Negative Contrast Enhancement Research Articles

GSH‐Responsive Shape‐Transformable Nanotheranostics for Dual‐Modal T1/T2 MRI‐Guided Enhanced PDT of Nasopharyngeal Carcinoma

AbstractBased on the properties of photodynamic therapy (PDT) and magnetic resonance imaging (MRI), combining them to construct multifunctional nanotheranostics can leverage strengths and avoid weaknesses for tumor diagnosis and treatment. However, certain problems remain unsolved, notably the short observation window caused by insufficient retention time. In this study, a GSH‐responsive shape‐transformable nanotheranostics Gd‐Ce6‐FFVLGGGC‐SS‐PEG are designed (abbreviated as GdCFS) by combining a single metal Gd with Ce6, and peptide (Phe‐Phe‐Val‐Leu‐Gly‐Gly‐Gly‐Cys) disulfide‐conjugated with polyethylene glycol (PEG) to perform dual‐modal T1/T2 MRI specifically at the tumor site. Due to its amphiphilic features, GdCFS can self‐assemble to spherical nanoparticles, while transforming to nanofibers (NFs) in the presence of intracellular overexpressed GSH stimuli. After NFs formation, the hydrophobic core of GdCFS is exposed, resulting in T1 positive contrast enhancement, whereas NFs can simultaneously achieve T2 negative contrast enhancement. Furthermore, GSH depletion can cause imbalance in intracellular redox state, ultimately improving PDT efficacy. GdCFS benefits from the shape‐transformation in terms of sufficient retention time, thus positively minimizing the toxicity risk. On the tumor model of nasopharyngeal carcinoma, in vivo and in vitro outcomes confirm that GdCFS can be a promising candidate for early diagnosis, real‐time monitoring, and precise treatment of tumors with great biocompatibility.

Ferumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow Imaging.

Ferumoxytol: Another Exciting Addition to the Growing Field of Bone Marrow Imaging.

Vessel wall imaging features of Moyamoya disease in a North American population: patterns of negative remodelling, contrast enhancement, wall thickening, and stenosis

BackgroundThis study characterized vessel wall imaging (VWI) features of Moyamoya disease (MMD) in a predominantly adult population at a North American center.MethodsConsecutive patients with VWI were included. Twelve arterial segments were analyzed for wall thickening, degree and pattern of contrast enhancement, and remodeling.ResultsOverall, 286 segments were evaluated in 24 patients (mean age = 36.0 years [range = 1–58]). Of 172 affected segments, 163 (95%) demonstrated negative remodeling. Complete vessel wall obliteration was most frequent in the proximal M1 (17/48, 35%). Affected segments enhanced in 72/172 (42%) (n = 15 for grade II; n = 54 for concentric and n = 18 for eccentric); 20 of 24 (83%) patients had at least one enhancing segment. Both enhancing and non-enhancing segments were present in 19/20 (95%) patients. Vessel wall enhancement was most common in the proximal segments and correlated to the degree of stenosis (p < 0.001), and outer wall diameter (p < 0.001), but not disease duration (p = 0.922) or Suzuki score (p = 0.477). Wall thickening was present in 82/172 (48%) affected segments and was associated with contrast enhancement (p < 0.001), degree of stenosis (p < 0.001), and smaller outer wall diameter (p = 0.004).ConclusionThis study presents VWI findings in North American patients with MMD. Negative remodeling was the most common finding. Most patients had both enhancing and non-enhancing abnormal segments. Vessel wall enhancement was most common in proximal segments, variable in pattern or degree and was correlated to the degree of stenosis and smaller outer wall diameter.

Theranostic Applications of an Ultra-Sensitive T1 and T2 Magnetic Resonance Contrast Agent Based on Cobalt Ferrite Spinel Nanoparticles.

Simple SummaryMagnetic nanoparticles (MNPs) represent an important class of nanomaterials that has been actively employed in multiple technological applications. The MNPs and their based composites have been intensively developed for magnetic resonance imaging, targeted drug delivery, magnetic hyperthermia, and other applications. Magnetic Resonance Imaging (MRI) has a prominent position among clinical imaging modalities as it allows for high spatial resolution and tissue specificity without harmful ionizing radiation. The aim of the study was the demonstration of the potential use of magnetic nanoparticles based on cobalt ferrite spinel as advanced MRI contrast agents that are capable of both T1-weighted positive and T2-weighted negative contrast enhancements in vitro and in vivo. Furthermore, in the present study, we combined novel physical, chemical, and biomedical approaches to develop a multifunctional MRI-detectable drug delivery system that was an efficient T1- and T2-weighted MRI contrast agent and a nanocarrier for targeted drug delivery in vivo.Nano-dimensional materials have become a focus of multiple clinical applications due to their unique physicochemical properties. Magnetic nanoparticles represent an important class of nanomaterials that are widely studied for use as magnetic resonance (MR) contrast and drug delivery agents, especially as they can be detected and manipulated remotely. Using magnetic cobalt ferrite spinel (MCFS) nanoparticles, this study was aimed at developing a multifunctional drug delivery platform with MRI capability for use in cancer treatment. We found that MCFS nanoparticles demonstrated outstanding properties for contrast MRI (r1 = 22.1 s–1mM–1 and r2 = 499 s–1mM–1) that enabled high-resolution T1- and T2-weighted MRI-based signal detection. Furthermore, MCFS nanoparticles were used for the development of a multifunctional targeted drug delivery platform for cancer treatment that is concurrently empowered with the MR contrast properties. Their therapeutic effect in systemic chemotherapy and unique MRI double-contrast properties were confirmed in vivo using a breast cancer mouse tumor model. Our study thus provides an empirical basis for the development of a novel multimodal composite drug delivery system for anticancer therapy combined with noninvasive MRI capability.

Trastuzumab conjugated PEG – Fe3O4@Au nanoparticle as an MRI biocompatible nano-contrast agent

A novel targeted tumor contrast agent in magnetic resonance imaging (MRI) was synthesized based on Fe3O4@Au nanoparticle coated with polyethylene glycol (PEG) and decorated with trastuzumab (TZ). The prepared system was fully characterized, and relaxivity, cytotoxicity, colloidal stability, blood compatibility, in vitro cell targeting ability, cytotoxicity, and in vivo MR contrast enhancement were evaluated. The developed system with a size of about 30 nm exhibited excellent stability, blood compatibility, proper relaxivity, negligible in vitro cytotoxicity, and suitable in vivo negative contrast enhancement. Appropriate negative signal enhancement in MRI confirmed the efficiency of the system to be suggested as an encouraging candidate for accurate cancer diagnosis.

COLLECTION OF THE STRAINS TESCHOVIRUS A, SAPELOVIRUS A, ENTEROVIRUS G OF THE INSTITUTE OF AGRICULTURAL MICROBIOLOGY AND AGROINDUSTRIAL MANUFACTURE OF THE NAAS

Objective. Arrangement of the collection of porcine enteroviruses (PEV) strains isolated on the territory of Ukraine in accordance with the requirements of the International Committee on Virus Taxonomy and supplementing it with new strains Teschovirus A (TV-A), Sapelovirus A (SV-A), Enterovirus G (EV-G). Methods. Virological, serological, molecular genetic, instrumental and statistical. Isolation, cultivation of viruses and determination of their biological activity were performed in passaged culture of porcine embryonic kidney cells (СНЕВ). The viral titre was calculated by the method of Reed and Muench. The typical affiliation of viruses was determined in the virus neutralization reaction in СНЕВ cell culture. Species affiliation was determined by reverse transcription polymerase chain reaction (RT PCR) using species-specific primers for TV-A, SV-A and EV-G, developed by us. Electron microscopy of viruses was performed on a transmission electron microscope by negative contrast enhancement method. Statistical processing was performed in Microsoft Office Excel and StatSoft STATISTICA 12. Results. As a result of the epizootic survey during 2002– 2019, 1,216 samples for virological testing were selected. Successive passages of СНЕВ cell culture resulted in obtaining 274 viral isolates. According to the results of studying physicochemical, morphological, biological properties of these isolated, they are classified as PEV. In connection with the change of taxonomy and nomenclature of PEV, serological and genetic reclassification of 30 strains of viruses isolated in Ukraine, including 14 reference strains according to the classification of V. P. Romanenko, 7 production strains, 9 strains with polyantigenic properties and 4 strains that did not have antigenic affinity with viruses of known PEV serotypes according to the classification of V. P. Romanenko was performed. It has been established that the reference strains of PEV according to the trivial classification of V. P. Romanenko belong to the species TV-A of the genus Teschovirus. As a result of conducted serological testing, PEV-10 M 2323, PEV-12 K 22, PEV-13 L 90, PEV-14 M 116, PEV-16 G 95, PEV-17 V 111, PEV-18 Ch 184, PEV-19 D 227, PEV-20 I 249, PEV-23 I 393 were classified as TV-A1; PEV-11 K 9, PEV-15 Ch 73 — as TV-A3, PEV-22 V 151 — as TV-A6. PEV-21 P 142 did not have antigen affinity with reference strains TV-A, SV-A and EV-G and belongs to a new serotype. Production strains of PEV-1 Perechynskyi 642, Bereznianskyi 652, Chernihivskyi 2372 were reclassified as TV-A1. PEV strains with polyantigenic properties such as G 31 and L 2661 have intertypic antigens with TV-A 1, 10, 11 and TV-A 3, 6, 10 serotypes, respectively. PEV strain of a new serotype Ch 881 was reclassified as SV-A. PEV strains Т 3, Ch 863, Ch 878 are the new serotypes of TV-A. Conclusion. As a result of studies, 274 viral isolates were isolated from 1,216 samples of material. The collection was supplemented with 20 reference strains of Teschovirus A, Sapelovirus A and Enterovirus G. Genetic and serological reclassification of 30 PEV strains isolated in Ukraine was performed. The collection of viral strains has been arranged in accordance with modern taxonomy and nomenclature. Seven viral strains were deposited. The collection of viruses has been supplemented with 4 strains of new serotypes of Teschovirus A.

What's Hot in Breast MRI.

Several articles in the literature have demonstrated a promising role for breast MRI techniques that are more economic in total exam time than others when used as supplement to mammography for detection and diagnosis of breast cancer. There are many technical factors that must be considered in the shortened breast MRI protocols to cut down time of standard ones, including using optimal fat suppression, gadolinium-chelates intravascular contrast administrations for dynamic imaging with post processing subtractions and maximum intensity projections (MIP) high spatial and temporal resolution among others. Multiparametric breast MRI that includes both gadolinium-dependent, i.e., dynamic contrast-enhanced (DCE-MRI) and gadolinium-free techniques, i.e., diffusion-weighted/diffusion-tensor magnetic resonance imaging (DWI/DTI) are shown by several investigators that can provide extremely high sensitivity and specificity for detection of breast cancer. This article provides an overview of the proven indications for breast MRI including breast cancer screening for higher than average risk, determining chemotherapy induced tumor response, detecting residual tumor after incomplete surgical excision, detecting occult cancer in patients presenting with axillary node metastasis, detecting residual tumor after incomplete breast cancer surgical excision, detecting cancer when results of conventional imaging are equivocal, as well patients suspicious of having breast implant rupture. Despite having the highest sensitivity for breast cancer detection, there are pitfalls, however, secondary to false positive and false negative contrast enhancement and contrast-free MRI techniques. Awareness of the strengths and limitations of different approaches to obtain state of the art MR images of the breast will facilitate the work-up of patients with suspicious breast lesions.

K2 Mn3 [FeII (CN)6 ]2 NPs with High T1 -Relaxivity Attributable to Water Coordination on the Mn(II) Center for Gastrointestinal Tract MR Imaging.

The lack of acid stability in the stomach and of temporal stability when moving through the gastrointestinal (GI) tract has made the development of oral magnetic resonance imaging (MRI) contrast agents based on the platform of Gd3+ -complexes problematic.On the other hand, the negative contrast enhancement produced by the T2 -weighted magnetic metal oxide nanoparticles (NPs) often renders the image readout difficult. Biocompatible NPs of the manganese Prussian blue analog K2 Mn3 [FeII (CN)6 ]2 exhibit extremely high stability under the acidic conditions of the gastric juice. Additionally, the high r1 relaxivity, low toxicity, and high temporal stability of such NPs offer great potential for the development of a true T1 -weighted oral contrast agent for MRI of the entire GI tract.

Synthesis, Characterizations, and 9.4 Tesla T2 MR Images of Polyacrylic Acid-Coated Terbium(III) and Holmium(III) Oxide Nanoparticles.

Polyacrylic acid (PAA)-coated lanthanide oxide (Ln2O3) nanoparticles (NPs) (Ln = Tb and Ho) with high colloidal stability and good biocompatibility were synthesized, characterized, and investigated as a new class of negative (T2) magnetic resonance imaging (MRI) contrast agents at high MR fields. Their r2 values were appreciable at a 3.0 T MR field and higher at a 9.4 T MR field, whereas their r1 values were negligible at all MR fields, indicating their exclusive induction of T2 relaxations with negligible induction of T1 relaxations. Their effectiveness as T2 MRI contrast agents at high MR fields was confirmed from strong negative contrast enhancements in in vivo T2 MR images at a 9.4 T MR field after intravenous administration into mice tails.

Citric acid coated ultrasmall superparamagnetic iron oxide nanoparticles conjugated with lactoferrin for targeted negative MR imaging of glioma.

The proposed study was to develop the preparation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs) modified with citric acid, with surface conjugated with lactoferrin (Lf), which used as a potential targeted contrast agent for magnetic resonance imaging (MRI) of brain glioma. USPIONs were prepared by the thermal decomposition method. The hydrophobic USPIONs were coated with citric acid by the ligand exchange method. Then, Lf was conjugated into the surface of USPIONs. The obtained Lf-USPIONs were analyzed by fourier transform infrared (FTIR) spectroscopy and polyacrylamide gel electrophoresis. The size, size distribution, shape and superparamagnetic property of Lf-USPIONs were investigated with TEM and vibrating sample magnetometer (VSM). Both FTIR and electrophoresis analysis demonstrated the successful conjugation of Lf to the surface of USPIONs. The average size of Lf-USPIONs was about 8.4 ± 0.5 nm, which was determined using the statistics of measured over 100 nanoparticles in the TEM image, with a negative charge of -7.3 ± 0.2 mV. TEM imaging revealed that Lf-USPIONs were good in dispersion and polygonal in morphology. VSM results indicated that Lf-USPIONs were superparamagnetic and the saturated magnetic intensity was about 69.8 emu/g. The Lf-USPIONs also showed good biocompatibility in hemolysis, cytotoxicity, cell migration and blood biochemistry studies. MR imaging results in vitro and in vivo indicated that Lf-USPIONs exhibited good negative contrast enhancement. Taken together, Lf-USPIONs hold great potential for brain gliomas MR imaging as a nanosized targeted contrast agent.

Molecular Stereocomplexation for Enhancing the Stability of Nanoparticles Encapsulated in Polymeric Micelles for Magnetic Resonance Imaging.

A generalizable approach for improving the stability of polylactide-based (PLA-based) micelles for encapsulating nanoparticles (NPs) is demonstrated, using stereocomplexation between a pair of poly (ethylene glycol)-b-poly(d-lactide)/poly(ethylene glycol)-b-poly(l-lactide) block copolymer blends. Three different superparamagnetic ferrite-based NPs with distinct nanostructures are first prepared by the high-temperature pyrolysis method, including spherical MnFe2O4, cubic MnFe2O4, and core-shell MnFe2O4@Fe3O4. The diameters of these NPs are approximately 7-10 nm as revealed by transmission electron microscopy. These hydrophobic NPs can be encapsulated within self-assembled, stereocomplexed PLA (sc-PLA) micelles. All sc-PLA micelle systems loaded with three different NPs exhibit enhanced stability at elevated temperatures (20-60 °C) and with extended storage time (∼96 h) compared with analogous samples without stereocomplex formation, confirmed by dynamic light scattering measurements. The magnetic NP-loaded micelles with mean diameters of approximately 150 nm show both biocompatibility and superparamagnetic property. Under a 1.5 T magnetic field, cubic MnFe2O4 (c-MnFe2O4)-loaded micelles exhibit an excellent negative contrast enhancement of MR signals (373 mM-1·s-1), while core-shell MnFe2O4@Fe3O4-loaded micelles show a slightly lower signal for MR imaging (275 mM-1·s-1). These results suggest the potential of using sc-PLA-based polymer micelles as universal carriers for magnetic resonance imaging contrast agents with improved stability for different applications such as cancer diagnosis.

New Class of Efficient T2 Magnetic Resonance Imaging Contrast Agent: Carbon-Coated Paramagnetic Dysprosium Oxide Nanoparticles.

Nanoparticles are considered potential candidates for a new class of magnetic resonance imaging (MRI) contrast agents. Negative MRI contrast agents require high magnetic moments. However, if nanoparticles can exclusively induce transverse water proton spin relaxation with negligible induction of longitudinal water proton spin relaxation, they may provide negative contrast MR images despite having low magnetic moments, thus acting as an efficient T2 MRI contrast agent. In this study, carbon-coated paramagnetic dysprosium oxide (DYO@C) nanoparticles (core = DYO = DyxOy; shell = carbon) were synthesized to explore their potential as an efficient T2 MRI contrast agent at 3.0 T MR field. Since the core DYO nanoparticles have an appreciable (but not high) magnetic moment that arises from fast 4f-electrons of Dy(III) (6H15/2), the DYO@C nanoparticles exhibited an appreciable transverse water proton spin relaxivity (r2) with a negligible longitudinal water proton spin relaxivity (r1). Consequently, they acted as a very efficient T2 MRI contrast agent, as proven from negative contrast enhancements seen in the in vivo T2 MR images.

Recent Advances of Bioresponsive Nano-Sized Contrast Agents for Ultra-High-Field Magnetic Resonance Imaging.

The ultra-high-field magnetic resonance imaging (MRI) nowadays has been receiving enormous attention in both biomaterial research and clinical diagnosis. MRI contrast agents are generally comprising of T1-weighted and T2-weighted contrast agent types, where T1-weighted contrast agents show positive contrast enhancement with brighter images by decreasing the proton's longitudinal relaxation times and T2-weighted contrast agents show negative contrast enhancement with darker images by decreasing the proton's transverse relaxation times. To meet the incredible demand of MRI, ultra-high-field T2 MRI is gradually attracting the attention of research and medical needs owing to its high resolution and high accuracy for detection. It is anticipated that high field MRI contrast agents can achieve high performance in MRI imaging, where parameters of chemical composition, molecular structure and size of varied contrast agents show contrasted influence in each specific diagnostic test. This review firstly presents the recent advances of nanoparticle contrast agents for MRI. Moreover, multimodal molecular imaging with MRI for better monitoring is discussed during biological process. To fasten the process of developing better contrast agents, deep learning of artificial intelligent (AI) can be well-integrated into optimizing the crucial parameters of nanoparticle contrast agents and achieving high resolution MRI prior to the clinical applications. Finally, prospects and challenges are summarized.

Enhancing selective photosensitizer accumulation and oxygen supply for high-efficacy photodynamic therapy toward glioma by 5-aminolevulinic acid loaded nanoplatform

The complex biology of glioma compromises therapeutic efficacy and results in poor prognosis. Photodynamic therapy (PDT) has emerged as a promising modality for localized tumor ablation with limited damage to healthy brain tissues. However, low photosensitizer concentration and hypoxic microenvironment in glioma tissue hamper the practical applications of PDT. To address the challenges, biocompatible periodic mesoporous organosilica coated Prussian blue nanoparticles (PB@PMOs) are constructed to load a biosafe prodrug 5-aminolevulinic acid (5-ALA), which is pronouncedly converted to protoporphyrin IX (PpIX) in malignant cells. PB@PMO-5-ALA induces a higher accumulation of PpIX in glioma cells compared to free 5-ALA. Meanwhile, the PB@PMOs, with a mean edge length of 81 nm and good biocompatibility, effectively decompose hydrogen peroxide to oxygen in a temperature-responsive manner. Oxygen supply further contributes to the promotion of 5-ALA-PDT. Thus, the photodynamic effect of PB@PMO-5-ALA is significantly improved, imposing augmented cytotoxicity to glioma U87MG cells. Furthermore, ex vivo fluorescence imaging elucidates the tumor PpIX increases by 75% in PB@PMO-5-ALA treated mice than that in 5-ALA treated ones post 12 h injection. Magnetic resonance imaging (MRI) and iron staining strongly demonstrate the accumulation of PB@PMO-5-ALA in glioma tissues with negative contrast enhancement and blue staining deposits, respectively. The nanoparticle accumulation and high PpIX level collaboratively enhance PDT efficacy through PB@PMO-5-ALA, which efficiently suppresses tumor growth, providing a promising option with safety for local glioma ablation.

Imaging Characteristics of USPIO Nanoparticles (

Iron nanoparticles have an increasingly more and more important role in MR molecular imaging due to their novel magnetic and surface chemical properties. They provide new possibilities for noninvasive diagnosis and treatment monitoring, especially for tissues that are rich in macrophages. The smaller size and prolongation of the plasma half-life change the in vivo fate of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles captured by liver in reticuloendothelial system (RES) or mononuclear phagocytic system (MPS). However, there is still a lack of MR imaging studies on the liver assessing USPIO nanoparticles <5 nm in size to reflect its absorption and clearance properties. In this study, we used MRI to study the in vitro phantom and in vivo rat liver imaging characteristics of USPIO nanoparticles (<5 nm). The results showed that USPIO nanoparticles (<5 nm) could potentially reduce longitudinal and transverse relaxation times and showed similar T1 relaxation rates compared with commercial gadolinium chelates. In addition, USPIO nanoparticles (<5 nm) in vivo demonstrated both positive (T1) and negative (T2) liver contrast enhancement in healthy rats' liver. Furthermore, USPIO nanoparticles showed relatively good in vitro biocompatibility and fast clearance (within 45.17 minutes after intravenous injection) in the normal liver. Taken together, these data might inspire a new personalized and precise diagnostic tool and stimulate new applications for specific targeted molecular probes.

Synthesis and characterisation of iron oxide nanoparticles conjugated with epidermal growth factor receptor (EGFR) monoclonal antibody as MRI contrast agent for cancer detection.

The aim of this study is to synthesise superparamagnetic iron oxide nanoparticles conjugated with anti-epidermal growth factor receptor monoclonal antibody (ANTI-EGFR-SPION) and investigate its physicochemical characterisation and biocompatibility as a targeted magnetic resonance imaging (MRI) contrast agent for the EGFR-specific detection in EGFR expressing tumour cells. These particles employed biocompatible polymers, poly(D,L-lactide-co-glycolide) (PLGA) and polyethylene glycol aldehyde (PEG-aldehyde), to increase the half-life of particles in circulation and reduce their side effects. The Fe3O4-loaded PLGA-PEG-aldehyde nanoparticles were prepared by a modified water-in-oil-in-water double emulsion method. The EGFR antibody was conjugated to the surface of SPIONs using the aldehyde-amine reaction. Synthesised conjugates (nanoprobes) were characterised using Fourier transform infrared spectrophotometry, dynamic light scattering, transmission electron microscopy images, and vibrating-sample magnetometery, and the results showed that the conjugation was successful. The mean diameter of nanoprobes was about 25 nm. These nanoprobes exhibited excellent water-solubility, stability, and biocompatibility. Meanwhile, MR susceptibility test proved that synthesised nanoprobes can be managed for negative contrast enhancement. The results of this study suggested the potential use of these nanoprobes for non-invasive molecular MRI in EGFR detection in the future.

Amphiphilic Nanoaggregates with Bimodal MRI and Optical Properties Exhibiting Magnetic Field Dependent Switching from Positive to Negative Contrast Enhancement.

Mixed micelles based on amphiphilic gadolinium(III)-DOTA and europium(III)-DTPA complexes were synthesized and evaluated for their paramagnetic and optical properties as potential bimodal contrast agents. Amphiphilic folate molecule for targeting the folate receptor protein, which is commonly expressed on the surface of many human cancer cells, was used in the self-assembly process in order to create nanoaggregates with targeting properties. Both targeted and nontargeted nanoaggregates formed monodisperse micelles having distribution maxima of 10 nm. The micelles show characteristic europium(III) emission with quantum yields of 2% and 1.1% for the nontargeted and targeted micelles, respectively. Fluorescence microscopy using excitation at 405 nm and emission at 575-675 nm was employed to visualize the nanoaggregates in cultured HeLa cells. The uptake of folate-targeted and nontargeted micelles is already visible after 5 h of incubation and was characterized with the europium(III) emission, which is clearly observable in the cytoplasm of the cells. The very fast longitudinal relaxivity r1 of ca. 26 s-1 mM-1 per gadolinium(III) ion was observed for both micelles at 60 MHz and 310 K. Upon increasing the magnetic field to 300 MHz, the nanoaggregates exhibited a large switching to transversal relaxivity with r2 value of ca. 52 s-1 mM-1 at 310 K. Theoretical fitting of the 1H NMRD profiles indicate that the efficient T1 and T2 relaxations are sustained by the favorable magnetic and electron-configuration properties of the gadolinium(III) ion, rotational correlation time, and coordinated water molecule. These nanoaggregates could have versatile application as a positive contrast agent at the currently used magnetic imaging field strengths and a negative contrast agent in higher field applications, while at the same time offering the possibility for the loading of hydrophobic therapeutics or targeting molecules.

Normalized averaged range (nAR), a robust quantification method for MPIO-content.

Micron-sized paramagnetic iron oxide particles (MPIO) are commonly used as contrast agents in magnetic resonance imaging (MRI) that produce negative contrast enhancement, i.e. darkening, on T2*-weighted images. However, estimation and quantification of MPIO in vivo is still challenging. This limitation mainly arises from smearing and displacement of the negative contrast of the MPIO, so-called blooming, potentially leading to false-positive detection. Further, the bias field induced by the MR coils also hinders visualization and quantification of the MPIO. To mitigate these drawbacks, a positive contrast image can be generated, for example by using a frequency offset technique, which can significantly improve the accuracy of quantification methods. In this research, we introduce the normalized average range (nAR) as a new way to quantify the relative MPIO content within a study. The method compares the average value of test ROIs to that of a control ROI in range filtered images. The nAR can be used on both positive and negative contrast images. The nAR was tested on agar phantoms containing various MPIO concentrations, and on a rostral migration model for MPIO labeled stem cells in mice. The amount of MPIO was quantified for biased and unbiased data, and both for positive and negative contrast images. In addition, the presence of MPIOs in the olfactory bulb was verified by histology. The results show the nAR can indicate the presence and relative content of MPIO for both negative and positive images. However, the nAR showed slightly higher sensitivity in optimized positive contrast images compared to negative contrast images. In all cases, the bias field played a minor role in the quantification, making debiasing less of a concern. The dependency of the nAR values on the MPIO content in the ROI was further validated histologically. Thus, the nAR provides a robust and reliable tool for quantification of MPIO in mice.

The effect of size and aspect ratio of Fe-MIL-88B-NH2 metal-organic frameworks on their relaxivity and contrast enhancement properties in MRI: in vitro and in vivo studies

Metal-organic frameworks (MOFs) have shown a great potential as a novel contrast agent in magnetic resonance imaging (MRI) due to their unique properties including versatile structures, composition, and surface chemistry. Fe-MIL-88B-NH2 (MILs) was synthesized using Fe+3 ions and 2-aminoterephthalic acids (NH2-BDC) in the presence of acetic acid and Pluronic F127 under a hydrothermal process. Three MILs in different sizes were synthesized by using variant CH3COOH/Fe+3 molar ratios and denoted as MIL-S, MIL-M, and MIL-L having average sizes of 60, 350, and 730 nm, respectively. The effect of aspect ratio and particle size of MILs was investigated on proton relaxivity and contrast enhancement in aqueous, in vitro, and in vivo MR images. MRI study indicated that by increasing the MILs size, the incremental transverse relaxivity was achieved from 13.53 to 50.80 for r2 and from 38.75 to 60.25 for r2*, while the difference between r2 and r2* was decreased obviously. The r2/r1 ratios were found to be 5.80, 42.27, and 127.00 for MIL-S, MIL-M, and MIL-L, respectively. All MILs demonstrated T2-weighted MR imaging performance. Furthermore, no susceptibility artifacts were observed on T2-weighted images of MILs. By decreasing the size of MILs, r2/r1 ratio was reduced sharply and T1 contrast was also observed for MIL-S. MIL-S was used for in vitro and in vivo study due to its capability in simultaneous T1 and T2 contrast enhancements. MTT and hemolysis assays showed no significant cytotoxicity and hemolysis for MIL-S against normal human breast cell line (MCF-10A) and red blood cells, respectively, at concentrations of Fe+3 up to 300 μg/mL (p < 0.05). T1-weighted images acquired from in vitro study interestingly showed that the signal intensity of MIL-S is more than Dotarem. The in vivo experiment revealed that the signal intensity of mice liver decreased sharply after injection resulting in increase of negative contrast enhancement. The negative contrast enhancement decreased gradually by the time under T2-weighted imaging mode confirming application of MIL-S as a T2 contrast agent in biomedical applications (up to 12 h post-injection). Although a decrease of the size resulted in bright contrast in aqueous solution for MIL-S, it did not show proper efficiency for in vivo positive contrast enhancement. The advantages, including simple preparation and accessibility, acceptable potency and selectivity, blood compatibility, and suitable cytocompatibility as well as enough circulation time, make MIL-S as a dual MRI contrast agent to differentiate between low-contrast tissues for in vivo experiments.

Co-delivery of mRNA and SPIONs through amino-ester nanomaterials.

Nanoparticles have been widely explored for combined therapeutic and diagnostic applications. For example, lipid-based nanoparticles have been used to encapsulate multiple types of agents and achieve multi-functions. Herein, we enabled a co-delivery of mRNA molecules and superparamagnetic iron oxide nanoparticles (SPIONs) by using an amino-ester lipid-like nanomaterial. An orthogonal experimental design was used to identify the optimal formulation. The optimal formulation, MPA-Ab-8 LLNs, not only showed high encapsulation of both mRNA and SPIONs, but also increased the r 2 relaxivity of SPIONs by more than 1.5-fold in vitro. MPA-Ab-8 LLNs effectively delivered mRNA and SPIONs into cells, and consequently induced high protein expression as well as strong MRI contrast. Consistent herewith, we observed both mRNA-mediated protein expression and an evident negative contrast enhancement of MRI signal in mice. In conclusion, amino-ester nanomaterials demonstrate great potential as delivery vehicles for theranostic applications.