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We describe the synthesis, characterization, molecular modeling, and in vitro anticancer activity of three benzothiazole aniline (BTA) ligands and their corresponding platinum (II) complexes. We designed the compounds based on the selective antitumor properties of BTA, along with three types of metallic centers, aiming to take advantage of the distinctive and synergistic activity of the complexes to develop anticancer agents. The compounds were characterized using nuclear magnetic resonance spectrometry, Fourier transform infrared spectroscopy, mass spectrometry, elemental analysis, and tested for antiproliferative activity against multiple normal and cancerous cell lines. L1, L2, and L1Pt had better cytotoxicity in the liver, breast, lung, prostate, kidney, and brain cells than clinically used cisplatin. Especially, L1 and L1Pt demonstrated selective inhibitory activities against liver cancer cells. Therefore, these compounds can be a promising alternative to the present chemotherapy drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

High sensitivity at ultra-high field (UHF) and sufficient potential to penetrate the brain are the most desirable characteristics in the development of contrast agents (CAs) for magnetic resonance imaging (MRI). However, incorporating such qualities into a single nanocarrier is challenging. Herein, we report a new strategy for a highly brain-permeable MR CA with high sensitivity at UHF by loading dysprosium chelates (DyL) in apoferritin cavities (Apo-DyL). We also design the chelate ligand structure to increase DyL loading capacity within the apoferritin cavity. Using the intracerebroventricular (ICV) injection approach as a new delivery route for Apo-DyL, we demonstrate that apoferritin loaded with DyL can penetrate the brain–ventricular barrier and diffuse into the brain. This brain-permeable capability is unique to Apo-DyL, compared with other types of nanoparticles used in MRI. Apo-DyL also shows significant increase in MR sensitivity of DyL at UHF. Furthermore, based on brain tumor imaging at UHF, Apo-DyL can significantly enhance the tumor for a lower dose of the CA than the previously reported Gd- or Mn-loaded apoferritin nanoplatform. Therefore, Apo-DyL can be a novel nanoplatform that is a highly sensitive and versatile MR CA for UHF brain imaging. [ABSTRACT FROM AUTHOR]

The study of ultra-small paramagnetic gadolinium oxide (Gd2O3) nanoparticles (NPs) as in vivo positive (T1) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd2O3 NP imaging agents depends on the surface-coating materials. In this study, poly(methyl vinyl ether-alt-maleic acid) (PMVEMA) was used as a surface-coating polymer. The PMVEMA-coated paramagnetic ultra-small Gd2O3 NPs with an average particle diameter of 1.9 nm were synthesized using the one-pot polyol method. They exhibited excellent colloidal stability in water and good biocompatibility. They also showed a very high longitudinal water proton spin relaxivity (r1) value of 36.2 s−1mM−1 (r2/r1 = 2.0; r2 = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r1 values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T1 MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T1 MRI contrast agent. [ABSTRACT FROM AUTHOR]

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r 1 = 3.9 s ‒1 mM ‒1 and high r 2 /r 1 ratio of 14.6. Their ability to function as a dual-modal T 1 /T 2 MRI-CA in T 1 -weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T 1 -weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor.&#xD., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Multi-functional nanoparticles are useful for various applications, such as biomedical imaging, detection, and display technologies. Colour-tunable GdEu x Tb 1- x O 3 nanoparticles were synthesized with emission colour ranging from green (545 nm) to red (616 nm) by varying x ( x = 0, 0.1, 0.3, 0.5, 0.7, 0.9, and 1). These nanoparticles were surface-grafted with polyacrylic acid and a small quantity of 2,6-pyridinedicarboxylic acid. This modification aimed to ensure long-term colloidal stability (>1 year without precipitation) and high quantum yields (>30%) in aqueous media. Additionally, they exhibited long emission lifetimes (∼1 ms), high longitudinal water proton spin relaxivities (>30 s -1 mM -1 ), and high X-ray attenuation efficiencies (∼10 HU mM -1 ). These multiple exceptional properties within a single nanoparticle make them highly valuable for applications in biomedical imaging, noise-free signal detection, and colour display.

High-manganese steel (high-Mn) is valuable for its excellent mechanical properties in cryogenic environments, making it essential to understand its deformation behavior at extremely low temperatures. The deformation behavior of high-Mn steels at extremely low temperatures depends on the stacking fault energy (SFE) that can lead to the formation of deformation twins or transform to ε-martensite or α'-martensite as the temperature decreases. In this study, submerged arc welding (SAW) was applied to fabricate thick pipes for cryogenic industry applications, but it may cause problems such as an uneven distribution of manganese (Mn) and a large weldment. To address these issues, post-weld heat treatment (PWHT) is performed to achieve a homogeneous microstructure, enhance mechanical properties, and reduce residual stress. It was found that the difference in Mn content between the dendrite and interdendritic regions was reduced after PWHT, and the SFE was calculated. At cryogenic temperatures, the SFE decreased below 20 mJ/m 2 , indicating the martensitic transformation region. Furthermore, an examination of the deformation behavior of welded high-Mn steels was conducted. This study revealed that the tensile deformed, as-welded specimens exhibited ε and α'-martensite transformations at cryogenic temperatures. However, the heat-treated specimens did not undergo α'-martensite transformations. Moreover, regardless of whether the specimens were subjected to Charpy impact deformation before or after heat treatment, ε and α'-martensite transformations did not occur.

Analysis of the heavy fractions in crude oil has been important in petroleum industries. It is well known that heavy fractions such as vacuum gas oils (VGOs) include heteroatoms, of which sulfur and nitrogen are often characterized in many cases. We conducted research regarding the molecular species analysis of VGOs. Further refine processes using VGOs are becoming important when considering carbon recycling. In this work, we attempted to classify compounds within VGOs provided by Kuwait Institute for Scientific Research. Two VGOs were priorly distillated from Kuwait Export crude and Lower Fars crude. Quantitative analysis was performed mainly using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOFMS). MALDI-TOF-MS has been developed for analyzing high-molecular-weight compounds such as polymer and biopolymers. As matrix selection is one of the most important aspects in MALDI-TOFMS, the careful selection of a matrix was firstly evaluated, followed by analysis using a Kendrick plot with nominal mass series (z*). The objective was to evaluate if this work could provide an effective classification of VGOs compounds. The Kendrick plot is a well-known method for processing mass data. The difference in the Kendrick mass defect (KMD) between C n H 2n-14 S and C n H 2n-20 O is only 0.0005 mass units, which makes it difficult in general to distinguish these compounds. However, since the z* value showed effective differences during the classification of these compounds, qualitative analysis could be possible. The analysis using nominal mass series showed the potential to be used as an effective method in analyzing heavy fractions.

Nanoparticles and nanomaterials are important, because they are potentially applicable to energy, storage, bioimaging, biosensors, catalysts, nanomedicine, batteries, solar energy, bioenergy, and so on (Figure 1) [...].

Owing to their theranostic properties, cerium oxide (CeO 2 ) nanoparticles have attracted considerable attention for their key applications in nanomedicine. In this study, ultrasmall CeO 2 nanoparticles (particle diameter = 1-3 nm) as X-ray contrast agents with an antioxidant effect were investigated for the first time. The nanoparticles were coated with hydrophilic and biocompatible poly(acrylic acid) (PAA) and poly(acrylic acid- co -maleic acid) (PAAMA) to ensure satisfactory colloidal stability in aqueous media and low cellular toxicity. The synthesized nanoparticles were characterized using high-resolution transmission electron microscopy, X-ray diffraction, Fourier transform-infrared spectroscopy, thermogravimetric analysis, dynamic light scattering, cell viability assay, photoluminescence spectroscopy, and X-ray computed tomography (CT). Their potential as X-ray contrast agents was demonstrated by measuring phantom images and in vivo CT images in mice injected intravenously and intraperitoneally. The X-ray attenuation of these nanoparticles was greater than that of the commercial X-ray contrast agent Ultravist and those of larger CeO 2 nanoparticles reported previously. In addition, they exhibited an antioxidant effect for the removal of hydrogen peroxide. The results confirmed that the PAA- and PAAMA-coated ultrasmall CeO 2 nanoparticles demonstrate potential as highly sensitive radioprotective or theranostic X-ray contrast agents., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Magnetite nanoparticles (Fe 3 O 4 NPs) have been intensively investigated because of their potential biomedical applications due to their high saturation magnetization. In this study, core-shell Fe 3 O 4 @C NPs (core = Fe 3 O 4 NPs and shell = amorphous carbons, d avg = 35.1 nm) were synthesized in an aqueous solution. Carbon coating terminated with hydrophilic -OH and -COOH groups imparted excellent biocompatibility and hydrophilicity to the NPs, making them suitable for biomedical applications. The Fe 3 O 4 @C NPs exhibited ideal relaxometric properties for T 2 magnetic resonance imaging (MRI) contrast agents (i.e., high transverse and negligible longitudinal water proton spin relaxivities), making them exclusively induce only T 2 relaxation. Their T 2 MRI performance as contrast agents was confirmed in vivo by measuring T 2 MR images in mice before and after intravenous injection.

Nanodiamonds (ND) are chemically inert and stable owing to their sp 3 covalent bonding structure, but their surface sp 2 graphitic carbons can be easily homogenized with diverse functional groups via oxidation, reduction, hydrogenation, amination, and halogenation. Further surface conjugation of NDs with hydrophilic ligands can boost their colloidal stability and functionality. In addition, NDs are non-toxic as they are made of carbons. They exhibit stable fluorescence without photobleaching. They also possess paramagnetic and ferromagnetic properties, making them suitable for use as a new type of fluorescence imaging (FI) and magnetic resonance imaging (MRI) probe. In this review, we focused on recently developed ND production methods, surface homogenization and functionalization methods, biocompatibilities, and biomedical imaging applications as FI and MRI probes. Finally, we discussed future perspectives., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Fluorescent nanoparticles used in biomedical applications should be stable in their colloidal form in aqueous media and possess a high quantum yield (QY). We report ultrasmall Ln 2 O 3 (Ln = Eu, Tb, or Dy) nanoparticle colloids with high QYs in aqueous media. The nanoparticles are grafted with hydrophilic and biocompatible poly(acrylic acid) (PAA) to ensure colloidal stability and biocompatibility and with organic photosensitizer 2,6-pyridinedicarboxylic acid (PDA) for achieving a high QY. The PAA/PDA-Ln 2 O 3 nanoparticle colloids were nearly monodispersed and ultrasmall (particle diameter: ∼2 nm). They exhibited excellent colloidal stability with no precipitation after synthesis (>1.5 years) in aqueous media, very low cellular toxicity, and very high absolute QYs of 87.6, 73.6, and 2.8% for Ln = Eu, Tb, and Dy, respectively. These QYs are the highest reported so far for lanthanides in aqueous media. Therefore, the results suggest their high potential as sensitive optical or imaging probes in biomedical applications.

X-ray computed tomography (CT) contrast agents offer extremely valuable tools and techniques in diagnostics via contrast enhancements. Heavy metal-based nanoparticles (NPs) can provide high contrast in CT images due to the high density of heavy metal atoms with high X-ray attenuation coefficients that exceed that of iodine (I), which is currently used in hydrophilic organic CT contrast agents. Nontoxicity and colloidal stability are vital characteristics in designing heavy metal-based NPs as CT contrast agents. In addition, a small particle size is desirable for in vivo renal excretion. In vitro phantom imaging studies have been performed to obtain X-ray attenuation efficiency, which is a critical parameter for CT contrast agents, and the imaging performance of CT contrast agents has been demonstrated via in vivo experiments. In this review, we focus on the in vitro and in vivo studies of various heavy metal-based NPs in pure metallic or chemical forms, including Au, Pt, Pd, Ag, Ce, Gd, Dy, Ho, Yb, Ta, W, and Bi, and provide an outlook on their use as high-performance CT contrast agents.

Hemagglutination assay has been used for blood typing and detecting viruses, thus applicable for the diagnosis of infectious diseases, including COVID-19. Therefore, the development of microfluidic devices for fast detection of hemagglutination is on-demand for point-of-care diagnosis. Here, we present a way to detect hemagglutination in 3D microfluidic devices via optical absorbance (optical density, OD) characterization. 3D printing is a powerful way to build microfluidic structures for diagnostic devices. However, mixing liquid in microfluidic chips is difficult due to laminar flow, which hampers practical applications such as antigen-antibody mixing. To overcome the issue, we fabricated 3D microfluidic chips with embedded microchannel and microwell structures to induce hemagglutination between red blood cells (RBCs) and antibodies. We named it a 3D microtrap chip. We also established an automated measurement system which is an integral part of diagnostic devices. To do this, we developed a novel way to identify RBC agglutination and non-agglutination via the OD difference. By adapting a 3D-printed aperture to the microtrap chip, we obtained a pure absorbance signal from the microchannels by eliminating the background brightness of the microtrap chip. By investigating the underlying optical physics, we provide a 3D device platform for detecting hemagglutination.

In recent decades, magnetic nanoparticles (MNPs) have attracted considerable research interest as versatile substances for various biomedical applications, particularly as contrast agents in magnetic resonance imaging (MRI). Depending on their composition and particle size, most MNPs are either paramagnetic or superparamagnetic. The unique, advanced magnetic properties of MNPs, such as appreciable paramagnetic or strong superparamagnetic moments at room temperature, along with their large surface area, easy surface functionalization, and the ability to offer stronger contrast enhancements in MRI, make them superior to molecular MRI contrast agents. As a result, MNPs are promising candidates for various diagnostic and therapeutic applications. They can function as either positive (T 1 ) or negative (T 2 ) MRI contrast agents, producing brighter or darker MR images, respectively. In addition, they can function as dual-modal T 1 and T 2 MRI contrast agents, producing either brighter or darker MR images, depending on the operational mode. It is essential that the MNPs are grafted with hydrophilic and biocompatible ligands to maintain their nontoxicity and colloidal stability in aqueous media. The colloidal stability of MNPs is critical in order to achieve a high-performance MRI function. Most of the MNP-based MRI contrast agents reported in the literature are still in the developmental stage. With continuous progress being made in the detailed scientific research on them, their use in clinical settings may be realized in the future. In this study, we present an overview of the recent developments in the various types of MNP-based MRI contrast agents and their in vivo applications.

Magnetic resonance imaging (MRI) is increasingly used to diagnose focal and diffuse liver disorders. Despite their enhanced efficacy, liver-targeted gadolinium-based contrast agents (GBCAs) raise safety concerns owing to the release of toxic Gd 3+ ions. A π-conjugated macrocyclic chelate, Mn-NOTA-NP , was designed and synthesized as a non-gadolinium alternative for liver-specific MRI. Mn-NOTA-NP exhibits an r 1 relaxivity of 3.57 mM -1 s -1 in water and 9.01 mM -1 s -1 in saline containing human serum albumin at 3 T, which is significantly greater than the clinically utilized Mn 2+ -based hepatobiliary drug, Mn-DPDP (1.50 mM -1 s -1 ), and comparable with that of GBCAs. Furthermore, the in vivo biodistribution and MRI enhancement patterns of Mn-NOTA-NP were similar to those of the Gd 3+ -based hepatobiliary agent, Gd-DTPA-EOB. Additionally, a 0.05 mmol/kg dose of Mn-NOTA-NP facilitated high-sensitivity tumor detection with tumor signal enhancement in a liver tumor model. Ligand-docking simulations further indicated that Mn-NOTA-NP differed from other hepatobiliary agents in their interactions with several transporter systems. Collectively, we demonstrated that Mn-NOTA-NP could be a new liver-specific MRI contrast agent.

Ultrasmall platinum nanoparticles (Pt-NPs) grafted with three types of hydrophilic and biocompatible polymers, i.e., poly(acrylic acid), poly(acrylic acid-co-maleic acid), and poly(methyl vinyl ether-alt-maleic acid) were synthesized using a one-pot polyol method. Their physicochemical and X-ray attenuation properties were characterized. All polymer-coated Pt-NPs had an average particle diameter (d avg ) of 2.0 nm. Polymers grafted onto Pt-NP surfaces exhibited excellent colloidal stability (i.e., no precipitation after synthesis for >1.5 years) and low cellular toxicity. The X-ray attenuation power of the polymer-coated Pt-NPs in aqueous media was stronger than that of the commercial iodine contrast agent Ultravist at the same atomic concentration and considerably stronger at the same number density, confirming their potential as computed tomography contrast agents.

In this study, we designed, synthesized, and evaluated gadolinium compounds conjugated with flavonoids as potential theranostic agents for the treatment of inflammation. These novel theranostic agents combine a molecular imaging agent and one of three flavonoids (galangin, chrysin, and 7-hydroxyflavone) as anti-inflammatory drugs as a single integrated platform. Using these agents, MR imaging showed contrast enhancement (>10 in CNR) at inflamed sites in an animal inflammation model, and subsequent MR imaging used to monitor the therapeutic efficacy of these integrated agents revealed changes in inflamed regions. The anti-inflammatory effects of these agents were demonstrated both in vitro and in vivo. Furthermore, the antioxidant efficacy of the agents was evaluated by measuring their reactive oxygen species scavenging properties. For example, Gd-galangin at 30 μM showed a three-fold higher ROS scavenging of DPPH. Taken together, our findings provide convincing evidence to indicate that flavonoid-conjugated gadolinium compounds can be used as potentially efficient theranostic agents for the treatment of inflammation.

Hydrophilic and biocompatible PAA-coated ultrasmall Gd 2 O 3 nanoparticles (d avg = 1.7 nm) were synthesized and conjugated with tumor-targeting ligands, i.e., cyclic arginylglycylaspartic acid (cRGD) and/or folic acid (FA). FA-PAA-Gd 2 O 3 and cRGD/FA-PAA-Gd 2 O 3 nanoparticles were successfully applied in U87MG tumor-bearing mice for tumor imaging using T 1 magnetic resonance imaging (MRI). cRGD/FA-PAA-Gd 2 O 3 nanoparticles with multiple tumor-targeting ligands exhibited higher contrasts at the tumor site than FA-PAA-Gd 2 O 3 nanoparticles with mono tumor-targeting ligands. In addition, the cRGD/FA-PAA-Gd 2 O 3 nanoparticles exhibited higher contrasts in all organs, especially the aorta, compared with those of the FA-PAA-Gd 2 O 3 nanoparticles, because of the blood cell hitchhiking effect of cRGD in the cRGD/FA-PAA-Gd 2 O 3 nanoparticles, which prolonged their circulation in the blood.

Here, we describe the synthesis, characterization, and in vitro biological evaluation of a series of transition metal complexes containing benzothiazole aniline (BTA). We employed BTA, which is known for its selective anticancer activity, and a salen-type Schiff-based ligand to coordinate several transition metals to achieve selective and synergistic cytotoxicity. The compounds obtained were characterized by NMR spectroscopy, mass spectrometry, Fourier transform infrared spectroscopy, and elemental analysis. The compounds L , MnL , FeL , CoL , and ZnL showed promising in vitro cytotoxicity against cancer cells, and they had a lower IC 50 than that of the clinically used cisplatin. In particular, MnL had synergistic cytotoxicity against liver, breast, and colon cancer cells. Moreover, MnL , CoL , and CuL promoted the production of reactive oxygen species in HepG2 tumor cell lines. The lead compound of this series, MnL , remained stable in physiological settings, and docking results showed that it interacted rationally with the minor groove of DNA. Therefore, MnL may serve as a viable alternative to platinum-based chemotherapy.

Water proton spin relaxivities, colloidal stability, and biocompatibility of nanoparticle magnetic resonance imaging (MRI) contrast agents depend on surface-coating ligands. In this study, hydrophilic and biocompatible polyethylenimines (PEIs) of different sizes (M n = 1200 and 60,000 amu) were used as surface-coating ligands for ultrasmall holmium oxide (Ho 2 O 3 ) nanoparticles. The synthesized PEI1200- and PEI60000-coated ultrasmall Ho 2 O 3 nanoparticles, with an average particle diameter of 2.05 and 1.90 nm, respectively, demonstrated low cellular cytotoxicities, good colloidal stability, and appreciable transverse water proton spin relaxivities (r 2 ) of 13.1 and 9.9 s -1 mM -1 , respectively, in a 3.0 T MR field with negligible longitudinal water proton spin relaxivities (r 1 ) (i.e., 0.1 s -1 mM -1 ) for both samples. Consequently, for both samples, the dose-dependent contrast changes in the longitudinal (R 1 ) and transverse (R 2 ) relaxation rate map images were negligible and appreciable, respectively, indicating their potential as efficient transverse T 2 MRI contrast agents in vitro.

The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy.

Owing to a higher demand for glucosamine (GlcN) in metabolic processes in tumor cells than in normal cells (i.e., GlcN effects), tumor imaging in magnetic resonance imaging (MRI) can be highly improved using GlcN-conjugated MRI contrast agents. Here, GlcN was conjugated with polyacrylic acid (PAA)-coated ultrasmall gadolinium oxide nanoparticles (UGONs) (d avg = 1.76 nm). Higher positive (brighter or T 1 ) contrast enhancements at various organs including tumor site were observed in human brain glioma (U87MG) tumor-bearing mice after the intravenous injection of GlcN-PAA-UGONs into their tail veins, compared with those obtained with PAA-UGONs as control, which were rapidly excreted through the bladder. Importantly, the contrast enhancements of the GlcN-PAA-UGONs with respect to those of the PAA-UGONs were the highest in the tumor site owing to GlcN effects. These results demonstrated that GlcN-PAA-UGONs can serve as excellent T 1 MRI contrast agents in tumor imaging via GlcN effects.

157 Gd (natural abundance = 15.7%) has the highest thermal neutron capture cross section (σ) of 254,000 barns (1 barn = 10 -28 m 2 ) among stable (nonradioactive) isotopes in the periodic table. Another stable isotope, 155 Gd (natural abundance = 14.8%), also has a high σ value of 60,700 barns. These σ values are higher than that of 10 B (3840 barns, natural abundance = 19.9%), which is currently used as a neutron-absorbing isotope for boron neutron capture therapy agents. Energetic particles such as electrons and γ-rays emitted from Gd-isotopes after neutron beam absorption kill cancer cells by damaging DNAs inside cancer-cell nuclei without damaging normal cells if Gd-chemicals are positioned in cancer cells. To date, various Gd-chemicals such as commercial Gd-chelates used as magnetic resonance imaging contrast agents, modified Gd-chelates, nanocomposites containing Gd-chelates, fullerenes containing Gd, and solid-state Gd-nanoparticles have been investigated as gadolinium neutron capture therapy (GdNCT) agents. All GdNCT agents had exhibited cancer-cell killing effects, and the degree of the effects depended on the GdNCT agents used. This confirms that GdNCT is a promising cancer therapeutic technique. However, the commercial Gd-chelates were observed to be inadequate in clinical use because of their low accumulation in cancer cells due to their extracellular and noncancer targeting properties and rapid excretion. The other GdNCT agents exhibited higher accumulation in cancer cells, compared to Gd-chelates; consequently, they demonstrated higher cancer-cell killing effects. However, they still displayed limitations such as poor specificity to cancer cells. Therefore, continuous efforts should be made to synthesize GdNCT agents suitable in clinical applications. Herein, the principle of GdNCT, current status of GdNCT agents, and general design strategy for GdNCT agents in clinical use are discussed and reviewed., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

In this study, hydrophilic and biocompatible chitosan oligosaccharide lactate (COL)-coated ultra-small gadolinium oxide nanoparticles (NPs) were synthesized through a one-pot polyol method and characterized by various experimental techniques. The In Vitro cellular cytotoxicity assay indicated that the COL-coated gadolinium oxide NPs were non-toxic up to 500 μ M Gd. In addition, their water proton spin relaxivities (i.e., r 1 and r ₂) were estimated to be 13.0 and 27.0 s -1 mM -1 , respectively, which are higher than those of commercial magnetic resonance imaging (MRI) contrast agents. The application potential of the solution sample as a T 1 MRI contrast agent was demonstrated In Vitro by measuring map images in which dose-dependent contrast enhancements were observed.

The water proton spin relaxivity, colloidal stability, and biocompatibility of nanoparticle-based magnetic resonance imaging (MRI) contrast agents depend on the surface-coating ligands. Here, poly(acrylic acid-co-maleic acid) (PAAMA) (M w = ~3000 amu) is explored as a surface-coating ligand of ultrasmall gadolinium oxide (Gd 2 O 3 ) nanoparticles. Owing to the numerous carboxylic groups in PAAMA, which allow its strong conjugation with the nanoparticle surfaces and the attraction of abundant water molecules to the nanoparticles, the synthesized PAAMA-coated ultrasmall Gd 2 O 3 nanoparticles (d avg = 1.8 nm and a avg = 9.0 nm) exhibit excellent colloidal stability, extremely low cellular toxicity, and a high longitudinal water proton spin relaxivity (r 1 ) of 40.6 s -1 mM -1 (r 2 /r 1 = 1.56, where r 2 = transverse water proton spin relaxivity), which is approximately 10 times higher than those of commercial molecular contrast agents. The effectiveness of PAAMA-coated ultrasmall Gd 2 O 3 nanoparticles as a T 1 MRI contrast agent is confirmed by the high positive contrast enhancements of the in vivo T 1 MR images at the 3.0 T MR field.

Ultrasmall Bi₂O₃ nanoparticles ( d avg = 1.5 nm) coated with biocompatible and hydrophilic D-glucuronic acid were prepared for the first time through a simple one-step polyol process and their potential as CT contrast agents were investigated by measuring their X-ray attenuation properties. Their observed X-ray attenuation power was stronger than that of a commercial iodine CT contrast agent at the same atomic concentration, as consistent with the magnitudes of atomic X-ray attenuation coefficients (i.e., Bi > I), and much stronger at the same number density. The results indicate that the nanoparticle sample is a potential CT contrast agent.

Advancements in recanalization therapies have rendered reperfusion injury an important challenge for stroke management. It is essential to work toward effective therapeutics that protect the ischemic brain from reperfusion injury. Here, we report a new concept of neuroprognostic agents, which combine molecular diagnostic imaging and targeted neuroprotection for treatment of reperfusion injury after stroke. These neuroprognostic agents are inflammation-targeted gadolinium compounds conjugated with nonsteroidal anti-inflammatory drugs (NSAIDs). Our results demonstrated that gadolinium-based MRI contrast agents conjugated with NSAIDs suppressed the increase in cyclooxygenase-2 (COX-2) levels, ameliorated glial activation, and neuron damage that are phenotypic for stroke by mitigating neuroinflammation, which prevented reperfusion injury. In addition, this study showed that the neuroprognostic agents are promising T 1 molecular MRI contrast agents for detecting precise reperfusion injury locations at the molecular level. Our results build on this new concept of neuroprognostics as a novel management strategy for ischemia-reperfusion injury, combining neuroprotection and molecular diagnostics.

Gadolinium neutron capture therapy (GdNCT) is considered as a new promising cancer therapeutic technique. Nevertheless, limited GdNCT applications have been reported so far. In this study, surface-modified ultrasmall gadolinium oxide nanoparticles (UGNPs) with cancer-targeting ability ( d avg = 1.8 nm) were for the first time applied to the in vivo GdNCT of cancer using nude model mice with cancer, primarily because each nanoparticle can deliver hundreds of Gd to the cancer site. For applications, the UGNPs were grafted with polyacrylic acid (PAA) for biocompatibility and colloidal stability, which was then conjugated with cancer-targeting arginylglycylaspartic acid (RGD) (shortly, RGD-PAA-UGNPs). The solution sample was intravenously administered into the tails of nude model mice with cancer. At the time of the maximum accumulation of the RGD-PAA-UGNPs at the cancer site, which was monitored using magnetic resonance imaging, the thermal neutron beam was locally irradiated onto the cancer site and the cancer growth was monitored for 25 days. The cancer growth suppression was observed due to the GdNCT effects of the RGD-PAA-UGNPs, indicating that the surface-modified UGNPs with cancer-targeting ability are potential materials applicable to the in vivo GdNCT of cancer., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Imaging agents are crucial in diagnosing diseases. Ultrasmall lanthanide oxide (Ln 2 O 3 ) nanoparticles (NPs) (Ln = Eu, Gd, and Dy) are promising materials as high-performance imaging agents because of their excellent magnetic, optical, and X-ray attenuation properties which can be applied as magnetic resonance imaging (MRI), fluorescence imaging (FI), and X-ray computed tomography (CT) agents, respectively. Ultrasmall Ln 2 O 3 NPs (Ln = Eu, Gd, and Dy) are reviewed here. The reviewed topics include polyol synthesis, characterization, properties, and biomedical imaging applications of ultrasmall Ln 2 O 3 NPs. Recently published papers were used as bibliographic databases. A polyol method is a simple and efficient one-pot synthesis for preparing ultrasmall Ln 2 O 3 NPs. Ligand-coated ultrasmall Ln 2 O 3 NPs have good colloidal stability, biocompatibility, and renal excretion ability suitable for in vivo imaging applications. Ultrasmall Eu2O3 NPs display photoluminescence in the red region suitable for use as FI agents. Ultrasmall Gd2O3 NPs have r1 values higher than those of commercial molecular contrast agents and r2/r1 ratios close to 1, which make them eligible for use as T1 MRI contrast agents. Ultrasmall Dy2O3 NPs exhibit high r2 and negligible r1 values, which make them suitable for use as T2 MRI contrast agents. All ultrasmall Ln 2 O 3 NPs have high X-ray attenuation powers which make them suitable for use as CT contrast agents. Unmixed, mixed, or doped ultrasmall Ln2O3 NPs with different Ln are extremely useful for in vivo imaging applications in MRI, CT, FI, MRI-CT, MRI-FI, CT-FI, and MRI-CT-FI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In this study, we designed and synthesized a highly stable manganese (Mn 2+ )-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd 3+ ) chelates and evaluated its usage as a T 1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r 1 relaxivity (2.3 mM -1 s -1 ) than clinically approved Mn 2+ -based hepatobiliary complex Mn-DPDP (1.6 mM -1 s -1 ) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd 3+ -based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn 2+ chelate are comparable to those of Gd 3+ -based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.

D-glucuronic acid-coated ultrasmall chromium oxide (Cr2O3) nanoparticles were synthesized by a one-pot polyol method and their relaxometric and optical properties were investigated. The as-synthesized D-glucuronic acid-coated nanoparticles were amorphous owing to ultrasmall particle diameters (davg = 2.0 nm), whereas orthorhombic Cr2O3 nanoparticles with two size groups (davg = 3.6 and 5.7 nm) were observed after thermogravimetric analysis (900 °C) as a result of particle growth. The nanoparticles exhibited size-dependent UV-visible absorption maxima at 238, 274, and 372 nm with increasing particle diameter, corresponding to band gaps of 5.13, 4.45, and 3.28 eV, respectively. D-glucuronic acid-coated ultrasmall Cr2O3 nanoparticles revealed low water proton relaxivities of r1 = 0.05 s-1mM-1 and r2 = 0.20 s-1mM-1, consistent with the antiferromagnetic property of Cr2O3. They showed good biocompatibility up to 500 μM of Cr.

Monodisperse and ultrasmall gadolinium oxide (Gd 2 O 3 ) nanoparticle colloids ( d avg = 1.5 nm) (nanoparticle colloid = nanoparticle coated with hydrophilic ligand) were synthesized and their performance as a multifunctional tumor theragnostic agent was investigated. The aqueous ultrasmall nanoparticle colloidal suspension was stable and non-toxic owing to hydrophilic polyacrylic acid (PAA) coating that was partly conjugated with rhodamine B (Rho) for an additional functionalization (mole ratio of PAA : Rho = 5 : 1). First, the ultrasmall nanoparticle colloids performed well as a powerful T 1 magnetic resonance imaging (MRI) contrast agent: they exhibited a very high longitudinal water proton relaxivity ( r 1 ) of 22.6 s -1 mM -1 ( r 2 / r 1 = 1.3, r 2 = transverse water proton relaxivity), which was ∼6 times higher than those of commercial Gd-chelates, and high positive contrast enhancements in T 1 MR images in a nude mouse after intravenous administration. Second, the ultrasmall nanoparticle colloids were applied to gadolinium neutron capture therapy (GdNCT) in vitro and exhibited a significant U87MG tumor cell death (28.1% net value) after thermal neutron beam irradiation, which was 1.75 times higher than that obtained using commercial Gadovist. Third, the ultrasmall nanoparticle colloids exhibited stronger fluorescent intensities in tumor cells than in normal cells owing to conjugated Rho, proving their pH-sensitive fluorescent tumor cell detection ability. All these results together demonstrate that ultrasmall Gd 2 O 3 nanoparticle colloids are the potential multifunctional tumor theragnostic agent., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

For use as positive ( T 1 ) magnetic resonance imaging contrast agents (MRI-CAs), gadolinium oxide (Gd 2 O 3 ) nanoparticle colloids ( i.e. nanoparticles coated with hydrophilic ligands) should be stable, non-toxic, and ultrasmall in particle diameter for renal excretion. In addition, they should have a high longitudinal water proton relaxivity ( r 1 ) and r 2 / r 1 ratio that is close to one ( r 2 = transverse water proton relaxivity) for high-performance. In this study, we report ultrasmall Gd 2 O 3 nanoparticle colloids [coating material = polyacrylic acid, M w = ∼5100 Da] satisfying these conditions. The particle diameter was monodisperse with an average value of 2.0 ± 0.1 nm. The colloidal suspension exhibited a high r 1 value of 31.0 ± 0.1 s -1 mM -1 and r 2 / r 1 ratio of 1.2, where r 1 was ∼8 times higher than that of commercial Gd-chelates: the cooperative induction model was proposed to explain this. The effectiveness of the colloidal suspension as a high-performance T 1 MRI-CA was confirmed by taking in vivo T 1 MR images in a mouse after intravenous administration. Highly positive contrast enhancements were observed in various organs of the mouse such as the liver, kidneys, and bladder. The colloidal suspension was then excreted through the bladder., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A new type of dual-mode T1 and T2 magnetic resonance imaging (MRI) contrast agent based on mixed lanthanide oxide nanoparticles was synthesized. Gd(3+) ((8)S7/2) plays an important role in T1 MRI contrast agents because of its large electron spin magnetic moment resulting from its seven unpaired 4f-electrons, and Dy(3+) ((6)H15/2) has the potential to be used in T2 MRI contrast agents because of its very large total electron magnetic moment: among lanthanide oxide nanoparticles, Dy2O3 nanoparticles have the largest magnetic moments at room temperature. Using these properties of Gd(3+) and Dy(3+) and their oxide nanoparticles, ultrasmall mixed gadolinium-dysprosium oxide (GDO) nanoparticles were synthesized and their potential to act as a dual-mode T1 and T2 MRI contrast agent was investigated in vitro and in vivo. The D-glucuronic acid coated GDO nanoparticles (davg = 1.0 nm) showed large r1 and r2 values (r2/r1 ≈ 6.6) and as a result clear dose-dependent contrast enhancements in R1 and R2 map images. Finally, the dual-mode imaging capability of the nanoparticles was confirmed by obtaining in vivo T1 and T2 MR images.

Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron ((10)B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis).

Magnetic resonance imaging (MRI) contrast agents have been used routinely for more than 20 years in order to increase sensitivity and specificity of lesion detection. MRI contrast agents (CAs) are usually categorized according to their magnetic behavior, biodistribution, and effect on the MR image. Typically, small molecular-weight gadolinium based CAs are examples of T1 agents, while magnetic nanoparticle (MNP) based CAs are examples of T2 agents. In addition to differences in magnetic relaxation behavior, small molecular-weight gadolinium based CAs and MNP based CAs show significantly different toxicity profiles. In the case of small molecular-weight gadolinium based CAs, many previous toxicological studies have reported favorable safety profiles of gadolinium based CAs. However, recently, a delayed serious adverse reaction known as nephrogenic systemic fibrosis (NSF) has been reported in patients, with a marked reduction in renal function after administration of certain types of gadolinium based CAs. For MNP based CAs, in addition to a wide spectrum of nanotoxicity common in nanomaterials, the emerging unexpected cytotoxicity of MNPs has become a new concern. Specifically, the combination of MNPs and strong static magnetic field (SMF) within MRI may give rise to potential adverse effects of MNPs in clinical application.

We report here paramagnetic dysprosium nanomaterial-based T(2) MRI contrast agents. A large r(2) and a negligible r(1) is an ideal condition for T(2) MR imaging. At this condition, protons are strongly and nearly exclusively induced for T(2) MR imaging. The dysprosium nanomaterials fairly satisfy this because they are found to possess a decent r(2) but a negligible r(1) arising from L + S state 4f-electrons in Dy(III) ion ((6)H(15/2)). Their r(2) will also further increase with increasing applied field because of unsaturated magnetization at room temperature. Therefore, MR imaging and various physical properties of the synthesized d-glucuronic acid coated ultrasmall dysprosium oxide nanoparticles (d(avg) = 3.2 nm) and dysprosium hydroxide nanorods (20 × 300 nm) are investigated. These include hydrodynamic diameters, magnetic properties, MR relaxivities, cytotoxicities, and 3 tesla in vivo T(2) MR images. Here, MR imaging properties of dysprosium hydroxide nanorods have not been reported so far. These two samples show r(2)s of 65.04 and 181.57 s(-1)mM(-1), respectively, with negligible r(1)s at 1.5 tesla and at room temperature, no in vitro cytotoxicity up to 100 μM Dy, and clear negative contrast enhancements in 3 tesla in vivo T(2) MR images of a mouse liver, which will be even more improved at higher MR fields. Therefore, d-glucuronic acid coated ultrasmall dysprosium oxide nanoparticles with renal excretion can be a potential candidate as a sensitive T(2) MRI contrast agent at MR field greater than 3 tesla., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Biomedical applications of magnetic nanoparticles (MNP), including superparamagnetic nanoparticles, have expanded dramatically in recent years. Systematic and standardized cytotoxicity assessment to ensure the biosafety and biocompatibility of those applications is compulsory. We investigated whether exposure to static magnetic field (SMF) from e.g. magnetic resonance imaging (MRI) could affect the cytotoxicity of superparamagnetic iron oxide (SPIO) nanoparticles using mouse hepatocytes and ferucarbotran, a liver-selective MRI contrast agent as a model system. We show that while the SPIO satisfied the conventional cytotoxicity assessment, clinical doses combined with SMF exposure exerts synergistic adverse effects such as reduced cell viability, apoptosis, and cell cycle aberrations on hepatocytes in vitro and in vivo. Concomitant treatments with the SPIO and SMF generated SPIO aggregates, which demonstrated enhanced cellular uptake, was sufficient to induce the cytotoxicity without further SMF, emphasizing that the SPIO aggregates were the predominant source of the cytotoxicity. Interestingly, the apoptotic effect was dependent on levels of reactive oxygen species (ROS) and SPIO uptake while the reduced cell viability was independent of these factors. Moreover, long-term monitoring showed a significant increase in multinuclear giant cells in the cells concomitantly treated with the SPIO and SMF compared with the control. The results demonstrate that the SPIO produces unidentified cytotoxicity on liver in the presence of SMF and the SPIO aggregates predominantly exert the effect. Since aggregation of MNP in biological milieu in the presence of strong SMF is inevitable, a fundamentally different approach to surface fabrication is essential to increase the biocompatibility of MNP., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Gd-complexes of the type [Gd(L)(H(2)O)]·xH(2)O (5a-c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K(GdL)) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R(1)-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T(1)-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs.

We report a facile one-pot synthesis of Fe3O4-CdX (X=S, Se) core-shell nanoparticles and characterized them with XRD, TEM, squid magnetometer, and UV-visible absorption and PL spectrometers. We observed that the core Fe3O4 nanoparticles showed a superparamagnetism at room temperature, whereas the shell CdX (X=S, Se) showed blue-shifts from the bulk materials in UV-visible absorption spectra, due to quantum confinement effect. These superparamagnetic and optical properties of the Fe3O4-CdX (X=S, Se) core-shell nanoparticles can be used for both MR and optical imagings. This dual imaging capability will increase a possibility of an early observation of disease such as cancer.

We report the first magnetic study of pure and metastable hexagonal close-packed (hcp) Ni nanoparticles (sample 1). We also produced stable face-centered cubic (fcc) Ni nanoparticles, as mixtures with the hcp Ni nanoparticles (samples 2 and 3). We compared the magnetic properties of the hcp Ni nanoparticles with those of the fcc Ni nanoparticles by observing the evolution of magnetic properties from those of the hcp Ni nanoparticles to those of the fcc Ni nanoparticles as the number of fcc Ni nanoparticles increased from sample 1 to sample 3. The blocking temperature (T(B)) of the hcp Ni nanoparticles is approximately 12 K for particle diameters ranging between 8.5 and 18 nm, whereas those of the fcc Ni nanoparticles are 250 and 270 K for average particle diameters of 18 and 26 nm, respectively. The hcp Ni nanoparticles seem to be antiferromagnetic for T < T(B) and paramagnetic for T > T(B). This is very different from the fcc Ni nanoparticles, which are ferromagnetic for T < T(B) and superparamagnetic for T > T(B). This unusual magnetic state of the metastable hcp Ni nanoparticles is likely related to their increased bond distance (2.665 angstroms), compared to that (2.499 angstroms) of the stable fcc Ni nanoparticles.