High-Quantum-Yield Ultrasmall Ln2O3 (Ln = Eu, Tb, or Dy) Nanoparticle Colloids in Aqueous Media Obtained via Photosensitization.

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 Ln2O3 (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-Ln2O3 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.

Enhanced Tumor Imaging Using Glucosamine-Conjugated Polyacrylic Acid-Coated Ultrasmall Gadolinium Oxide Nanoparticles in Magnetic Resonance Imaging.

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) (davg = 1.76 nm). Higher positive (brighter or T1) 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 T1 MRI contrast agents in tumor imaging via GlcN effects.

In Vivo Positive Magnetic Resonance Imaging Applications of Poly(methyl vinyl ether-alt-maleic acid)-coated Ultra-small Paramagnetic Gadolinium Oxide Nanoparticles.

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.

Relaxometric, Optical and Cell Viability Properties of D-Glucuronic Acid Coated Cr2O3 Nanoparticles.

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.

Longitudinal Water Proton Relaxivity and In Vivo T1 MR Images of Mixed Zn(II)/Gd(III) Oxide Nanoparticles.

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.

Dual-mode T1 and T2 magnetic resonance imaging contrast agent based on ultrasmall mixed gadolinium-dysprosium oxide nanoparticles: synthesis, characterization, and in vivo application.

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.

Core-Shell Fe3O4@C Nanoparticles as Highly Effective T2 Magnetic Resonance Imaging Contrast Agents: In Vitro and In Vivo Studies.

Magnetite nanoparticles (Fe3O4 NPs) have been intensively investigated because of their potential biomedical applications due to their high saturation magnetization. In this study, core-shell Fe3O4@C NPs (core = Fe3O4 NPs and shell = amorphous carbons, davg = 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 Fe3O4@C NPs exhibited ideal relaxometric properties for T2 magnetic resonance imaging (MRI) contrast agents (i.e., high transverse and negligible longitudinal water proton spin relaxivities), making them exclusively induce only T2 relaxation. Their T2 MRI performance as contrast agents was confirmed in vivo by measuring T2 MR images in mice before and after intravenous injection.

Ultrasmall cerium oxide nanoparticles as highly sensitive X-ray contrast agents and their antioxidant effect.

Owing to their theranostic properties, cerium oxide (CeO2) nanoparticles have attracted considerable attention for their key applications in nanomedicine. In this study, ultrasmall CeO2 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 CeO2 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 CeO2 nanoparticles demonstrate potential as highly sensitive radioprotective or theranostic X-ray contrast agents.

Surface coated Eu(OH)3 nanorods: a facile synthesis, characterization, MR relaxivities and in vitro cytotoxicity.

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.

Magnetic Nanoparticle-Based High-Performance Positive and Negative Magnetic Resonance Imaging 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 (T1) or negative (T2) MRI contrast agents, producing brighter or darker MR images, respectively. In addition, they can function as dual-modal T1 and T2 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.

Heavy Metal-Based Nanoparticles as High-Performance X-ray Computed Tomography Contrast Agents.

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.

Production, surface modification, physicochemical properties, biocompatibility, and bioimaging applications of nanodiamonds.

Nanodiamonds (ND) are chemically inert and stable owing to their sp3 covalent bonding structure, but their surface sp2 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.

Facile Synthesis and X-ray Attenuation Properties of Ultrasmall Platinum Nanoparticles Grafted with Three Types of Hydrophilic Polymers.

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 (davg) 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.

Gadolinium Neutron Capture Therapy (GdNCT) Agents from Molecular to Nano: Current Status and Perspectives.

157Gd (natural abundance = 15.7%) has the highest thermal neutron capture cross section (σ) of 254,000 barns (1 barn = 10-28 m2) among stable (nonradioactive) isotopes in the periodic table. Another stable isotope, 155Gd (natural abundance = 14.8%), also has a high σ value of 60,700 barns. These σ values are higher than that of 10B (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.

Mono and Multiple Tumor-Targeting Ligand-Coated Ultrasmall Gadolinium Oxide Nanoparticles: Enhanced Tumor Imaging and Blood Circulation.

Hydrophilic and biocompatible PAA-coated ultrasmall Gd2O3 nanoparticles (davg = 1.7 nm) were synthesized and conjugated with tumor-targeting ligands, i.e., cyclic arginylglycylaspartic acid (cRGD) and/or folic acid (FA). FA-PAA-Gd2O3 and cRGD/FA-PAA-Gd2O3 nanoparticles were successfully applied in U87MG tumor-bearing mice for tumor imaging using T1 magnetic resonance imaging (MRI). cRGD/FA-PAA-Gd2O3 nanoparticles with multiple tumor-targeting ligands exhibited higher contrasts at the tumor site than FA-PAA-Gd2O3 nanoparticles with mono tumor-targeting ligands. In addition, the cRGD/FA-PAA-Gd2O3 nanoparticles exhibited higher contrasts in all organs, especially the aorta, compared with those of the FA-PAA-Gd2O3 nanoparticles, because of the blood cell hitchhiking effect of cRGD in the cRGD/FA-PAA-Gd2O3 nanoparticles, which prolonged their circulation in the blood.

Polyethylenimine-Coated Ultrasmall Holmium Oxide Nanoparticles: Synthesis, Characterization, Cytotoxicities, and Water Proton Spin Relaxivities.

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 (Mn = 1200 and 60,000 amu) were used as surface-coating ligands for ultrasmall holmium oxide (Ho2O3) nanoparticles. The synthesized PEI1200- and PEI60000-coated ultrasmall Ho2O3 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 (r2) of 13.1 and 9.9 s-1mM-1, respectively, in a 3.0 T MR field with negligible longitudinal water proton spin relaxivities (r1) (i.e., 0.1 s-1mM-1) for both samples. Consequently, for both samples, the dose-dependent contrast changes in the longitudinal (R1) and transverse (R2) relaxation rate map images were negligible and appreciable, respectively, indicating their potential as efficient transverse T2 MRI contrast agents in vitro.

Functionalized Lanthanide Oxide Nanoparticles for Tumor Targeting, Medical Imaging, and Therapy.

Recent progress in functionalized lanthanide oxide (Ln2O3) 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 Ln2O3 nanoparticles are applicable as MRI contrast agents for tumor-targeting and nontumor-targeting imaging and image-guided tumor therapy. Primarily, Gd2O3 nanoparticles have been intensively investigated as tumor-targeting T1 MRI contrast agents. T2 MRI is also possible due to the appreciable paramagnetic moments of Ln2O3 nanoparticles (Ln = Dy, Ho, and Tb) at room temperature arising from the nonzero orbital motion of 4f electrons. In addition, Ln2O3 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 Ln2O3 nanoparticles are also discussed.

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.

Chitosan Oligosaccharide Lactate-Coated Ultrasmall Gadolinium Oxide Nanoparticles: Synthesis, In Vitro Cytotoxicity, and Relaxometric Properties.

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 µM Gd. In addition, their water proton spin relaxivities (i.e., r1 and r2) were estimated to be 13.0 and 27.0 s-1mM-1, respectively, which are higher than those of commercial magnetic resonance imaging (MRI) contrast agents. The application potential of the solution sample as a T1 MRI contrast agent was demonstrated In Vitro by measuring map images in which dose-dependent contrast enhancements were observed.

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.