Magnetic Resonance Imaging Contrast Agents Research Articles

Structural Defect-Enabled Magnetic Neutrality Nanoprobes for Ultra-High-Field Magnetic Resonance Imaging of Isolated Tumor Cells In Vivo.

The identification of metastasis "seeds", isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for non-invasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T2-decaying effects under UHF conditions, which compromises T1 MRI capability and further impedes the precise imaging of small lesions. Herein, we report a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost non-magnetic. This unique characteristic effectively mitigates T2-decaying effect while concurrently enhancing UHF T1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r2/r1 value (∼1.06), enabling non-invasive visualization of ITCs with an exceptional detection threshold of ∼0.16mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research. This article is protected by copyright. All rights reserved.

Green synthesis and optimization of iron oxide nanoparticles as MRI contrast agent

Iron nanoparticles (FeNPs) derived from herbal plants are being explored as potential magnetic resonance imaging (MRI) contrast agents due to their biocompatibility and ability to perform targeted drug delivery. For the first time, the usage of various novel combinations of leaf extracts such as those of Azadirachta indica and Piper betle and extracts of two other Ayurvedic herbs – namely, Asparagus racemosus and Symplocos – was attempted for eco-friendly green synthesis of FeNPs. The nanoparticles were coated onto nanofibers made from a banana pseudo-stem (FENPs-NF) to enhance their biocompatibility. The synthesis process was optimized using response surface methodology, and techniques such as ultraviolet–visible (UV–Vis) spectroscopy, vibrating-sample magnetometry, atomic absorption spectroscopy (AAS), field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX) and Fourier transform infrared spectroscopy (FT-IR) were used for characterization. Hemolytic and immune cell assays, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and MRI analysis were carried out. A peak at 325 nm observed in UV–Vis spectroscopy, AAS, FE-SEM, EDX and FT-IR proved the presence of FeNPs. Hemolytic and immune cell assays indicated biocompatibility, and the MTT assay (MCF-7) showed inhibition at 250 μg/ml. FeNPs and FeNPs-NF showed a good signal loss in MRI analysis at 1.5 T, proving their contrast agent nature. Thus, FeNPs synthesized from herbal plant sources may open a new door for potential application in the biomedical field as a chemical-free and biocompatible MRI contrast agent.

Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

Evolving Characteristics of Gadolinium-Based Contrast Agents for MR Imaging: A Systematic Review of the Importance of Relaxivity.

Gadolinium-based contrast agents (GBCAs) are widely and routinely used to enhance the diagnostic performance of magnetic resonance imaging and magnetic resonance angiography examinations. T1 relaxivity (r1) is the measure of their ability to increase signal intensity in tissues and blood on T1-weighted images at a given dose. Pharmaceutical companies have invested in the design and development of GBCAs with higher and higher T1 relaxivity values, and "high relaxivity" is a claim frequently used to promote GBCAs, with no clear definition of what "high relaxivity" means, or general concurrence about its clinical benefit. To understand whether higher relaxivity values translate into a material clinical benefit, well-designed, and properly powered clinical studies are necessary, while mere in vitro measurements may be misleading. This systematic review of relevant peer-reviewed literature provides high-quality clinical evidence showing that a difference in relaxivity of at least 40% between two GBCAs results in superior diagnostic efficacy for the higher-relaxivity agent when this is used at the same equimolar gadolinium dose as the lower-relaxivity agent, or similar imaging performance when used at a lower dose. Either outcome clearly implies a relevant clinical benefit. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

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

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

A self-assembled theranostic nanoplatform for efficient tumor sonodynamic-gas therapy

The powerful antioxidant system in tumor tissues limits the efficacy of sonodynamic therapy (SDT) by reducing the availability of the produced reactive oxygen species (ROS). To address this problem, a pH/ultrasound (US) responsive theranostic nanoplatform is elaborately constructed by self-assembly of nitrogen-doped graphene quantum dots (NGQDs), benzothiazole sulfinate (BTS), Gd3+ ions and poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-PEG). The NGQD component with excellent sonodynamic activity wrapped in the resulting Gd-NGQDs/BTS@PLGA-PEG can efficaciously respond to ultrasonic irradiation and cause abundant ROS generation. Importantly, in response to acidic tumor microenvironment, the loaded BTS sustainably releases SO2, which induces the increase of intracellular •O2− level by inhibiting superoxide dismutase activity and further promotes the enrichment of ROS by reducing intracellular glutathione level and suppressing glutathione peroxidase 4 activity. The well-designed SO2 gas therapy-enhanced SDT strategy leads to high oxidative stress in tumor cells and effective inhibition of the growth of bilateral tumors with only a single intravenous injection of the nanomedicine and a subsequent single US irradiation. Gd-NGQDs/BTS@PLGA-PEG can also be employed as a good T1-weighted magnetic resonance imaging contrast agent to guide tumor therapy. This innovative therapeutic strategy developed in our contribution may provide a new paradigm for the exploration of deep tumor therapy.

Unravelling pituitary tumours in medically treated patients with acromegaly: the impact of systematic MRI reassessment.

In acromegaly, the primary tumor is usually found during magnetic resonance imaging (MRI) of the pituitary gland. A remnant tumor after surgery is, however, harder to depict. When a tumor is missed, the remaining option is usually lifelong pharmacological treatment. To identify tumors by reassessment of all available MRI scans in pharmacologically treated patients, operated or not, and to compare our results with the routine MRI reports. Adult patients diagnosed with acromegaly and managed at a tertiary care center between 2005 and 2021 and currently on pharmacological treatment were included. MRI scans were evaluated in a standardized manner and classified independently by a radiologist and an endocrinologist into "certain," "suspected," or "no tumor." In case of disagreement, consensus was achieved with a senior neuroradiologist. The results were compared using the clinical radiologists' routine MRI reports. We identified certain and suspected tumors in 29/74 and 36/74 patients, respectively. No tumor was identified in nine patients. In five of these, no MRI contrast agent was given. Discrepancy between our results and the routine MRI reports was found in 31/74 patients (P = 0.01). In 22 patients, the routine reports described no tumor while we identified certain tumors in 2/22 patients and suspected tumors in 13/22 patients. In most patients with pharmacologically treated acromegaly, we identified a certain or suspected pituitary tumor. These findings were more frequent compared to the routine MRI reports. Based on our results, patients will be considered for a change in long-term treatment modality.

Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood.

Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the "EU Joint Programme - Neurodegenerative Disease Research (JPND)" consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration-time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

Development of Manganese Carbonyl Loaded Upconversion Nanoparticles for Near‐Infrared‐Triggered Carbon Monoxide and Mn2+ Delivery

Photoactivatable carbon monoxide‐releasing molecules (CORMs), typically based on transition‐metal carbonyl complexes, have reliance on activation by UV or visible light that restricts their biomedical applications. To address this limitation, a near‐infrared (NIR)‐responsive nanoplatform is presented based on upconversion nanoparticles (UCNPs) loading with manganese carbonyl complex Mn2(CO)10 that concurrently releases CO and manganese ion (Mn2+). With the UCNPs, the more tissue‐penetrable NIR is used to locally generate UV light for photodecomposition of Mn2(CO)10 into CO and manganese oxide (MnOX), after which MnOX is reduced to Mn2+ by the overexpressed glutathione in cancer cells. Moreover, the released Mn2+ can serve as a magnetic resonance imaging contrast agent to monitor the NIR‐controlled corelease of CO and Mn2+ in real time. Therefore, this nanoplatform can provide a potential strategy for NIR‐enabled spatiotemporally release of CO and Mn2+, enhancing the controlled delivery and biomedical application of CORMs.

Safe and Informed Use of Gadolinium-Based Contrast Agent in Body Magnetic Resonance Imaging: Where We Were and Where We Are.

Gadolinium-based contrast agents (GBCAs) have helped to improve the role of magnetic resonance imaging (MRI) for the diagnosis and treatment of diseases. There are currently nine different commercially available gadolinium-based contrast agents (GBCAs) that can be used for body MRI cases, and which are classifiable according to their structures (cyclic or linear) or biodistribution (extracellular-space agents, target/specific-agents, and blood-pool agents). The aim of this review is to illustrate the commercially available MRI contrast agents, their effect on imaging, and adverse reaction on the body, with the goal to lead to their proper selection in different clinical contexts. When we have to choose between the different GBCAs, we have to consider several factors: (1) safety and clinical impact; (2) biodistribution and diagnostic application; (3) higher relaxivity and better lesion detection; (4) higher stability and lower tissue deposit; (5) gadolinium dose/concentration and lower volume injection; (6) pulse sequences and protocol optimization; (7) higher contrast-to-noise ratio at 3.0 T than at 1.5 T. Knowing the patient's clinical information, the relevant GBCAs properties and their effect on body MRI sequences are the key features to perform efficient and high-quality MRI examination.

Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent

To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r2/r1 ratio of the reported Gd macrochelates that is an important factor for T1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r1 value of 16.35 mM−1 s−1 and r2/r1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 ℃ or 1.8 cP at 37 ℃, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.Graphical

A Review on the Design of Carbon-Based Nanomaterials as MRI Contrast Agents.

The administration of magnetic resonance imaging (MRI) contrast agents (CAs) has been conducted since 1988 by clinicians to enhance the clarity and interpretability of MR images. CAs based on gadolinium chelates are the clinical standard used worldwide for the diagnosis of various pathologies, such as the detection of brain lesions, the visualization of blood vessels, and the assessment of soft tissue disorders. However, due to ongoing concerns associated with the safety of gadolinium-based contrast agents, considerable efforts have been directed towards developing contrast agents with better relaxivities, reduced toxicity, and eventually combined therapeutic modalities. In this context, grafting (or encapsulating) paramagnetic metals or chelates onto (within) carbon-based nanoparticles is a straightforward approach enabling the production of contrast agents with high relaxivities while providing extensive tuneability regarding the functionalization of the nanoparticles. Here, we provide an overview of the parameters defining the efficacy of lanthanide-based contrast agents and the subsequent developments in the field of nanoparticular-based contrast agents incorporating paramagnetic species.

A Hexanuclear Gadolinium(III)-Based Nanoprobe for Magnetic Resonance Imaging of Tumor Apoptosis.

Magnetic resonance imaging (MRI) is instrumental in the noninvasive evaluation of tumor tissues in patients subjected to chemotherapy, thereby yielding essential diagnostic data crucial for the prognosis of tumors and the formulation of therapeutic strategies. Currently, commercially available MRI contrast agents (CAs) predominantly consist of mononuclear gadolinium(III) complexes. Because there is only one Gd(III) atom per molecule, these CAs often require administration in high doses to achieve the desired contrast quality, which inevitably leads to some adverse events. Herein, we develop a six-nuclei, apoptosis-targeting T1 CA, Gd6-ZnDPA nanoprobe, which consists of a hexanuclear gadolinium nanocluster (Gd6) with an apoptosis-targeting group (ZnDPA). The amplification of Gd(III) by the hexanuclear structure generates its high longitudinal relaxivity (44.67 mM-1 s-1, 1T) and low r1/r2 ratio (0.68, 1T). Based on the Solomon-Bloembergen-Morgan (SBM) theory, this notable improvement is primarily ascribed to a long correlation tumbling time (τR). More importantly, the Gd6-ZnDPA nanoprobe shows excellent tumor apoptosis properties with an enhanced MR signal ratio (∼74%) and a long MRI imaging acquisition time window (∼48 h) in 4T1 tumor-bearing mice. This study introduces an experimental gadolinium-based CA for the potential imaging of tumor apoptosis in the context of MRI.

Disentangling the intrinsic relaxivities of highly purified graphene oxide

The chemistry of contrast agents (CAs) for magnetic resonance imaging (MRI) applications is an active area of research and, in recent work, it was shown that CA-based graphene oxide (GO) has valuable properties for biomedical uses. GO has a potential as MRI CAs thanks to several functionalities, like its ability to penetrate tissues and cell membranes, as well as easy coupling with therapeutic agents, therefore showing the potential for both a diagnostic and therapeutic role. In this study, we performed a thorough cleaning of the GO sample (synthesized using a modified Hummers method), minimizing the amount of residual manganese down to 73 ppm. Using a wide range of physical–chemical methods (morphology, chemical composition, elemental analysis, spectroscopies, and imaging), we characterized the intrinsic longitudinal and transverse relaxivities of highly purified GO nanosheets. X-band electron paramagnetic resonance allowed to recognize the paramagnetic species involved, and 1.0 T MRI was used to disentangle the relative contributions to the MRI contrast of pristine GO nanosheets arising from structural defects and residual paramagnetic manganese impurities embedded in the nanomaterial. Although experiments show that the MRI relaxivity of GO nanosheets arises from the cumulative effect of structural defects and paramagnetic impurities, we conclude that the latter contribution to the longitudinal and transverse relaxivities becomes irrelevant for highly purified (pristine) GO. This novel finding clearly demonstrates that, apart from trivial manganese inclusion, pristine GO produces an inherent MRI response via structural defects, and therefore it is on its own a suitable candidate as MRI contrast agent.

Ultra-small Janus nanoparticle-induced activation of ferroptosis for synergistic tumor immunotherapy

Ferroptosis induced by lipid peroxide (LPO) accumulation is an effective cell death pathway for cancer therapy. However, how to effectively induce ferroptosis at tumor sites and improve its therapeutic effectiveness remains challenging. Here, MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex with tumor-specific targeting and TME response is constructed to overcome immunosuppressive tumor microenvironment (TME) to potentiate the curative effect of ferroptosis by coupling the immune checkpoint indoleamine 2,3-dioxygenase (IDO) inhibitor, NLG919, and hyaluronic acid (HA) to novel ultra-small MnFe2O4@NaGdF4 (MG) nanoparticles with a Janus structure. Firstly, tumor site-precise delivery of MG and NLG919 is achieved with HA targeting. Secondly, MG acts as a magnetic resonance imaging contrast agent, which not only has a good photothermal effect to realize tumor photothermal therapy, but also depletes glutathione and catalyzes the production of reactive oxygen species from endogenous H2O2, which effectively promotes the accumulation of LPO and inhibits the expression of glutathione peroxidase 4, achieving enhanced ferroptosis. Thirdly, NLG919 inhibits the differentiation of Tregs by blocking the tryptophan/kynurenine immune escape pathway, thereby reversing immunosuppressive TME together with the Mn2+-activated cGAS-STING pathway. This work contributes new perspectives for the development of novel ultra-small Janus nanoparticles to reshape immunosuppressive TME and ferroptosis activation. Statement of significanceThe Janus structured MnFe2O4@NaGdF4@NLG919@HA (MGNH) nanocomplex was synthesized, which can realize the precise delivery of T1/T2 contrast agents MnFe2O4@NaGdF4 (MG) and NLG919 at the tumor site under the ultra-small Janus structural characteristics and targeted molecule HA. The production of ROS, consumption of GSH, and photothermal properties of MGNH make it possible for CDT/PTT activated ferroptosis, and synergistically disrupt and reprogram tumor growth and immunosuppressive tumor microenvironment with NLG919 and Mn2+-mediated activation of cGAS-STING pathway, achieving CDT/PTT/immunotherapy activated by ferroptosis. Meanwhile, ultra-small structural properties of MGNH facilitate subsequent metabolic clearance by the body, allowing for the minimization of potential biotoxicity associated with its prolonged retention.

Radiomodulating Properties of Superparamagnetic Iron Oxide Nanoparticle (SPION) Agent Ferumoxytol on Human Monocytes: Implications for MRI-Guided Liver Radiotherapy.

Superparamagnetic iron oxide nanoparticles (SPION) have attracted great attention not only for therapeutic applications but also as an alternative magnetic resonance imaging (MRI) contrast agent that helps visualize liver tumors during MRI-guided stereotactic body radiotherapy (SBRT). SPION can provide functional imaging of liver parenchyma based upon its uptake by the hepatic resident macrophages or Kupffer cells with a relative enhancement of malignant tumors that lack Kupffer cells. However, the radiomodulating properties of SPION on liver macrophages are not known. Utilizing human monocytic THP-1 undifferentiated and differentiated cells, we characterized the effect of ferumoxytol (Feraheme®), a carbohydrate-coated ultrasmall SPION agent at clinically relevant concentration and therapeutically relevant doses of gamma radiation on cultured cells in vitro. We showed that ferumoxytol affected both monocytes and macrophages, increased the resistance of monocytes to radiation-induced cell death and inhibition of cell activity, and supported the anti-inflammatory phenotype of human macrophages under radiation. Its effect on human cells depended on the duration of SPION uptake and was radiation dose-dependent. The results of this pilot study support a strong mechanism-based optimization of SPION-enhanced MRI-guided liver SBRT for primary and metastatic liver tumors, especially in patients with liver cirrhosis awaiting a liver transplant.

Gem-bisphosphonic acid-based double hydrophilic block copolymers: RAFT synthesis and comparative assembly with gadolinium ions for the formation of MRI contrast agents

The synthesis of double hydrophilic block copolymers (DHBCs) with one block containing bisphosphonic acid groups was performed by aqueous RAFT polymerization with two approaches, either starting from a PEO-based macro-chain transfer agent (macro-CTA) or by chain extension of a RAFT-capped bisphosphonic acrylate homopolymer with oligo(ethylene glycol) methyl ether acrylate (OEGA). By complexation with gadolinium and europium ions, these polymers are prone to form hybrid polyionic complexes (HPICs) as evidenced by mono- and multi-angle DLS, TEM and luminescence measurements. The obtained HPICs showed better chemical stability at low pH values compared to previously reported counterparts based on carboxylic and monophosphonic acid groups (i.e., PEO-b-PAA and PEO-b-PVPA respectively). Due to their high relaxivity values, the proposed HPICs show potential as contrast agents for magnetic resonance imaging (MRI).

Rational Design of Magnetic Nanoparticles as T1-T2 Dual-Mode MRI Contrast Agents.

Magnetic nanoparticles (MNPs), either paramagnetic or superparamagnetic depending on their composition and size, have been thoroughly studied as magnetic resonance imaging (MRI) contrast agents using in vitro and in vivo biomedical preclinical studies, while some are clinically used. Their magnetic properties responsible in some cases for high magnetization values, together with large surface area-to-volume ratios and the possibility of surface functionalization, have been used in MRI-based diagnostic and theranostics applications. MNPs are usually used as positive (T1) or negative (T2) MRI contrast agents, causing brightening or darkening of selected regions in MRI images, respectively. This review focusses on recent developments and optimization of MNPs containing Gd, Mn, Fe and other lanthanide ions which may function as dual-mode T1-T2 MRI contrast agents (DMCAs). They induce positive or negative contrast in the same MRI scanner upon changing its operational mode between T1-weighted and T2-weighted pulse sequences. The type of contrast they induce depends critically on their r2/r1 relaxivity ratio, which for DMCAs should be in the 2-10 range of values. After briefly discussing the basic principles of paramagnetic relaxation in MNPs, in this review, the basic strategies for the rational design of DMCAs are presented and typical examples are discussed, including in vivo preclinical applications: (1) the use of NPs with a single type of contrast material, Gd- or Mn-based NPs or superparamagnetic NPs with appropriate size and magnetization to provide T2 and T1 contrast; and (2) inclusion of both types of T1 and T2 contrast materials in the same nanoplatform by changing their relative positions.

Walking Dead Macrophage-Based Positive Enhancement MRI for Ultrahighly Efficient Diagnosis of Nephritis.

Nephritis is an inflammatory condition of the glomerulus, and the clinical gold standard for its diagnosis is a kidney biopsy. However, obtaining biopsy results can take several days, which does not meet the requirement of rapid diagnosis, especially for rapidly progressive types. To achieve an effective and noninvasive diagnosis, we propose a nephritis-specific, positive magnetic resonance imaging (MRI) contrast agent based on Gd3+ anchored walking dead macrophage Gd-RAW. Gd-RAW exhibits high selectivity for inflammatory renal parenchyma and provides comparable results to histopathology methods. The Gd-RAW-based MRI contrast agent reduces the diagnostic time of nephritis from 14 days of biopsy to 1 h. Furthermore, in a unilateral nephritis model constructed by increasing the glycerol concentration, the T1WI of renal parenchyma exhibits an increased signal-to-noise ratio, which is crucial for evaluating nephritic severity. This work promotes rapid diagnosis of nephritis and potentially provides sufficient evidence for clinicians to offer timely treatment to patients. The methodology of paramagnetic ion-anchored macrophage corpse also opens up new prospects for designing more specific and biosafe MRI contrast agents.

A Facile NMR Method for Pre-MRI Evaluation of Trigger-Responsive T1 Contrast Enhancement.

There is a growing interest in developing paramagnetic nanoparticles as responsive magnetic resonance imaging (MRI) contrast agents, which feature switchable T1 image contrast of water protons upon biochemical cues for better discerning diseases. However, performing an MRI is pragmatically limited by its cost and availability. Hence, a facile, routine method for measuring the T1 contrast is highly desired in early-stage development. This work presents a single-point inversion recovery (IR) nuclear magnetic resonance (NMR) method that can rapidly evaluate T1 contrast change by employing a single, optimized IR pulse sequence that minimizes water signal for "off-state" nanoparticles and allows for sensitively measuring the signal change with "switch-on" T1 contrast. Using peptide-induced liposomal gadopentetic acid (Gd3+ -DTPA) release and redox-sensitive manganese oxide (MnO2 ) nanoparticles as a demonstration of generality, this method successfully evaluates the T1 shortening of water protons caused by liposomal Gd3+ -DTPA release and Mn2+ formation from MnO2 reduction. Furthermore, the NMR measurement is highly correlated to T1 -weighted MRI scans, suggesting its feasibility to predict the MRI results at the same field strength. This NMR method can be a low-cost, time-saving alternative for pre-MRI evaluation for a diversity of responsive T1 contrast systems.