Smart Magnetic Resonance Imaging Research Articles

Ligand‐Mediated Magnetism‐Conversion Nanoprobes for Activatable Ultra‐High Field Magnetic Resonance Imaging

AbstractUltra‐high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low‐field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand‐mediated magnetism‐conversion nanoprobe (MCNP) composed of 3‐mercaptopropionic acid ligand‐coated silver‐gadolinium bimetallic nanoparticles. The MCNP exhibits a pH‐dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH‐activatable UHF MRI. Under neutral pH, the thiolate (−S−) ligands lead to short τ′m and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (−SH) ligands, resulting in prolonged τ′m and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH‐sensitive changes in Ag−S binding affinity of the MCNP lead to a remarkable (>10‐fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next‐generation UHF‐tailored smart MRI contrast agent.

Ligand-Mediated Magnetism-Conversion Nanoprobes for Activatable Ultra-High Field Magnetic Resonance Imaging.

Ultra-high field (UHF) magnetic resonance imaging (MRI) has emerged as a focal point of interest in the field of cancer diagnosis. Despite the ability of current paramagnetic or superparamagnetic smart MRI contrast agents to selectively enhance tumor signals in low-field MRI, their effectiveness at UHF remains inadequate due to inherent magnetism. Here, we report a ligand-mediated magnetism-conversion nanoprobe (MCNP) composed of 3-mercaptopropionic acid ligand-coated silver-gadolinium bimetallic nanoparticles. The MCNP exhibits a pH-dependent magnetism conversion from ferromagnetism to diamagnetism, facilitating tunable nanomagnetism for pH-activatable UHF MRI. Under neutral pH, the thiolate (-S- ) ligands lead to short τ'm and increased magnetization of the MCNPs. Conversely, in the acidic tumor microenvironment, the thiolate ligands are protonated and transform into thiol (-SH) ligands, resulting in prolonged τ'm and decreased magnetization of the MCNP, thereby enhancing longitudinal relaxivity (r1) values at UHF MRI. Notably, under a 9 T MRI field, the pH-sensitive changes in Ag-S binding affinity of the MCNP lead to a remarkable (>10-fold) r1 increase in an acidic medium (pH 5.0). In vivo studies demonstrate the capability of MCNPs to amplify MRI signal of hepatic tumors, suggesting their potential as a next-generation UHF-tailored smart MRI contrast agent.

The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity.

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd3+ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a "switch-off" contrast agent. Conversely, the use of Yb3+ as the metal leads to a "switch-on" effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker.

Extremely Small Iron Oxide Nanoparticles with pH-Dependent Solubility Transition as T1/T2 Switchable Contrast Agents for MRI

Extremely small iron oxide nanoparticles (ESIONPs), which have a switchable contrast signal and a favorable biocompatibility, are gaining considerable attention as smart magnetic resonance imaging (MRI) contrast agents (CAs). Adaptive MRI CAs could improve the accuracy of tumor diagnosis because they realize rapid imaging signal conversion under an endogenous stimulus. Herein, based on the hydrophilic to hydrophobic transition of polymers, we propose a pH-responsive T1/T2 switchable ESIONP contrast agent. ESIONPs are functionalized at the surface with adamantane groups through a polyethylene glycol (PEG) chain, and subsequently, a stimuli-responsive polymer (PSDM) with pH-dependent solubility is introduced through the host–guest interaction between adamantane and β-cyclodextrin (β-CD). The obtained ESIONPs-PEG-PSDM is equipped with remarkable pH responsiveness, which triggers the aggregation of ESIONPs under the tumor acid condition, leading to the switch from a T1 to a T2 contrast agent. In vivo MRI experiments show that the T2 contrast signal is selectively enhanced at the tumor location after injection of ESIONPs-PEG-PSDM. Therefore, ESIONPs-PEG-PSDM with pH-induced hydrophilic to hydrophobic transition is a potential smart MRI contrast agent for precise tumor diagnosis.

The Design of Abnormal Microenvironment Responsive MRI Nanoprobe and Its Application.

Magnetic resonance imaging (MRI) is often used to diagnose diseases due to its high spatial, temporal and soft tissue resolution. Frequently, probes or contrast agents are used to enhance the contrast in MRI to improve diagnostic accuracy. With the development of molecular imaging techniques, molecular MRI can be used to obtain 3D anatomical structure, physiology, pathology, and other relevant information regarding the lesion, which can provide an important reference for the accurate diagnosis and treatment of the disease in the early stages. Among existing contrast agents, smart or activatable nanoprobes can respond to selective stimuli, such as proving the presence of acidic pH, active enzymes, or reducing environments. The recently developed environment-responsive or smart MRI nanoprobes can specifically target cells based on differences in the cellular environment and improve the contrast between diseased tissues and normal tissues. Here, we review the design and application of these environment-responsive MRI nanoprobes.

A Polypeptide-Based, Membrane-Penetrating, Target-Specific Contrast Agent for Magnetic Resonance Molecular Imaging.

Molecular imaging based on magnetic resonance imaging (MRI) requires a contrast agent with high relaxivity and specificity. Much effort has been devoted to this goal over the past decades. In this work, we continue this endeavor by synthesizing an MRI contrast agent that can penetrate the cellular membrane and bind with specific proteins. It was characterized with one- and two-dimensional NMR spectroscopy, NMR micro-imaging, and mass spectroscopy. The target specificity has been further confirmed by both molecular dynamics simulation and micro-imaging on a living biological system. It is one of the largest of peptide-based bioactivated MRI contrast agents, and its relaxivity enhancement factor is among the highest of MRI contrast agents hitherto published. We envision interesting applications and extension of this smart MRI contrast agent with bio-specificity and high contrast for molecular imaging.

Tumor Acid Microenvironment-Triggered Self-Assembly of ESIONPs for T1/T2 Switchable Magnetic Resonance Imaging.

Smart magnetic resonance imaging (MRI) contrast agents (CAs), whose MRI contrasting enhancement is variable in response to the specific stimulus from tumor tissues, possess great potential in precise tumor diagnosis. Herein, we design a type of extremely small iron oxide nanoparticle (ESIONP)-based pH-responsive system for activatable T2 MRI in the tumor acid microenvironment. The ESIONP system is composed of ESIONP-PEG-PGA and ESIONP-PEG-PDC, which were respectively constructed through the surface modification with poly (l-glutamic acid) (PGA) and poly(N-{N'-[N″-(2-carbox aminoethyl)]-2-aminoethyl}glutamide) (PDC) on the surface of ESIONP. The pH-responsive system exhibits the dispersed state under the neutral condition, and when it is exposed to the weakly acid environment, ESIONP-PEG-PDC switches from the neutral to positive charge, finally leading to the aggregation by the electrostatic interaction between the positively charged ESIONP-PEG-PDC and negatively charged ESIONP-PEG-PGA. On the basis of the aggregation, the T1 contrasting effect of the pH-responsive system switches to a T2 contrasting effect, which can be employed to realize the selective enhancement of imaging contrast at the tumor location owing to the weakly acid microenvironment. Moreover, on the basis of size increase originated from the aggregation effect, the residence time of extremely small iron oxide nanoparticles (ESIONPs) in the tumor site is effectively prolonged, which is beneficial for the MRI of tumors. Therefore, the pH-responsive system based on the ESIONPs is a potential smart MRI contrast agent for accurate tumor diagnosis.

In Vivo Tumor Visualization through MRI Off-On Switching of NaGdF4 -CaCO3 Nanoconjugates.

The development of high-performance contrast agents in magnetic resonance imaging (MRI) has recently received considerable attention, as they hold great promise and potential as a powerful tool for cancer diagnosis. Despite substantial achievements, it remains challenging to develop nanostructure-based biocompatible platforms that can generate on-demand MRI signals with high signal-to-noise ratios and good tumor specificity. Here, the design and synthesis of a new class of nanoparticle-based contrast agents comprising self-assembled NaGdF4 and CaCO3 nanoconjugates is reported. In this design, the spatial confinement of the T1 source (Gd3+ ions) leads to an "OFF" MRI signal due to insufficient interaction between the protons and the crystal lattices. However, when immersed in the mildly acidic tumor microenvironment, the embedded CaCO3 nanoparticles generate CO2 bubbles and subsequently disconnect the nanoconjugate, thus resulting in an "ON" MRI signal. The in vivo performance of these nanoconjugates shows more than 60-fold contrast enhancement in tumor visualization relative to the commercially used contrast agent Magnevist. This work presents a significant advance in the construction of smart MRI nanoprobes ideally suited for deep-tissue imaging and target-specific cancer diagnosis.

High-Field Detection of Biomarkers with Fast Field-Cycling MRI: The Example of Zinc Sensing.

Many smart magnetic resonance imaging (MRI) probes provide response to a biomarker based on modulation of their rotational correlation time. The magnitude of such MRI signal changes is highly dependent on the magnetic field and the response decreases dramatically at high fields (>2 T). To overcome the loss of efficiency of responsive probes at high field, with fast‐field cycling magnetic resonance imaging (FFC‐MRI) we exploit field‐dependent information rather than the absolute difference in the relaxation rate measured in the absence and in the presence of the biomarker at a given imaging field. We report here the application of fast field‐cycling techniques combined with the use of a molecular probe for the detection of Zn2+ to achieve 166 % MRI signal enhancement at 3 T, whereas the same agent provides no detectable response using conventional MRI. This approach can be generalized to any biomarker provided the detection is based on variation of the rotational motion of the probe.

Recent advances in gadolinium-based MRI metal responsive agent

Smart magnetic resonance imaging (MRI) contrast agent has the ability to increase or decrease the signal intensity through response to certain analyte. Among the growing class of responsive agent, imaging probes based on gadolinium ion are developing fast in the last decade since they play an important role in physiological and pathology process in living system. This minireview would highlight recent progress in metal responsive gadolinium-based MRI contrast agent.

Novel bionanotechnological solutions based on metal oxide and metal to preserve and assess organs for transplantation

Our research has focused on nanomaterials for the diagnosis and treatment of cardiovascular disease (CVD) such as thrombosis. These materials can be adapted for preserving and assessing organs for transplantation. Magnetic resonance imaging (MRI) has been used as a powerful and indispensable tool in medical research and clinical diagnosis. We have developed both targeted negative contrast agents and targeted dual positive/negative contrast agents for molecular imaging of thrombosis. The simultaneous use of positive and negative MRI imaging that employs the same contrast agents will significantly improve detection accuracy. Using the dual contrast agent, both T1- and T2-weighted MRI of thrombosis can be simultaneously recorded which enables self-confirmation of images and leads to a greater diagnostic accuracy1 . To prepare these targeted agents, we employed a single-chain antibody that targets activated platelets, a major player in thrombus formation. Our contrast agents can be adapted for assessing organs during and after transplantation. It has been reported that platelets are activated early during reperfusion after an ischaemia/reperfusion injury (IRI). Therefore, by targeting activated platelets and platelet accumulation, it is possible to noninvasively detect and assess IRI early, maximizing medical interventions. We have also developed smart MRI nanosensors based on iron oxide and gadolinium that can not only detect, but also sense and report the stage or progression of CVD such as thrombosis. The early detection and accurate characterization of life-threatening diseases such as CVD are critical to the design of treatment. Knowing whether a thrombus in a blood vessel is new/fresh or old/constituted is very important for physicians to decide on a treatment protocol. These nanosensors can be adapted, modified and applied for detecting and grading other diseases such as cancer, and also for sensitive detection of inflammatory reactions during organ preservation, perfusion and transplantation processes. It can be a useful technique to potentially allow other researchers to access information previously difficult to obtain. It can also be a new tool for clinicians to assess organs before and after transplantation, maximizing opportunities for medical intervention. Since our nanosensors are iron oxide and gadolinium based materials, they can also be used for preservation of organs/tissues. Recently researchers have reported a way to safely thaw frozen tissues with the aid of iron oxide nanoparticles2 . By suffusing the nanosensors over organs/tissues before freezing, they may help in the thawing process and may directly provide information on inflammatory reactions within the organs/tissues after thawing and reperfusion

Recent advances in biological-environment-responsive smart MRI contrast agents

With the rapid advancement in biology and medicine, there is an urgent need to study metabolisms in lives and mechanisms of diseases at molecular levels. Magnetic resonance imaging (MRI), which is capable of non-invasive and three-dimensional deep imaging, is a powerful tool to meet this demand. Environment-responsive contrast agents, whose contrast abilities change once stimulated, are necessary for this purpose. With the use of these responsive contrast agents, related biological information, such as pH, concentration of ions, activity of enzymes, could be easily extracted and analyzed from MR images. Considerable progress has been made in the field of biological-environment-responsive smart MRI contrast agents over the two decades. In this review, we describe achievements in recent years, discuss several representative works in detail, summarize current difficulties that have been met and possible solutions that have been formulated, and finally look into the promising future of biological-environment-responsive smart MRI contrast agents.

Surface Modification of Gd Nanoparticles with pH-Responsive Block Copolymers for Use As Smart MRI Contrast Agents.

Despite recent advances in the understanding of fundamental cancer biology, cancer remains the second most common cause of death in the United States. One of the primary factors indicative of high cancer morbidity and mortality and aggressive cancer phenotypes is tumors with a low extracellular pH (pHe). Thus, the ability to measure tumor pHe in vivo using noninvasive and accurate techniques that also provide high spatiotemporal resolution has become increasingly important and is of great interest to researchers and clinicians. In an effort to develop a pH-responsive magnetic resonance imaging (MRI) contrast agent (CA) that has the potential to be used to measure tumor pHe, well-defined pH-responsive polymers, synthesized via reversible addition-fragmentation chain transfer polymerization, were attached to the surface of gadolinium-based nanoparticles (GdNPs) via a "grafting to" method after reduction of the thiocarbonylthio end groups. The successful modification of the GdNPs was verified by transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis and dynamic light scattering. The performance of the pH-responsive polymer modified GdNPs was then evaluated for potential use as smart MRI CAs via monitoring the relaxivity changes with changing environmental pH. The results suggested that the pH-responsive polymers can be used to effectively modify the GdNPs surface to prepare a smart contrast agent for MRI.

Dual-frequency calcium-responsive MRI agents.

Responsive or smart magnetic resonance imaging (MRI) contrast agents are molecular sensors that alter the MRI signal upon changes in a particular parameter in their microenvironment. Consequently, they could be exploited for visualization of various biochemical events that take place at molecular and cellular levels. In this study, a set of dual-frequency calcium-responsive MRI agents are reported. These are paramagnetic, fluorine-containing complexes that produce remarkably high MRI signal changes at the (1)H and (19)F frequencies at varying Ca(2+) concentrations. The nature of the processes triggered by Ca(2+) was revealed, allowing a better understanding of these complex systems and their further improvement. The findings indicate that these double-frequency tracers hold great promise for development of novel functional MRI methods.

Giant Vesicles Containing Superparamagnetic Iron Oxide as Biodegradable Cell-Tracking MRI Probes

A major breakthrough in in vivo cellular imaging has been the clinical/preclinical use of magnetic resonance imaging (MRI) with contrast agent. Superparamagnetic iron oxide (SPIO) is a promising candidate for the development of smart MRI probes for cell-tracking. In the present study, we describe biodegradable probes made of giant vesicles (GVs; closed lipid membranes with diameters >1 μm) that encapsulate SPIO for use as an MRI contrast agent. These SPIO-containing GVs (SPIO-GVs) exhibited excellent contrast enhancement in the single cell of medaka fish (Oryzias latipes) embryos immediately after their microinjection, and this enhancement disappeared when the GV membranes were destroyed. Our results demonstrate that SPIO-GVs are useful MRI probes for single cell-tracking that have minimum cytotoxicity and will greatly improve clinical/preclinical in vivo cellular imaging techniques.

ChemInform Abstract: Development of Responsive Lanthanide‐Based Magnetic Resonance Imaging and Luminescent Probes for Biological Applications

AbstractReview: 93 refs.

A smart magnetic resonance imaging contrast agent responsive to adenosine based on a DNA aptamer-conjugated gadolinium complex.

We report a general strategy for developing a smart MRI contrast agent for the sensing of small molecules such as adenosine based on a DNA aptamer that is conjugated to a Gd compound and a protein streptavidin. The binding of adenosine to its aptamer results in the dissociation of the Gd compound from the large protein, leading to decreases in the rotational correlation time and thus change of MRI contrast.

In Vivo Characterization of a Smart MRI Agent That Displays an Inverse Response to Calcium Concentration

Contrast agents for magnetic resonance imaging (MRI) that exhibit sensitivity toward specific ions or molecules represent a challenging but attractive direction of research. Here a Gd(3+) complex linked to an aminobis(methylenephosphonate) group for chelating Ca(2+) was synthesized and investigated. The longitudinal relaxivity (r(1)) of this complex decreases during the relaxometric titration with Ca(2+) from 5.76 to 3.57 mM(-1) s(-1) upon saturation. The r(1) is modulated by changes in the hydration number, which was confirmed by determination of the luminescence emission lifetimes of the analogous Eu(3+) complex. The initial in vivo characterization of this responsive contrast agent was performed by means of electrophysiology and MRI experiments. The investigated complex is fully biocompatible, having no observable effect on neuronal function after administration into the brain ventricles or parenchyma. Distribution studies demonstrated that the diffusivity of this agent is significantly lower compared with that of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA).

Catalyst‐functionalized nanomaterials

With rapid development in both nanotechnology and biotechnology, it is now possible to combine these two exciting fields to modulate the physical properties of nanomaterials with the molecular recognition and catalytic functional properties of biomolecules. Such research efforts have resulted in a larger number of sensors that can detect a broad range of analytes ranging from metal ions, small molecules, and nucleic acids down to proteins. These sensors will find important applications in nanomedicine. In this article, the design of sensors with four classes of nanomaterials (metallic, semiconductor, magnetic, and carbon nanotube nanoparticles) is reviewed. Metallic nanoparticles possess distance-dependent optical properties and are useful for designing colorimetric sensors. Semiconductor nanoparticles or quantum dots (QDs) appear to be superior alternatives to traditional organic fluorophores in many aspects, such as broad excitation range, narrow emission peaks, and high photo stability. QD sensors based on either energy transfer or charge transfer are summarized. Furthermore, magnetic nanoparticles are shown to be useful as smart magnetic resonance imaging (MRI) contrast agents. Finally, some carbon nanotubes show near-IR emission properties, and thus, are potentially useful for in vivo sensing. Sensors based on either tuning the emission intensity or wavelength are discussed.

Smart Magnetic Resonance Imaging Agents that Sense Extracellular Calcium Fluctuations

Image brain function: Gd3+ chelates linked to a modified EGTA moiety were prepared in order to respond to extracellular Ca2+ fluctuations in the brain. Upon interaction with Ca2+, they exhibit high and reversible relaxivity changes in buffered solution or in a model of the brain extracellular medium. These efficient Ca2+ magnetic resonance imaging sensors might open new perspectives in functional molecular imaging.