Biocompatible Polyhydroxyethylaspartamide-based Micelles with Gadolinium for MRI Contrast Agents

Biocompatible poly-[N-(2-hydroxyethyl)-d,l-aspartamide]-methoxypoly(ethyleneglycol)-hexadecylamine (PHEA-mPEG-C₁₆) conjugated with 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid-gadolinium (DOTA-Gd) via ethylenediamine (ED) was synthesized as a magnetic resonance imaging (MRI) contrast agent. Amphiphilic PHEA-mPEG-C₁₆-ED-DOTA-Gd forms micelle in aqueous solution. All the synthesized materials were characterized by proton nuclear magnetic resonance (¹H NMR). Micelle size and shape were examined by dynamic light scattering (DLS) and atomic force microscopy (AFM). Micelles with PHEA-mPEG-C₁₆-ED-DOTA-Gd showed higher relaxivities than the commercially available gadolinium contrast agent. Moreover, the signal intensity of a rabbit liver was effectively increased after intravenous injection of PHEA-mPEG-C₁₆-ED-DOTA-Gd.     

A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities

The simultaneous detection of multiple enzyme activities can improve the specificity of disease diagnoses. We therefore synthesized and characterized a diamagnetic chemical exchange saturation transfer (CEST) MRI contrast agent that can simultaneously detect two enzyme activities. Sulfatase and esterase enzymes cleave the ligands of the CEST agent, releasing salicylic acid that can be detected with CEST MRI. Importantly, both enzymes are required to activate the agent to produce a CEST MRI contrast, and the CEST agent was stable without enzyme treatment. These results established that this diamagnetic CEST MRI contrast agent is a platform technology with a modular design that can be potentially exploited to detect other combinations of enzyme activities, which can expand the armamentarium of contrast agents for molecular imaging.     

Aptamer-modified magnetic nanoprobe for molecular MR imaging of VEGFR2 on angiogenic vasculature

Nucleic acid-based aptamers have been developed for the specific delivery of diagnostic nanoprobes. Here, we introduce a new class of smart imaging nanoprobe, which is based on hybridization of a magnetic nanocrystal with a specific aptamer for specific detection of the angiogenic vasculature of glioblastoma via magnetic resonance (MR) imaging. The magnetic nanocrystal imaging core was synthesized using the thermal decomposition method and enveloped by carboxyl polysorbate 80 for water solubilization and conjugation of the targeting moiety. Subsequently, the surface of the carboxylated magnetic nanocrystal was modified with amine-functionalized aptamers that specifically bind to the vascular growth factor receptor 2 (VEGFR2) that is overexpressed on angiogenic vessels. To assess the targeted imaging potential of the aptamer-conjugated magnetic nanocrystal for VEGFR2 markers, the magnetic properties and MR imaging sensitivity were investigated using the orthotopic glioblastoma mouse model. In in vivo tests, the aptamer-conjugated magnetic nanocrystal effectively targeted VEGFR2 and demonstrated excellent MR imaging sensitivity with no cytotoxicity.     

一种磁性N-羧甲基壳聚糖造影剂的制备及性能研究

采用简单经济（与传统微乳法、热分解法等比较）的方法制备出一种磁性N-羧甲基壳聚糖造影剂。首先对壳聚糖的氨基进行羧甲基化制备N-羧甲基壳聚糖,然后在其链上采用原位生成Fe3O4纳米粒子的方法制备出磁性N-羧甲基壳聚糖,并对其进行了表征及性能的测试。热重分析结果表明：Fe3O4的生成量与N-羧甲基壳聚糖中羧甲基的含量有关,其生成量随着羧甲基含量的增加而增加,但当羧甲基的含量增加到一定程度时,Fe3O4的生成量达到某一峰值。透射电镜结果表明：生成的Fe3O4纳米粒子的粒径约为5-10 nm。磁共振成像结果显示：此磁性N-羧甲基壳聚糖的横向弛豫率为82.82 mmoL/L/s,高于超顺磁性氧化铁作为磁共振成像造影剂时R2需大于62 mmoL/L/s的最低标准,可作为潜在的磁共振成像阴性造影剂。     

磁性N-羧甲基壳聚糖造影剂的制备及性能

采用简单经济(与传统微乳法、热分解法等比较)的方法制备出一种磁性N-羧甲基壳聚糖造影剂。首先对壳聚糖的氨基进行羧甲基化制备N-羧甲基壳聚糖,然后在其链上采用原位生成Fe3O4纳米粒子的方法制备出磁性N-羧甲基壳聚糖,并对其进行了表征及性能的测试。热重分析结果表明,Fe3O4的生成量与N-羧甲基壳聚糖中羧甲基的含量有关,其生成量随着羧甲基含量的增加而增加,但当羧甲基的含量增加到一定程度时,Fe3O4的生成量达到某一峰值。透射电镜结果表明,生成的Fe3O4纳米粒子的粒径约为5～10 nm。磁共振成像结果显示,该磁性N-羧甲基壳聚糖的横向弛豫率为82.82 mmol/(L.s),高于超顺磁性氧化铁作为磁共振成像造影剂时R2需大于62 mmol/(L.s)的最低标准,可作为潜在的磁共振成像阴性造影剂。     

Modelling thixotropic behavior of fresh cement pastes from MRI measurements

From MRI measurements we show that in a flowing cement paste thixotropic effects dominate over short time scales while irreversible effects become significant over larger timescales. The steady and transient flows exhibit a yielding behavior which differs from usual yield stress model: the transition from the solid to the liquid regime is abrupt. We propose a simple thixotropic model based on these observations. The validation is done on the steady and transient state on local experimental tests. We build the “local” rheogram which is representative of the intrinsic rheological properties. Comparisons with “apparent” rheograms demonstrate that it is possible to use correction techniques from the literature to have access to the real behavior law of the material from standard measurements but that, in the case of the material studied in this paper, this would nevertheless lead to an underestimation of the yield stress.     

Albumin-Coated Single-Core Iron Oxide Nanoparticles for Enhanced Molecular Magnetic Imaging (MRI/MPI)

Colloidal stability of magnetic iron oxide nanoparticles (MNP) in physiological environments is crucial for their (bio)medical application. MNP are potential contrast agents for different imaging modalities such as magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). Applied as a hybrid method (MRI/MPI), these are valuable tools for molecular imaging. Continuously synthesized and in-situ stabilized single-core MNP were further modified by albumin coating. Synthesizing and coating of MNP were carried out in aqueous media without using any organic solvent in a simple procedure. The additional steric stabilization with the biocompatible protein, namely bovine serum albumin (BSA), led to potential contrast agents suitable for multimodal (MRI/MPI) imaging. The colloidal stability of BSA-coated MNP was investigated in different sodium chloride concentrations (50 to 150 mM) in short- and long-term incubation (from two hours to one week) using physiochemical characterization techniques such as transmission electron microscopy (TEM) for core size and differential centrifugal sedimentation (DCS) for hydrodynamic size. Magnetic characterization such as magnetic particle spectroscopy (MPS) and nuclear magnetic resonance (NMR) measurements confirmed the successful surface modification as well as exceptional colloidal stability of the relatively large single-core MNP. For comparison, two commercially available MNP systems were investigated, MNP-clusters, the former liver contrast agent (Resovist), and single-core MNP (SHP-30) manufactured by thermal decomposition. The tailored core size, colloidal stability in a physiological environment, and magnetic performance of our MNP indicate their ability to be used as molecular magnetic contrast agents for MPI and MRI.     

Fluorescence Modified Chitosan-Coated Magnetic Nanoparticles for High-Efficient Cellular Imaging

Labeling of cells with nanoparticles for living detection is of interest to various biomedical applications. In this study, novel fluorescent/magnetic nanoparticles were prepared and used in high-efficient cellular imaging. The nanoparticles coated with the modified chitosan possessed a magnetic oxide core and a covalently attached fluorescent dye. We evaluated the feasibility and efficiency in labeling cancer cells (SMMC-7721) with the nanoparticles. The nanoparticles exhibited a high affinity to cells, which was demonstrated by flow cytometry and magnetic resonance imaging. The results showed that cell-labeling efficiency of the nanoparticles was dependent on the incubation time and nanoparticles’ concentration. The minimum detected number of labeled cells was around 10⁴ by using a clinical 1.5-T MRI imager. Fluorescence and transmission electron microscopy instruments were used to monitor the localization patterns of the magnetic nanoparticles in cells. These new magneto-fluorescent nanoagents have demonstrated the potential for future medical use.     

Rationally Designing Molecularly Imprinted Polymers Toward a Highly Specific Recognition by Using a Stoichiometric Molecular Self-assembly

This article presents work on designing a highly specific imprinted polymer for molecular recognition. Based on a stoichiometric molecular self-assembly, the imprinted material was prepared using adenine as the template and methacrylic acid as the functional monomer. The result indicates that the stoichiometric molecular self-assembly plays a positive role in increasing the specificity of prepared materials, so as to adsorb more for the template but less for its analogue. Furthermore, the results indicate that higher or lower extents of self-assembly cause a dramatic decrease in the specificity. Related information indicates that these changes can be an increase in the match of template and the binding framework, which thereby makes the polymer capable of specifically recognizing the imprint species.     

Synthesis,Characterization, and Biodistribution of a Dinuclear Gadolinium Complex with Improved Properties as a Blood Pool MRI Agent

A dinuclear gadolinium(III) chelate containing two moieties of diethylenetriaminepentaacetic acid (DTPA), covalently conjugated to an analogue of deoxycholic acid, was synthesized and thoroughly characterized. A full relaxometric analysis was carried out, consisting of 1) the acquisition of nuclear magnetic resonance dispersion (NMRD) profiles in various media; 2) the study of binding affinity to serum albumin; 3) the measurement of ¹⁷O transverse relaxation rate versus temperature, and 4) a transmetallation assay. In vivo biodistribution MRI studies at 1 T and blood pharmacokinetics assays were carried out in comparison with Gd‐DTPA (Magnevist) and gadocoletic acid trisodium salt (B22956/1), two well‐known Gd complexes that share the same chelating cage and the same deoxycholic acid residue of the Gd complex investigated herein ((GdDTPA)₂‐Chol). High affinity for plasma protein and, in particular, the availability of more than one binding site, allows the complex to reach a fairly high relaxivity value in plasma (～20 mm ^?1 s^?1, 20 MHz, 310 K) as well as to show unexpectedly enhanced properties of blood pooling, with an elimination half‐life in rats approximately seven times longer than that of B22956/1.     

Double-ligand modulation for engineering magnetic nanoclusters

Magnetic nanoclusters (MNCs) are agglomerated individual magnetic nanoparticles (MNPs) that show great promise in increasing magnetic resonance imaging (MRI) sensitivity. Here, we report an effective strategy to engineer MNCs based on double-ligand modulation to enhance MRI sensitivity. The oleic acid-coated individual MNPs self-assembled and then were enveloped by polysorbate 80, using a nanoemulsion method to prepare MNCs. By modulating the amounts of the two ligands, and thus the size and magnetic content of the resultant MNCs, we were able to enormously improve MRI sensitivity.     

Encapsulin Based Self-Assembling Iron-Containing Protein Nanoparticles for Stem Cells MRI Visualization

Over the past decade, cell therapy has found many applications in the treatment of different diseases. Some of the cells already used in clinical practice include stem cells and CAR-T cells. Compared with traditional drugs, living cells are much more complicated systems that must be strictly controlled to avoid undesirable migration, differentiation, or proliferation. One of the approaches used to prevent such side effects involves monitoring cell distribution in the human body by any noninvasive technique, such as magnetic resonance imaging (MRI). Long-term tracking of stem cells with artificial magnetic labels, such as magnetic nanoparticles, is quite problematic because such labels can affect the metabolic process and cell viability. Additionally, the concentration of exogenous labels will decrease during cell division, leading to a corresponding decrease in signal intensity. In the current work, we present a new type of genetically encoded label based on encapsulin from Myxococcus xanthus bacteria, stably expressed in human mesenchymal stem cells (MSCs) and coexpressed with ferroxidase as a cargo protein for nanoparticles’ synthesis inside encapsulin shells. mZip14 protein was expressed for the enhancement of iron transport into the cell. Together, these three proteins led to the synthesis of iron-containing nanoparticles in mesenchymal stem cells—without affecting cell viability—and increased contrast properties of MSCs in MRI.     

19F MRI Nanotheranostics for Cancer Management: Progress and Prospects

Fluorine magnetic resonance imaging (¹⁹F MRI) is a promising imaging technique for cancer diagnosis because of its excellent soft tissue resolution and deep tissue penetration, as well as the inherent high natural abundance, almost no endogenous interference, quantitative analysis, and wide chemical shift range of the ¹⁹F nucleus. In recent years, scientists have synthesized various ¹⁹F MRI contrast agents. By further integrating a wide variety of nanomaterials and cutting-edge construction strategies, magnetically equivalent ¹⁹F atoms are super-loaded and maintain satisfactory relaxation efficiency to obtain high-intensity ¹⁹F MRI signals. In this review, the nuclear magnetic resonance principle underlying ¹⁹F MRI is first described. Then, the construction and performance of various fluorinated contrast agents are summarized. Finally, challenges and future prospects regarding the clinical translation of ¹⁹F MRI nanoprobes are considered. This review will provide strategic guidance and panoramic expectations for designing new cancer theranostic regimens and realizing their clinical translation.     

Efficient CD44-targeted magnetic resonance imaging (MRI) of breast cancer cells using hyaluronic acid (HA)-modified MnFe2O4 nanocrystals

Targeted molecular imaging with hyaluronic acid (HA) has been highlighted in the diagnosis and treatment of CD44-overexpressing cancer. CD44, a receptor for HA, is closely related to the growth of cancer including proliferation, metastasis, invasion, and angiogenesis. For the efficient detection of CD44, we fabricated a few kinds of HA-modified MnFe₂O₄ nanocrystals (MNCs) to serve as specific magnetic resonance (MR) contrast agents (HA-MRCAs) and compared physicochemical properties, biocompatibility, and the CD44 targeting efficiency. Hydrophobic MNCs were efficiently phase-transferred using aminated polysorbate 80 (P80) synthesized by introducing spermine molecules on the hydroxyl groups of P80. Subsequently, a few kinds of HA-MRCAs were fabricated, conjugating different ratios of HA on the equal amount of phase-transferred MNCs. The optimized conjugation ratio of HA against magnetic content was identified to exhibit not only effective CD44 finding ability but also high cell viability through in vitro experiments. The results of this study demonstrate that the suggested HA-MRCA shows strong potential to be used for accurate tumor diagnosis.     

Anti-CEA-functionalized superparamagnetic iron oxide nanoparticles for examining colorectal tumors in vivo

Although the biomarker carcinoembryonic antigen (CEA) is expressed in colorectal tumors, the utility of an anti-CEA-functionalized image medium is powerful for in vivo positioning of colorectal tumors. With a risk of superparamagnetic iron oxide nanoparticles (SPIONPs) that is lower for animals than other material carriers, anti-CEA-functionalized SPIONPs were synthesized in this study for labeling colorectal tumors by conducting different preoperatively and intraoperatively in vivo examinations. In magnetic resonance imaging (MRI), the image variation of colorectal tumors reached the maximum at approximately 24 h. However, because MRI requires a nonmetal environment, it was limited to preoperative imaging. With the potentiality of in vivo screening and intraoperative positioning during surgery, the scanning superconducting-quantum-interference-device biosusceptometry (SSB) was adopted, showing the favorable agreement of time-varied intensity with MRI. Furthermore, biological methodologies of different tissue staining methods and inductively coupled plasma (ICP) yielded consistent results, proving that the obtained in vivo results occurred because of targeted anti-CEA SPIONPs. This indicates that developed anti-CEA SPIONPs owe the utilities as an image medium of these in vivo methodologies.     

Highly sensitive magnetite nano clusters for MR cell imaging

ABSTRACT: High sensitivity and suitable sizes are essential for magnetic iron oxide contrast agents for cell imaging. In this study, we have fabricated highly MR sensitive magnetite nanoclusters (MNCs) with tunable sizes. These clusters demonstrate high MR sensitivity. Especially, water suspensions of the MNCs with average size of 63 nm have transverse relaxivity as high as 630 s-1mM-1, which is among the most sensitive iron oxide contrast agents ever reported. Importantly, such MNCs have no adverse effects on cells (RAW 264.7). When used for cell imaging, they demonstrate much higher efficiency and sensitivity than those of SHU555A (Resovist), a commercially available contrast agent, both in vitro and in vivo, with detection limits of 3,000 and 10,000 labeled cells, respectively. The studied MNCs are sensitive for cell imaging and promising for MR cell tracking in clinics.     

Rationalising MRI, conductance and pressure drop measurements of the trickle-to-pulse transition in trickle beds

Recent MRI data have shown that the transition from trickle to pulsing flow in trickle-bed reactors occurs over a range of liquid velocities at constant gas velocity. The transition is initiated by isolated local pulsing events, which increase in number with increase in liquid velocity until a maximum number exists. Above this liquid velocity, which we have termed the transition point, the individual pulses merge until a single macro-scale pulse is formed and the whole bed demonstrates pulsing flow. In this paper we compare the characterisation of the transition obtained using conductance and pressure drop measurements with that obtained using MRI. Using the insights gained from the 3-D MRI measurements, recorded with a data acquisition time of 280 ms, it is shown that the conductance and pressure drop measurements are sensitive to different stages of the evolution of the hydrodynamic transition, a factor important when using these different measurements in the development and validation of numerical and theoretical models. Conductance measurements identify unambiguously only the onset of the single macro-scale pulse regime, consistent with a determination of the transition point made by visual observation. In contrast, pressure drop measurements are sensitive to both the onset of formation of local pulses and the liquid velocity at which the maximum number of liquid pulses occurs. We also show how a combination of conductance and pressure drop measurements can be used to fully characterise the transition, thereby enabling translation of the insights gained by MRI into a robust measurement strategy for use on larger-scale reactors. Data are reported for a cylindrical column of length 70 cm and inner diameter 43 mm, packed with cylindrical porous γ-Al₂O₃ packing elements of length and diameter 3 mm. The bed was operated under conditions of co-current downflow of air and water, at ambient temperature and a pressure of 2 barg. Gas and liquid superficial velocities were in the range 25-300 and 0.9-, respectively.     

Transferrin-targeted magnetic/fluorescence micelles as a specific bi-functional nanoprobe for imaging liver tumor

In order to delineate the location of the tumor both before and during operation, we developed targeted bi-functional polymeric micelles for magnetic resonance (MR) and fluorescence imaging in liver tumors. Hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) were loaded into the polymeric micelles through self-assembly of an amphiphilic block copolymer poly(ethylene glycol)-poly(ϵ-caprolactone). After, transferrin (Tf) and near-infrared fluorescence molecule Cy5.5 were conjugated onto the surface of the polymeric micelles to obtain the nanosized probe SPIO@PEG-b-PCL-Tf/Cy5.5 (SPPTC). Imaging capabilities of this nanoprobe were evaluated both in vitro and in vivo. The accumulation of SPPTC in HepG2 cells increased over SPIO@PEG-b-PCL-Cy5.5 (SPPC) by confocal microscopy. The targeted nanoprobe SPPTC possessed favorable properties on the MR and fluorescence imaging both in vitro and in vivo. The MTT results showed that the nanoprobes were well tolerated. SPPTC had the potential for pre-operation evaluation and intra-operation navigation of tumors in clinic.     

Liposomes Loaded with Hydrophobic Iron Oxide Nanoparticles: Suitable T2 Contrast Agents for MRI

There has been a recent surge of interest in the use of superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents (CAs) for magnetic resonance imaging (MRI), due to their tunable properties and their low toxicity compared with other CAs such as gadolinium. SPIONs exert a strong influence on spin-spin T₂ relaxation times by decreasing the MR signal in the regions to which they are delivered, consequently yielding darker images or negative contrast. Given the potential of these nanoparticles to enhance detection of alterations in soft tissues, we studied the MRI response of hydrophobic or hydrophilic SPIONs loaded into liposomes (magnetoliposomes) of different lipid composition obtained by sonication. These hybrid nanostructures were characterized by measuring several parameters such as size and polydispersity, and number of SPIONs encapsulated or embedded into the lipid systems. We then studied the influence of acyl chain length as well as its unsaturation, charge, and presence of cholesterol in the lipid bilayer at high field strength (7 T) to mimic the conditions used in preclinical assays. Our results showed a high variability depending on the nature of the magnetic particles. Focusing on the hydrophobic SPIONs, the cholesterol-containing samples showed a slight reduction in r₂, while unsaturation of the lipid acyl chain and inclusion of a negatively charged lipid into the bilayer appeared to yield a marked increase in negative contrast, thus rendering these magnetoliposomes suitable candidates as CAs, especially as a liver CA.