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In recent years, significant advances in enhancing the quantum yield (QY) of trivalent lanthanide (Ln 3+ ) ion-based nanoparticles have been achieved through photosensitization, using host matrices or capping organic ligands as photosensitizers to absorb incoming photons and transfer energy to the Ln 3+ ions. The Ln 3+ ion-based nanoparticles possess several excellent fluorescent properties, such as nearly constant transition energies, atomic-like sharp transitions, long emission lifetimes, large Stokes shifts, high photostability, and resistance to photobleaching; these properties make them more promising candidates as next-generation fluorescence probes in the visible region, compared with other traditional materials such as organic dyes and quantum dots. However, their QYs are generally low and thus need to be improved to facilitate and extend their applications. Considerable efforts have been made to improve the QYs of Ln 3+ ion-based nanoparticles through photosensitization. These efforts include the doping of Ln 3+ ions into host matrices or capping the nanoparticles with organic ligands. Among the Ln 3+ ion-based nanoparticles investigated in previous studies, this review focuses on those containing Eu 3+ , Tb 3+ , and Dy 3+ ions with red, green, and yellow emission colors, respectively. The emission intensities of Eu 3+ and Tb 3+ ions are stronger than those of other Ln 3+ ions; therefore, the majority of the reported studies focused on Eu 3+ and Tb 3+ ion-based nanoparticles. This review discusses the principles of photosensitization, several examples of photosensitized Ln 3+ ion-based nanoparticles, and in vitro and in vivo biomedical fluorescent imaging (FI) applications. This information provides valuable insight into the development of Ln 3+ ion-based nanoparticles with high QYs through photosensitization, with future potential applications in biomedical FI.

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.

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.

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.

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.

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.

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.

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.)

Recent progress in functionalized lanthanide oxide (Ln 2 O 3 ) nanoparticles for tumor targeting, medical imaging, and therapy is reviewed. Among the medical imaging techniques, magnetic resonance imaging (MRI) is an important noninvasive imaging tool for tumor diagnosis due to its high spatial resolution and excellent imaging contrast, especially when contrast agents are used. However, commercially available low-molecular-weight MRI contrast agents exhibit several shortcomings, such as nonspecificity for the tissue of interest and rapid excretion in vivo. Recently, nanoparticle-based MRI contrast agents have become a hot research topic in biomedical imaging due to their high performance, easy surface functionalization, and low toxicity. Among them, functionalized Ln 2 O 3 nanoparticles are applicable as MRI contrast agents for tumor-targeting and nontumor-targeting imaging and image-guided tumor therapy. Primarily, Gd 2 O 3 nanoparticles have been intensively investigated as tumor-targeting T 1 MRI contrast agents. T 2 MRI is also possible due to the appreciable paramagnetic moments of Ln 2 O 3 nanoparticles (Ln = Dy, Ho, and Tb) at room temperature arising from the nonzero orbital motion of 4f electrons. In addition, Ln 2 O 3 nanoparticles are eligible as X-ray computed tomography contrast agents because of their high X-ray attenuation power. Since nanoparticle toxicity is of great concern, recent toxicity studies on Ln 2 O 3 nanoparticles are also discussed.

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 , 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 , 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.

Polyacrylic acid (PAA)-coated lanthanide oxide (Ln 2 O 3 ) nanoparticles (NPs) (Ln = Tb and Ho) with high colloidal stability and good biocompatibility were synthesized, characterized, and investigated as a new class of negative (T 2 ) magnetic resonance imaging (MRI) contrast agents at high MR fields. Their r 2 values were appreciable at a 3.0 T MR field and higher at a 9.4 T MR field, whereas their r 1 values were negligible at all MR fields, indicating their exclusive induction of T 2 relaxations with negligible induction of T 1 relaxations. Their effectiveness as T 2 MRI contrast agents at high MR fields was confirmed from strong negative contrast enhancements in in vivo T 2 MR images at a 9.4 T MR field after intravenous administration into mice tails.

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.

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 T 2 MRI contrast agent. In this study, carbon-coated paramagnetic dysprosium oxide (DYO@C) nanoparticles (core = DYO = Dy x O y ; shell = carbon) were synthesized to explore their potential as an efficient T 2 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) ( 6 H 15/2 ), the DYO@C nanoparticles exhibited an appreciable transverse water proton spin relaxivity (r 2 ) with a negligible longitudinal water proton spin relaxivity (r 1 ). Consequently, they acted as a very efficient T 2 MRI contrast agent, as proven from negative contrast enhancements seen in the in vivo T 2 MR images.

The study of ultra-small paramagnetic gadolinium oxide (Gd 2 O 3 ) nanoparticles (NPs) as in vivo positive (T 1 ) magnetic resonance imaging (MRI) contrast agents is one of the most attractive fields in nanomedicine. The performance of the Gd 2 O 3 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 Gd 2 O 3 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 (r 1 ) value of 36.2 s -1 mM -1 (r 2 /r 1 = 2.0; r 2 = transverse water proton spin relaxivity) under a 3.0 tesla MR field which is approximately 10 times higher than the r 1 values of commercial molecular contrast agents. High positive contrast enhancements were observed in in vivo T 1 MR images after intravenous administration of the NP solution sample, demonstrating its potential as a T 1 MRI contrast agent.

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 = 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 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 = transverse water proton relaxivity), which was ∼6 times higher than those of commercial Gd-chelates, and high positive contrast enhancements in T 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.)

Mixed Zn(II)/Gd(III) oxide nanoparticles (~8 mole%Zn) with d(avg) of 2.1 nm were synthesized. The D-glucuronic acid coated Zn(II)/Gd(III) oxide nanoparticles showed a longitudinal water proton relaxivity (r₁) of 12.3 s⁻¹mM⁻¹ with r₂/r₁ = 1.1, corresponding to an ideal condition for T₁ MRI contrast agent. We attribute this to reduced magnetization of the mixed nanoparticles owing to non-magnetic Zn in the nanoparticles. Their effectiveness as a T₁ MRI contrast agent was confirmed by acquiring In Vivo T₁ MR images of a mouse after intravenous injection.

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.

The water-soluble and biocompatible D-glucuronic acid coated Eu(OH)3 nanorods (average thickness x average length = 9.0 x 118.3 nm) have been prepared in one-pot synthesis. The D-glucuronic acid coated Eu(OH)3 nanorods showed a strong fluorescence at approximately 600 nm with a narrow emission band width. A cytotoxicity test by using DU145 cells showed that D-glucuronic acid coated Eu(OH)3 nanorods are not toxic up to 100 microM, making them a promising candidate for biomedical applications such as fluorescent imaging. The minimum Eu concentration needed for a conventional confocal imaging was estimated to be approximately 0.1 mM. Therefore, D-glucuronic acid coated Eu(OH)3 nanorods can be applied to fluorescent imaging. However, a very tiny magnetization of approximately 1.2 emu/g at room temperature and at an applied field of 5 tesla was observed. As a result, very small r1 and r2 water proton relaxivities were estimated, implying that surface coated Eu(OH)3 nanorods are not sufficient for MRI contrast agents.