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.

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.

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.

Monodisperse and ultrasmall gadolinium oxide (Gd2O3) 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 T1 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 T1 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 Gd2O3 nanoparticle colloids are the potential multifunctional tumor theragnostic agent.

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.

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.

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.

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) 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.

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.

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) (Mw = ~3000 amu) is explored as a surface-coating ligand of ultrasmall gadolinium oxide (Gd2O3) 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 Gd2O3 nanoparticles (davg = 1.8 nm and aavg = 9.0 nm) exhibit excellent colloidal stability, extremely low cellular toxicity, and a high longitudinal water proton spin relaxivity (r1) of 40.6 s-1mM-1 (r2/r1 = 1.56, where r2 = transverse water proton spin relaxivity), which is approximately 10 times higher than those of commercial molecular contrast agents. The effectiveness of PAAMA-coated ultrasmall Gd2O3 nanoparticles as a T1 MRI contrast agent is confirmed by the high positive contrast enhancements of the in vivo T1 MR images at the 3.0 T MR field.