Magnetic Resonance Imaging Contrast Agents Research Articles

Advancing MRI with magnetic nanoparticles: a comprehensive review of translational research and clinical trials.

The nexus of advanced technology and medical therapeutics has ushered in a transformative epoch in contemporary medicine. Within this arena, Magnetic Resonance Imaging (MRI) emerges as a paramount tool, intertwining the advancements of technology with the art of healing. MRI's pivotal role is evident in its broad applicability, spanning from neurological diseases, soft-tissue and tumour characterization, to many more applications. Though already foundational, aspirations remain to further enhance MRI's capabilities. A significant avenue under exploration is the incorporation of innovative nanotechnological contrast agents. Forefront among these are Superparamagnetic Iron Oxide Nanoparticles (SPIONs), recognized for their adaptability and safety profile. SPION's intrinsic malleability allows them to be tailored for improved biocompatibility, while their functionality is further broadened when equipped with specific targeting molecules. Yet, the path to optimization is not devoid of challenges, from renal clearance concerns to potential side effects stemming from iron overload. This review endeavors to map the intricate journey of SPIONs as MRI contrast agents, offering a chronological perspective of their evolution and deployment. We provide an in-depth current outline of the most representative and impactful pre-clinical and clinical studies centered on the integration of SPIONs in MRI, tracing their trajectory from foundational research to contemporary applications.

Ultrasmall Mn-doped iron oxide nanoparticles with dual hepatobiliary and renal clearances for T1 MR liver imaging.

Although magnetic nanoparticles demonstrate significant potential as magnetic resonance imaging (MRI) contrast agents, their negative contrasts, liver accumulation, and limited excretion hinder their application. Herein, we developed ultrasmall Mn-doped iron oxide nanoparticles (UMIOs) with distinct advantages as T1 MRI contrast agents. Exceptionally small particle sizes (ca. 2 nm) and magnetization values (5 emu gMn+Fe-1) of UMIOs provided optimal T1 contrast effects with an ideally low r2/r1 value of ∼1. Furthermore, the use of Mn as a dopant facilitated hepatocyte uptake of the particles, allowing liver imaging. In animal studies, UMIOs exhibited significantly enhanced contrasts for sequential T1 imaging of blood vessels and the liver, distinguishing them from conventional magnetic nanoparticles. UMIOs were systematically cleared via dual hepatobiliary and renal excretion pathways, highlighting their safety profile. These characteristics imply substantial potential of UMIOs as T1 contrast agents for the accurate diagnosis of liver diseases.

A polymeric 1H/19F dual-modal MRI contrast agent with a snowman-like Janus nanostructure.

Magnetic resonance imaging (MRI) has emerged as a pivotal tool in contemporary medical diagnostics, offering non-invasive and high-resolution visualization of internal structures. Contrast agents are essential for enhancing MRI resolution, accurate lesion detection, and early pathology identification. While gadolinium-based contrast agents are widely used in clinics, safety concerns have prompted exploration of metal-free alternatives, including fluorine and nitroxide radical-based MRI contrast agents. Fluorine-containing compounds exhibit excellent MRI capabilities, with 19F MRI providing enhanced resolution and quantitative assessment. Nitroxide radicals, such as PROXYL and TEMPO, offer paramagnetic properties for MRI contrast. Despite their versatility, nitroxide radicals suffer from lower relaxivity values (r1) compared to gadolinium. Dual-modal imaging, combining 1H and 19F MRI, has gained prominence for its comprehensive insights into biological processes and disease states. However, existing dual-modal agents predominantly utilize gadolinium-organic ligands without incorporating nitroxide radicals. Here, we introduce a novel dual-modal MRI contrast agent (J-CA) featuring a Janus asymmetric nanostructure synthesized via seeded emulsion polymerization and post-modification. J-CA demonstrates excellent in vitro and in vivo performance in both 19F and 1H MRI, with a T2 relaxation time of 5 ms and an r1 value of 0.31 mM-1 s-1, ensuring dual-modal imaging capability. Moreover, J-CA exhibits superior biocompatibility and organ targeting, making it a promising candidate for precise lesion imaging and disease diagnosis. This work introduces a new avenue for metal-free dual-modal MRI, addressing safety concerns associated with traditional contrast agents.

Efficient one-step amide formation using amino porphyrins.

Amide bonds are one of the most prevalent phenomena in nature and are utilized frequently in drug and material design. However, forming amide bonds is not always efficient or high yielding, particularly when the amine used to conjugate to a carboxylic acid is a weak nucleophile. This limitation precludes many useful amino compounds from participating in conjugation reactions to form amides. A particularly valuable amino compound, which is also a very weak nucleophile, is the amino porphyrin, valued for its role as a photosensitizer, fluorescent agent, catalyst, or, upon metalation, even a very efficient contrast agent for magnetic resonance imaging (MRI). In this work, we propose fast and high-yield coupling of an unreactive amine - the amino porphyrin - to carboxylic acid via isothiocyanate conjugation. Reactions can be achieved in one step at room temperature in one hour, achieving quantitative conversion and near perfect selectivity. Both metalated and unmetalated porphyrin, as well as fluorescein isothiocyanate (FITC), demonstrated efficient conjugation. To illustrate the value of the proposed method, we created a new blood-pool MRI contrast agent that reversibly binds to serum albumin. This new blood-pool agent, known as MITC-Deox (MRI isothiocyanate that links with deoxycholic acid), substantially reduced T1 relaxation times in blood vessels in mice, remained stable for 1 hour, cleared from blood by 24 hours, and was eliminated from the body after 4 days. The proposed method for efficient amide formation is a superior alternative to existing coupling methods, opening a door to novel synthesis of MRI contrast agents and beyond.

PH-responsive i-motif-conjugated nanoparticles for MRI analysis.

Gadolinium (Gd)-based contrast agents (CAs) are widely used to enhance anatomical details in magnetic resonance imaging (MRI). Significant research has expanded the field of CAs into bioresponsive CAs by modulating the signal to image and monitor biochemical processes, such as pH. In this work, we introduce the modular, dynamic actuation mechanism of DNA-based nanostructures as a new way to modulate the MRI signal based on the rotational correlation time, τR. We combined a pH-responsive oligonucleotide (i-motif) and a clinical standard CA (Gd-DOTA) to develop a pH-responsive MRI CA. The i-motif folds into a quadruplex under acidic conditions and was incorporated onto gold nanoparticles (iM-GNP) to achieve increased relaxivity, r1, compared to the unbound i-motif. In vitro, iM-GNP resulted in a significant increase in r1 over a decreasing pH range (7.5-4.5) with a calculated pKa = 5.88 ± 0.01 and a 16.7% change per 0.1 pH unit. In comparison, a control CA with a non-responsive DNA strand (T33-GNP) did not show a significant change in r1 over the same pH range. The iM-GNP was further evaluated in 20% human serum and demonstrated a 28.14 ± 11.2% increase in signal from neutral pH to acidic pH. This approach paves a path for novel programmable, dynamic DNA-based complexes for τR-modulated bioresponsive MRI CAs.

Precise air oxidation for continuous production of superparamagnetic Fe3O4 nanoparticles at room temperature through a microfilm reactor.

Superparamagnetic iron oxide nanoparticles (SPIONs) find vast applications in biomedicine such as drug delivery, magnetic resonance imaging (MRI) contrast agents, cell separation, tissue repair, etc. The synthesis of pure and uniform SPIONs involves tedious processes, complex precursors, the assistance of organic solvents, capping agents and/or high temperature. Herein, we report a continuous mass production of pure and uniform SPIONs in aqueous microfilm at room temperature without using any surfactant. The air oxidation rate and nanocrystal formation kinetics were precisely controlled by process intensification in the continuously flowing microfilm. Precise oxidation of Fe(ii) is a synergy of disc spinning speed and feeding concentration. The production process was continuous and conducted at room temperature in an aqueous medium with a high yield of 55.4 g h-1. The obtained products were proved to be highly pure through XRD and a colorimetric method. The resulting SPIONs exhibited a narrow size distribution, ranging from 6.5 to 12.6 nm. All sizes of the produced nanoparticles showed characteristic superparamagnetism, with the 12.6 nm SPIONs exhibiting the highest magnetization saturation (M s) of 87 emu g-1.

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.

PH-Responsive magnetic nanocarriers for chelator-free bimodal (MRI/SPECT-CT) image-guided chemo-hyperthermia therapy in human breast carcinoma.

Although chemotherapy with magnetic nanocarriers has witnessed significant advancement in the field of cancer treatment, multimodal diagnosis and combinatorial therapy using a single nanoplatform will have much better efficacy in achieving superior results. Herein, we constructed a smart theranostic system by combining pH-sensitive tartaric acid-stabilized Fe3O4 magnetic nanocarriers (TMNCs) with SPECT imaging and a chemotherapeutic agent for image-guided chemo-hyperthermia therapy. The carboxyl-enriched exteriors of TMNCs provided sites for the conjugation of a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and radiolabeling (141Ce). The usage of 145.4 keV gamma rays made this platform an ideal choice for in vivo SPECT-CT imaging, showing the retention of the nanoformulation in the tumor site even after 28 days. Further, TMNCs showed a very high transverse relaxation rate (r2) of 171 mM-1 s-1, which is higher than that of clinically approved magnetic resonance imaging (MRI) contrast agents such as ferumoxtran (65 mM-1 s-1) and ferumoxides (120 mM-1 s-1). Further, the developed drug-loaded hybrid platform showed significantly higher cytotoxicity towards breast cancer cells, which was augmented by in vitro magnetic hyperthermia. Bright-field microscopy and cell cycle analysis suggested that cell death occurred through induction of G2-M arrest and subsequent apoptosis. These findings clearly suggest the potential of the developed hybrid nanoplatform for image-guided combination therapy.

Controlled synthesis and characterization of porous silicon nanoparticles for dynamic nuclear polarization.

Si nanoparticles (NPs) have been actively developed as a hyperpolarized magnetic resonance imaging (MRI) contrast agent with an imaging window close to one hour. However, the progress in the development of NPs has been hampered by the incomplete understanding of their structural properties that correspond to efficient hyperpolarization buildup and long polarization decays. In this work we study dynamic nuclear polarization (DNP) of single crystal porous Si (PSi) NPs with defined doping densities ranging from nominally undoped to highly doped with boron or phosphorus. To develop such PSi NPs we perform low-load metal-assisted catalytic etching for electronic grade Si powder followed by thermal oxidation to form the dangling bonds in the Si/SiO2 interface, the Pb centers. Pb centers are the endogenous source of the unpaired electron spins necessary for DNP. The controlled fabrication and oxidation procedures allow us to thoroughly investigate the impact of the magnetic field, temperature and doping on the DNP process. We argue that the buildup and decay rate constants are independent of size of Si crystals between approximately 10 and 60 nm. Instead, the rates are limited by the polarization transfer across the nuclear spin diffusion barrier determined by the large hyperfine shift of the central 29Si nuclei of the Pb centers. The size-independent rates are then weakly affected by the doping degree for low and moderately doped Si although slight doping is required to achieve the highest polarization. Thus, we find the room temperature relaxation of low boron doped PSi NPs reaching 75 ± 3 minutes and nuclear polarization levels exceeding ∼6% when polarized at 6.7 T and 1.4 K. Our study thus establishes solid grounds for further development of Si NPs as hyperpolarized contrast agents.

Targeted opening of the blood-brain barrier using VCAM-1 functionalised microbubbles and "whole brain" ultrasound.

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound. Methods: Microbubbles functionalised with anti-VCAM1 were synthesised and shown to bind to VCAM-1-expressing cells in vitro. Experiments were then conducted in vivo in a unilateral breast cancer brain metastasis mouse model using Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening. Following injection of Gd-DTPA and targeted microbubbles, the whole brain volume was simultaneously exposed to ultrasound (0.5 MHz, 10% duty cycle, 0.7 MPa peak negative pressure, 2 min treatment time). T1-weighted MRI was then performed to identify BBB opening, followed by histological confirmation via immunoglobulin G (IgG) immunohistochemistry. Results: In mice treated with targeted microbubbles and ultrasound, statistically significantly greater extravasation of Gd-DTPA and IgG was observed in the left tumour-bearing hemisphere compared to the right hemisphere 5 min after treatment. No acute adverse effects were observed. There was no investigation of longer term bioeffects owing to the nature of the study. Conclusion: The results demonstrate the feasibility of using targeted microbubbles in combination with low intensity ultrasound to localise opening of the BBB to metastatic sites in the brain. This approach has potential application in the treatment of metastatic tumours whose location cannot be established a priori with conventional imaging methods.

Magnetic nanoparticles for use in bioimaging.

Magnetic nanoparticles (MNPs) are well-known contrast agents for use in medical imageology, facilitating disease detection via magnetic resonance imaging (MRI). With the development of nanotechnology, various MNPs have been exploited with strong contrast enhancement effects as well as multiple functions to conquer challenges related to the low detection accuracy and sensitivity. In this review, the typical characteristics and types of MNPs are outlined, and the design and fabrication of MNP-based MRI contrast agents as well as multi-mode imaging agents are also introduced by discussing the representative studies. In the pursuit of performance-enhanced MNPs, novel MNPs are expected to be developed as the next generation of contrast agents for precise bioimaging applications in a broad spectrum of fields.

Ag2S quantum dot-based magnetic resonance/fluorescence dual-mode imaging nanoprobes for tumor diagnosis.

Accurate tumor detection is crucial for the early discovery and subsequent treatment of small neoplastic foci. Molecular imaging, which combines non-invasiveness, high specificity, and strong sensitivity, excels in diagnosing early tumors and stands out among tumor diagnosis methods. Here, we introduced a dual-modal imaging probe capable of actively targeting tumor cells, suitable for both near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI). Dendritic mesoporous silica was used as a carrier for the probe, encapsulating Ag2S quantum dots (QDs) for NIR fluorescence imaging. Additionally, the probe conjugated the MRI contrast agent Gd-DOTA and cetuximab, which targeted EGFR on the tumor cell membrane surface, to achieve dual-modal imaging in the tumor area. This strategy provided a methodology for the accurate diagnosis of early-stage tumor lesions and guides precise lesion resection during surgery, offering significant potential for clinical application.

A dual-targeted Gd-based contrast agent for magnetic resonance imaging in tumor diagnosis.

Enhanced magnetic resonance imaging (MRI) has important clinical value in the diagnosis of tumors. Much effort has been made to improve the relaxivity and specificity of contrast agents (CAs) in tumor diagnosis over the past few decades. However, there is still a lack of CAs which not only enhance the signal intensity of tumors rather than surrounding tissues in MRI but also maintain a high signal intensity prolonged for a long time. Herein, we synthesized a dual-targeted CA, RGD-(DOTA-Gd)-TPP (RDP), in which RGD is used to target the αvβ3 integrin receptor overexpressed in tumor cells and TPP is used to bind to a mitochondrion further. The structure of RDP was characterized and its properties, such as relaxivity and biosafety, were measured and in vitro and in vivo MRI assays were carried out. It has been proven that RDP has higher relaxivity of aqueous solution than Magnevist used in clinics. Moreover, RDP achieved higher signal intensity and a longer signal duration in tumor imaging. Therefore, RDP can be applied as the potential dual-targeted MRI CA for clinical tumor diagnosis.

Folic acid functionalized gadolinium-doped carbon dots as fluorescence / magnetic resonance imaging contrast agent for targeted imaging of liver cancer

Gadolinium-doped carbon dots (Gd-CDs), as a new class of nanomaterial, has a wide application prospect in targeted imaging and monitoring diagnosis and treatment of liver cancer because of their good fluorescence (FL)-magnetic resonance (MR) imaging properties. First, Gd-CDs were synthesized by hydrothermal method with gadodiamide as gadolinium source, citric acid as carbon source and silane coupling agent (KH-792) as coupling agent with FL quantum yield (QY) of 48.2%. Then, folic acid (FA), which is highly expressed in liver cancer, was used as a targeting component to modify Gd-CDs to obtain targeted imaging agent (Gd-CDs-FA). The results showed that Gd-CDs and Gd-CDs-FA have low cytotoxicity and good biocompatibility, and the targeting and selectivity of Gd-CDs-FA to HepG2 cells could be observed under confocal laser scanning microscope (CLSM). The T1 longitudinal relaxation rates (r1) of Gd-CDs and Gd-CDs-FA are 15.92 mM−1s−1 and 13.56 mM−1s−1, respectively. They showed good MR imaging ability in vitro and in vivo, and MR imaging in nude mice further proved the targeting imaging performance of Gd-CDs-FA. Therefore, Gd-CDs-FA with higher QY showed good FL-MR targeting imaging ability of liver cancer, which broke through the limitations of single molecular imaging probe in sensitivity and soft tissue resolution. This study provides a new idea for the application of Gd-CDs in FL and MR targeting imaging of liver cancer.

Platelets as delivery vehicles for targeted enrichment of NO· to cerebral glioma for magnetic resonance imaging

Using a magnetic resonance imaging (MRI) contrast agent, MRI has made substantial contributions to glioma diagnosis. Metal-free MRI agents, such as the nano free radical nitric oxide (NO·) micelle, can overcome the inherent toxicity of metal-based agents in certain patient populations. However, the low spatial resolution of nano NO· micelle in MRI limits its clinical development. In this study, we pretreated platelets (PLTs) and loaded them with nano NO· micelles to synthesize NO·@PLT, which can overcome the low contrast and poor in vivo stability of nitroxide-based MRI contrast agents. The PLTs can serve as potential drug carriers for targeting and delivering nano NO· micelles to gliomas and thus increase the contrast in T1-weighted imaging (T1WI) of MRI. This drug carrier system uses the unique tumor-targeting ability of PLTs and takes advantage of the high signal presentation of steady nano NO· micelles in T1WI, thereby ultimately achieving signal amplification of glioma in T1WI. With the effect of PLTs-tumor cell adhesion, NO·@PLT has per-nitroxide transverse relativities of approximately 2-fold greater than those of free NO· particles. These features allow a sufficient NO·@PLT concentration to accumulate in murine subcutaneous glioma tumors up from 5 min to 2.5 h (optimum at 1.5 h) after systemic administration. This results in MRI contrast comparable to that of metal-based agents. This study established a promising metal-free MRI contrast agent, NO·@PLT, for glioma diagnosis, because it has superior spatial resolution owing to its high glioma-targeting ability and has significant translational implications in the clinic.

Assessing Perfusion in Steno-Occlusive Cerebrovascular Disease Using Transient Hypoxia-Induced Deoxyhemoglobin as a Dynamic Susceptibility Contrast Agent.

Resting brain tissue perfusion in cerebral steno-occlusive vascular disease can be assessed by MR imaging using gadolinium-based susceptibility contrast agents. Recently, transient hypoxia-induced deoxyhemoglobin has been investigated as a noninvasive MR imaging contrast agent. Here we present a comparison of resting perfusion metrics using transient hypoxia-induced deoxyhemoglobin and gadolinium-based contrast agents in patients with known cerebrovascular steno-occlusive disease. Twelve patients with steno-occlusive disease underwent DSC MR imaging using a standard bolus of gadolinium-based contrast agent compared with transient hypoxia-induced deoxyhemoglobin generated in the lungs using an automated gas blender. A conventional multi-slice 2D gradient echo sequence was used to acquire the perfusion data and analyzed using a standard tracer kinetic model. MTT, relative CBF, and relative CBV maps were generated and compared between contrast agents. The spatial distributions of the perfusion metrics generated with both contrast agents were consistent. Perfusion metrics in GM and WM were not statistically different except for WM MTT. Cerebral perfusion metrics generated with noninvasive transient hypoxia-induced changes in deoxyhemoglobin are very similar to those generated using a gadolinium-based contrast agent in patients with cerebrovascular steno-occlusive disease.

Shaped Magnetogel Microparticles for Multispectral Magnetic Resonance Contrast and Sensing.

Multispectral magnetic resonance imaging (MRI) contrast agents are microfabricated three-dimensional magnetic structures that encode nearby water protons with discrete frequencies. The agents have a unique radiofrequency (RF) resonance that can be tuned by engineering the geometric parameters of these microstructures. Multispectral contrast agents can be used as sensors by incorporating a stimulus-driven shape-changing response into their structure. These geometrically encoded magnetic sensors (GEMS) enable MRI-based sensing via environmentally induced changes to their geometry and their corresponding RF resonance. Previously, GEMS have been made using thin-film lithography techniques in a cleanroom environment. While these approaches offer precise control of the microstructure, they can be a limitation for researchers who do not have cleanroom access or microfabrication expertise. Here, an alternative approach for GEMS fabrication based on soft lithography is introduced. The fabrication scheme uses cheap, accessible materials and simple chemistry to produce shaped magnetic hydrogel microparticles with multispectral MRI contrast properties. The microparticles can be used as sensors by fabricating them out of shape-reconfigurable, "smart" hydrogels. The change in shape causes a corresponding shift in the resonance of the GEMS, producing an MRI-addressable readout of the microenvironment. Proof-of-principle experiments showing a multispectral response to pH change with cylindrical shell-shaped magnetogel GEMS are presented.

Effects of gadolinium (Gd) and a Gd-based contrast agent (GBCA) on early life stages of zebrafish (Danio rerio)

Gadolinium (Gd) is one of the rare earth elements (REY) and is widely used in magnetic resonance imaging (MRI) contrast agents. Anthropogenic Gd enrichment has frequently been found in wastewater treatment plant effluents in industrialised countries, rising concerns regarding effects on aquatic biota. This study investigates the acute toxicity and sublethal effects of Gd in two forms, as inorganic salt (GdCl3) and as Gd-based contrast agent (GBCA), on early life stages of zebrafish (Danio rerio). Nominal exposure concentrations ranged from 3 to 3000 μg L−1, with an exposure duration of 96 h. None of the two tested compounds were acutely toxic to embryos and larvae. Similarly, we did not observe any effects on larval development and locomotive behaviour. However, we found significant changes in the brain activity of larvae exposed to the highest concentrations of GdCl3 and the GBCA. Our findings show that Gd can have sublethal effects on developing fish at lower concentrations than reported previously, highlighting the necessity of investigating the long-term fate and effects of GBCAs released into the aquatic environment.

In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem.

BACKGROUNDIntrathecal injection is an attractive route through which drugs can be administered and directed to the spinal cord, restricted by the blood-spinal cord barrier. However, in vivo data on the distribution of cerebrospinal fluid (CSF) substances in the human spinal cord are lacking. We conducted this study to assess the enrichment of a CSF tracer in the upper cervical spinal cord and the brain stem.METHODSAfter lumbar intrathecal injection of a magnetic resonance imaging (MRI) contrast agent, gadobutrol, repeated blood samples and MRI of the upper cervical spinal cord, brain stem, and adjacent subarachnoid spaces (SAS) were obtained through 48 hours. The MRI scans were then analyzed for tracer distribution in the different regions and correlated to age, disease, and amounts of tracer in the blood to determine CSF-to-blood clearance.RESULTSThe study included 26 reference individuals and 35 patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH). The tracer enriched all analyzed regions. Moreover, tracer enrichment in parenchyma was associated with tracer enrichment in the adjacent SAS and with CSF-to-blood clearance. Clearance from the CSF was delayed in patients with iNPH compared with younger reference patients.CONCLUSIONA CSF tracer substance administered to the lumbar thecal sac can access the parenchyma of the upper cervical spinal cord and brain stem. Since CSF-to-blood clearance is highly individual and is associated with tracer level in CSF, clearance assessment may be used to tailor intrathecal treatment regimes.FUNDINGSouth-Eastern Norway Regional Health and Østfold Hospital Trust supported the research and publication of this work.

Chelating ligand-bridged IO-Gd nanoparticles with enhanced contrast performance for dual-mode MRI

Magnetic resonance imaging (MRI) is a non-invasive medical imaging technique that has been widely applied in the clinical diagnosis of diseases across various fields. Currently, there is a dearth of high-performance dual-mode contrast agents that provide precise diagnostic information for complex diseases. In this study, iron oxide-gadolinium nanoparticles (IO-Gd NPs) bridged by hydrophilic ligand ethylenediamine tetramethylenephosphonic acid (EDTMP) are designed inspired by Solomon-Bloembergen–Morgan (SBM) theory, where T1 and T2 relaxivity increase with a reduction in Gd content. In particular, the NPs with minimum Gd content exhibit excellent dual-mode contrast performance (r1 = 94.42 mM−1 s−1, r2 = 343.62 mM−1 s−1). The underlying mechanism is that the bridged EDTMP coordinate limits Gd tumbling and forces Gd3+ to expose itself to the surface of the NPs. This provides more opportunities for water molecules to coordinate with Gd3+ and significantly enhances proton relaxivity. Moreover, the hydrophilicity of the ligand enhances the water dispersion stability of the NPs and increases the exchange rate of water protons near the NPs, further enhancing the dual-mode contrast effect. Finally, the biocompatibility and in vitro/vivo imaging performances of the IO@EDTMP-Gd NPs are systematically evaluated, and the results demonstrate their potential as dual-mode contrast agents. This study provides a new strategy for developing dual-mode MRI contrast agents that can further improve the accuracy of MRI in the diagnosis of complex diseases.