrosols with different nanoparticle sizes were measured and compared with the same data for the commercial Gd-complex (Gadovist). Magnetic circular dichroism spectroscopy indicated that aggregation occurs in magnetic field, but 9 nm samples slightly aggregate in the fields above 1.0 T, whereas 3.5 nm colloids are stable and do not exhibit aggregation behavior even at 1.5 T. The obtained series were examined in phantom test in clinical 1.5 T MRI scanner, which showed that increasing the particle core size resulted in an enhanced T2 contrast, while T1 contrast declined. Finally, the smallest CA-SPION colloid nanoparticles with the size of 3.5 nm exhibited significant T1 contrast enhancement, comparable with the commercial Gd-complex in water and human plasma as well. The maghemite hydrosol formed by nanoparticles with 3.5 nm size thus has a promising future as a T1 MRI contrast agent.

Lanthanide vanadate-based nanoparticles as multimodal T1 -T2 MRI contrast agent and NIR luminescent imaging probe

We report the development of a multimodal lanthanide vanadate system suitable as dual T1-T2 MRI contrast agent as well as a luminescent imaging probe in the near-infrared region, using Dy3+ and Gd3+ as T2 and T1 components, respectively, and Nd3+ as the luminescent center. The vanadate matrix was chosen to avoid the undesired solubility associated to previously reported fluoride-based contrast agents. With such aim, we first optimized the design of the MRI system by comparatively evaluating the magnetic relaxivities of two different architectures consisting of i) uniform NPs incorporating both paramagnetic cations in solid solution (single-phase NPs), and ii) core-shell NPs consisting of a DyVO4 core coated with a homogeneous GdVO4 shell (DyVO4@GdVO4). We found that, although both samples presented magnetic relaxivity properties that make them adequate for their use as dual T1-T2 contrast agents for magnetic resonance imaging, the core-shell architecture would be more suitable because of their higher magnetic relaxivity values. Secondly, to prepare the multimodal system, the GdVO4 layer of such optimal dual T1-T2 MRI probe was doped with Nd3+ cations. An inert YVO4 intermediate shell was also introduced between the cores and the outer layer aiming to avoid energy transfer from Nd3+ to Dy3+, which would cause luminescence quenching. These core-shell-shell nanoparticles showed magnetic relaxivity values similar to those of the core-shell system and an intense luminescence in the near-infrared region. Moreover, they were dispersible and chemically stable under conditions that mimic the physiological media, and they were nontoxic for cells. Therefore, such multimodal nanoparticles meet the main requirements for their use as a dual T1-T2 contrast agent for magnetic resonance imaging and as a probe for luminescent imaging in the near-infrared region.

Size-Dependent Oxygen Vacancy of Iron Oxide Nanoparticles.

Prior research has highlighted the reduction of iron oxide nanoparticle (IONPs) sizes to the "ultra-small" dimension as a pivotal approach in developing T1-MRI contrast agents, and the enhancement in T1 contrast performance with the reducing size is usually attributed to the increased specific surface area and weakened magnetization. Nonetheless, as the size decreases, the variation in surface defects, particularly oxygen vacancy (VO) defects, significantly impacts the T1 imaging efficacy. In this study, the VO on IONPs is meticulously investigated through XPS, Raman, and EPR spectroscopy. As the nanoparticle size decreased, the VO concentration rose initially but subsequently declined, with the peak concentration observed in the size of 8.27nm. Further insights gained from synchrotron XAS analysis and DFT calculations indicate that both surface tension and phase transition in IONPs contribute to alterations in the Fe─O bond length, thereby influencing the VO formation energy across varying nanoparticle sizes. The MRI tests reveal that the VO in IONPs serve as pivotal sites for the attachment of water molecules to iron ions, and IONPs with fewer VO exhibited a deterioration in T1-MRI contrast effects. This research may provide a deeper understanding of the relationship between T1 contrast performance and the size of IONPs.

High temperature flow synthesis of iron oxide nanoparticles: Size tuning via reactor engineering

Batch thermal decomposition syntheses of iron oxide nanoparticles (IONPs) provide precise control of particle properties, but their scalability and reproducibility is challenging. This is addressed in this work via a versatile high temperature flow reactor with adjustable temperature profiles through three individual stages operated between 180 °C and 280 °C. The tuneable temperature profiles in combination with self-seeded growth methods made it possible to synthesise IONPs between 2 and 17 nm (a size increase that corresponds to a >600 fold particle volume increase) at production rates of several gIONP per day. The precursor solutions contained only iron(III) acetylacetonate in a polyol solvent and no nucleation or growth inhibitors, oxidation or reducing agents, ligands or any other additives . This broad size range covers most biomedical applications and is of special interest for T1 MRI contrast agents (2–5 nm), as well as for magnetic hyperthermia cancer therapy (>10 nm). The potential of the IONPs produced was demonstrated by their high longitudinal relaxivity >16 mM−1s−1 at a transversal/longitudinal relaxivity ratio <2.5 (small IONPs) and specific absorption rates increasing with the IONP size up to180 W/gFe. In addition, the polyol method employed allowed for simple ligand exchange with biocompatible sodium tripolyphosphate to make the IONPs stable in water, thus rendering them suitable for biomedical applications. The continuous high temperature process presented shows how to control the particle size not via the chemistry (e.g., chemical additives affecting the particle size through the surface chemistry), but engineering parameters, i.e., reactor temperature profiles, reagent addition sequences and seeded growth strategies.

Polyethylene glycol and chitosan functionalized manganese oxide nanoparticles for antimicrobial and anticancer activities

Biocompatible polymer-functionalized magnetic nanoparticles could offer promising applications in biomedical sciences. We fabricated polymer functionalized tri-manganese tetra oxide (Mn3O4) nanoparticles with the co-precipitation method and an octahedral crystal structure having a crystallite size of 10–17 nm was identified via XRD analyses. The SEM graph depicted the non-uniform and smooth surface of PEG-functionalized Mn3O4 NPs as compared to Mn3O4 and chitosan-coated Mn3O4 NPs. Elemental composition in the prepared sample was examined by EDX analysis. Various modes such as MnO, MnOH, OH, symmetric, and anti-symmetric of CH2 attached to the spectrum of Mn3O4 NPs were observed with FTIR analysis. The magnetization factor decreased and increase the coreacivity and retentivity of surface functionalized Mn3O4-NPs was calculated via VSM analysis. In-vitro bioassay, antibacterial activity was tested against Escherichiacoli, Bacillus cereus, and anti-fungal activities against two Fusarium strains indicated clear antimicrobial activities. The MTT assay to examine the anticancer activity against the MCF-7 cancer cell line was performed and the T1 MRI contrast agent demonstrated that PEG-coated Mn3O4 NPs exhibited anti-cancer activities. We propose that surface-functionalized magnetic NPs used for the treatment of cancer by using a remote controlled process of hyperthermia therapy.

High relaxivity Gd3+-based organic nanoparticles for efficient magnetic resonance angiography

Contrast-enhanced MR angiography (MRA) is a critical technique for vascular imaging. Nevertheless, the efficacy of MRA is often limited by the low rate of relaxation, short blood-circulation time, and metal ion-released potential long-term toxicity of clinical available Gd-based contrast agents. In this work, we report a facile and efficient strategy to achieve Gd-chelated organic nanoparticles with high relaxivity for T1-weighted MRA imaging. The Gd-chelated PEG-TCPP nanoparticles (GPT NPs) have been engineered composite structured consisting of Gd-chelated TCPP and PEG. The spherical structure of TCPP offers more chemical sites for Gd3+ coordination to improve the relaxivity and avoid leakage of the Gd3+ ions. The synthesized GPT NPs exhibit a high relaxation rate of 35.76 mM− 1 s− 1 at 3.0 T, which is higher than the rates for most reported MR contrast agents. Therefore, GPT NPs can be used for MRA with much stronger vascular signals, longer circulation time, and high-resolution arterial vascular visualization than those using clinical MR contrast agents at the same dose. This work may make the T1 MRI contrast agents for high-resolution angiography possible and offer a new candidate for preclinical and clinical applications of MR vascular imaging and vascular disease diagnosis.Graphical

Effects of iron oxide nanoparticles as T2-MRI contrast agents on reproductive system in male mice

Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T2-weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different timepoints. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not obviously impaired the overall testicular function or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB especially at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress and apoptotic activity in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T2-MRI contrast agents.Graphical

Prussian blue nanoparticles: an advanced platform for multimodal imaging

Iron-oxide nanoparticles have long been studied for their superparamagnetic properties. These T2-MRI contrast agents (CAs) cause a hypointense change of the MR image, making it difficult to visually detect and diagnose most small tumor detail. Currently, Gd and Mn-containing substances are commercially available as contrast agents; however, they are known to have strong toxic effects. Recently we developed Prussian blue nanoparticles (PBNPs) with a biocompatible surface by using a modified and improved one-step synthesis method.

Paramagnetic ultrasmall Ho2O3 and Tm2O3 nanoparticles: characterization of r2 values and in vivo T2 MR images at a 3.0 T MR field

Paramagnetic ultrasmall Ho2O3 and Tm2O3 nanoparticles grafted with various hydrophilic and biocompatible ligands as a new class of efficient T2 MRI contrast agents were investigated in this study.

Nanosized T1 MRI Contrast Agent Based on a Polyamidoamine as Multidentate Gd Ligand.

A linear polyamidoamine (PAA) named BAC-EDDS, containing metal chelating repeat units composed of two tert-amines and four carboxylic groups, has been prepared by the aza-Michael polyaddition of ethylendiaminodisuccinic (EDDS) with 2,2-bis(acrylamido)acetic acid (BAC). It was characterized by size exclusion chromatography (SEC), FTIR, UV–Vis and NMR spectroscopies. The pKa values of the ionizable groups of the repeat unit were estimated by potentiometric titration, using a purposely synthesized molecular ligand (Agly-EDDS) mimicking the structure of the BAC-EDDS repeat unit. Dynamic light scattering (DLS) and ζ-potential analyses revealed the propensity of BAC-EDDS to form stable nanoaggregates with a diameter of approximately 150 nm at pH 5 and a net negative charge at physiological pH, in line with an isoelectric point <2. BAC-EDDS stably chelated Gd (III) ions with a molar ratio of 0.5:1 Gd (III)/repeat unit. The stability constant of the molecular model Gd-Agly-EDDS (log K = 17.43) was determined as well, by simulating the potentiometric titration through the use of Hyperquad software. In order to comprehend the efficiency of Gd-BAC-EDDS in contrasting magnetic resonance images, the nuclear longitudinal (r1) and transverse (r2) relaxivities as a function of the externally applied static magnetic field were investigated and compared to the ones of commercial contrast agents. Furthermore, a model derived from the Solomon–Bloembergen–Morgan theory for the field dependence of the NMR relaxivity curves was applied and allowed us to evaluate the rotational correlation time of the complex (τ = 0.66 ns). This relatively high value is due to the dimensions of Gd-BAC-EDDS, and the associated rotational motion causes a peak in the longitudinal relaxivity at ca. 75 MHz, which is close to the frequencies used in clinics. The good performances of Gd-BAC-EDDS as a contrast agent were also confirmed through in vitro magnetic resonance imaging experiments with a 0.2 T magnetic field.

Mn(II) complexes of phenylenediamine based macrocyclic ligands as T1-MRI contrast agents

The Mn(II) complexes are emerging as alternative T1-MRI contrast agents (CAs) to the currently available Gd-based CAs. The complexes [Mn(L1)] 1 and [Mn(L2)] 2 of o-phenylenediamine based macrocyclic ligands are reported as T1-CAs for MRI applications. The high spin state of the Mn(II) complexes (S = 5/2) is confirmed by EPR spectra. The complexes showed an irreversible Mn(II)/Mn(III) redox potential at pH 7.28, which became more and less positive at the acidic and alkaline pHs, respectively. The species [MnL], [Mn(LH−1), and [Mn(LH−2) are persisted in solution. Complex 1 is inert towards Ca(II), Mg(II), and Zn(II), whereas complex 2 is inert for Ca(II) and Mg(II) and labile under Zn(II) and Cu(II) ions. Complex 1 showed an r1-relaxivity of 3.27 and 2.32 mM−1 s−1 at 1.41 T, 25, and 37 °C respectively via inner-sphere water relaxation, which is lower than that of 2 (r1, 5.56, and 4.19 mM−1 s−1) at pH 7.28 and 1.41 T. The Mn(II) complexes showed a 2–8% enhancement of r1-relaxivity while lowering the pH to acidic, which corresponds to the release of free Mn(II) ions. In contrast, the r1-relaxivity is dropped to 52% and 20% for 1 and 2 respectively under alkaline pH due to the deprotonation of inner-sphere water. Phantom images obtained on Bruker ‘BIOSPEC’ 47/40 animal research MRI/MRS scanner showed concentration-dependent brightness. The interaction of human serum albumin (HSA) with 1 and 2 exhibited five times higher r1-relaxivities (11.3 and 22.0 mM−1 s−1 at 1.41 T, respectively).

Facile synthesis of superparamagnetic manganese ferrite nanoparticles as a novel T2 MRI contrast agent

With co-precipitation method we successfully synthesized an aqueous dispersible, superparamagnetic manganese ferrite nanoparticles at relatively low temperature (190 ​°C). This material shows potential application as T2 MRI contrast agent. Cost-effective and less toxic manganese (II) chloride (MnCl2·4H2O) and iron (III) chloride hexahydrate (FeCl3·6H2O) were used as precursors and 2-[2-(2-Hydroxyethoxy)ethoxy] ethanol (TEG) were utilized as solvent which served as stabilizer and provided a reduction system. The mean diameter of these nanoparticles is about 7 ​nm. Its saturation magnetization (Ms) and relaxivity value (r2) are as high as 46 emu/g and 593.9 ​mM−1s−1 respectively. In vitro cell study demonstrated pancreatic cancer cells could keep viable when the manganese ferrite nanoparticles concentration reached up to 50 ​μg/mL.

Fabrication of SiO2@upconversion nanoparticles composites with tunable magneto-fluorescent properties for bimodal imaging

This study presents Mn and Fe co-doped NaYF4:Yb/Er upconversion nanoparticles for potential biomedical applications. Solvothermally prepared nanoparticles were rendered hydrophilic through acidic surface treatment. Hydrophilic nanoparticles were immobilized on SiO2 particles. Effect of co-doping on optical and magnetic properties was studied through photoluminescence spectra and magnetic characterization. Higher Mn/Fe mole ratio improved red emission intensity in NaYF4:Yb/Er upconversion nanoparticles whereas lower Mn/Fe mole ratio improved paramagnetic properties. Co-doping with Mn and Fe is a useful way to tune properties of NaYF4:Yb/Er upconversion nanoparticles as bioimaging and T1 MRI contrast agents.

Manganese(III) porphyrin oligomers as high-relaxivity MRI contrast agents

Manganese(III) porphyrins (MnIIIPs) as MRI contrast agents (CAs) have drawn particular attention due to their high longitudinal relaxivity (r1) and unique biodistribution. In this work, two MnIIIP-based oligomers, MnPD and MnPT, were designed to further improve the relaxivity with ease of synthesis. The two compounds were fully characterized and their nuclear magnetic relaxation dispersion (NMRD) profiles were acquired with a fast field cycling NMR relaxometer. Both of the compounds exhibited extended high molar r1 at high fields, higher than that of Gd-DTPA, the first clinical gadolinium(III)-based MRI CA. The r1 value of per manganese atom increased with the increasing number of MnIIIP building blocks, suggesting rotational correlation time (τR) played dominant role in the r1 dispersion. The toxicity of the two MnIIIPs and the imaging effectiveness were estimated in vitro and in vivo. With good biocompatibility, significant contrast enhancement, and complete excretion in 24 h, MnPD and MnPT are both promising for high field clinical applications. The applied strategy also potentially provided a facile approach for creation of more MnIIIP oligomer as efficient T1 MRI CAs.

Theragnostic Magnetic Core-Shell Nanoparticle as Versatile Nanoplatform for Magnetic Resonance Imaging and Drug Delivery

In this study, magnetic core-shell (MCS) nanoparticles were prepared as theragnostic potential nanoplatforms for simultaneously targeted drug delivery systems for tamoxifen and diagnosis. MCS nanoparticles were prepared in a well-shaped spherical form by the o/w emulsion method and characterized by means of dynamic light scattering (DLS), Scanning electron microscopy (SEM), Nuclear magnetic resonance (NMR), transform infrared (FT-IR) spectroscopy, and vibrating sample magnetometer (VSM). Scanning electron microscopy (SEM) indicated spherical nanostructures' formation with the final average particle size of around 80 nm. The findings proved the superparamagnetic properties of the MCS nanoparticles with relatively high-magnetization values (11.69 emu/g), which indicate that they were sensitive enough to external magnetic fields as a magnetic drug carrier. The nanoparticles showed 8.14% and 52.19% drug loading and encapsulation efficiency, respectively. MCS nanoparticles showed sustained release behavior for 120 h in the phosphate-buffered saline (PBS, pH= 7.4, 5.4) at 37 °C. The ratio between transverse and longitudinal relaxivity (r2/r1) value of the MCS nanoparticles was around 20, indicating their potential as a T2 MRI contrast agent. It can be concluded that the prepared MCS nanoparticles may serve as a promising carrier as an MRI contrast agent and targeted controlled anticancer drug delivery.

Zeolitic imidazolate framework nanoparticles loaded with gadolinium chelate as efficient T1 MRI contrast agent

Zeolitic imidazolate framework nanoparticles loaded with gadolinium chelate as efficient T1 MRI contrast agent

Ultrasmall Fe@Fe3O4 nanoparticles as T1–T2 dual-mode MRI contrast agents for targeted tumor imaging

Targeted T1–T2 MRI contrast agents, which can eliminate the difficulty of image matching across multiple imaging instruments and permit specific localization of lesions, are promising candidates for more accurate diagnosis of tumors. In this study, ultrasmall Fe@Fe3O4 nanoparticles were designed and synthesized as T1–T2 dual-mode MRI contrast agents for accurate tumor imaging. First, to investigate the influence of nanoparticle size, Fe@Fe3O4 nanoparticles with diameters of 4, 8, and 12 nm were prepared, among which the 8 nm 3-(3,4-dihydroxyphenyl)propionic acid (DHCA)-modified nanoparticles exhibited the optimal T1–T2 dual-mode MRI performance. Next, to develop a tumor-targeted contrast agent, the DHCA-Fe@Fe3O4 nanoparticles were conjugated with the F56 peptide, which targets the vascular endothelial growth factor receptor, and the resulting F56-DHCA-Fe@Fe3O4 nanoparticles were found to exhibit good T1–T2 dual-mode imaging and tumor-targeting performance both in vitro and in vivo, indicating the nanoparticles represent a new research tool for accurate tumor diagnosis.

Facile synthesis of ultra-small hollow manganese silicate nanoparticles as pH/GSH-responsive T1-MRI contrast agents

Manganese silicate nanoparticles have recently attracted great attention due to the effectiveness of T1-weighted magnetic resonance imaging (MRI) contrast agents (CAs) in the mildly acidic and high glutathione (GSH) conditions of the tumor microenvironment. Herein, ultra-small hollow manganese silicate (UHMS) nanoparticles were prepared via a facile, economical, and eco-friendly method based on a hydrothermal process using small silica nanoparticles as both the silicon source and templates. The nanoparticles showed remarkable biocompatibility and dispersion stability after modification with polyethylene glycol (PEG). Owing to their ultra-high longitudinal relaxation rate (r1) at low pH values and high GSH levels, the UHMS@PEG nanoparticles have performed an excellent pH/GSH-responsive T1-weighted MRI. Meanwhile, the nanoparticles showed insignificant cytotoxicity in vitro and in vivo. Therefore, the UHMS@PEG nanoparticles show promise as T1-MRI CAs in the tumor microenvironment and may be used to assist in clinical cancer diagnosis.

Binding and Release of FeIII Complexes from Glucan Particles for the Delivery of T1 MRI Contrast Agents.

Yeast-derived β-glucan particles (GPs) are a class of microcarriers under development for the delivery of drugs and imaging agents to immune-system cells for theranostic approaches. However, the encapsulation of hydrophilic imaging agents in the porous GPs is challenging. Here, we show that the unique coordination chemistry of FeIII -based macrocyclic T1 MRI contrast agents permits facile encapsulation in GPs. Remarkably, GPs labeled with the simple FeIII complexes are stable under physiologically relevant conditions, despite the absence of amphiphilic groups. In contrast to the free FeIII coordination complex, the labeled FeIII -GPs have lowered T1 relaxivity and act as a silenced form of the contrast agent. Addition of a fluorescent tag to the FeIII complex produces a bimodal agent to further enable tracking of the nanoparticles and to monitor release. Treatment of the iron-labeled GPs with a maltol chelator or with mildly acidic conditions releases the intact iron complex and restores enhanced T1 relaxation of the water protons.

Cathodic protected Mn2+ by NaxWO3 nanorods for stable magnetic resonance imaging-guided tumor photothermal therapy

The stability and safety of magnetic resonance imaging (MRI) contrast agents (CAs) are crucial for accurate diagnosis and real-time monitor of tumor development. Paramagnetic Mn2+ as nonlanthanide metal ion has been widely studied for use in T1-MRI CAs, but unfortunately, Mn2+ can be oxidized by H2O2 in tumor to nonparamagnetic Mn4+ via a Fenton-like reaction. The concurrent loss of paramagnetism and production of toxic hydroxyl radical (OH) go against the basic requirment of CAs, thus restricting the further development of Mn2+-based CAs. Based on the different standard potential of W6+/W5+ (~0.26 V) and Mn4+/Mn2+ (~1.2 V), a “cathodic protection” strategy was exploited in Mn2+-doped NaxWO3 nanorods (NaxMnWO3), with W5+ as the sacrificial anode and Mn2+ as the protected cathode, to protect Mn2+ from oxidation in tumor for stable MR contrast performance, as well as repress its Fenton-like reaction activity for good biosafety. Moreover, the tungsten bronze crystal structure endows NaxMnWO3 with excellent near-infrared (NIR)-photothermal properties for effective tumor hyperthermia, without effect from the changed oxidation state of W. This “cathodic protection” strategy offers a new method for the development of reliable and hypotoxic biomaterials for stable imaging and therapeutic applications in clinic.