Kwon Seok Chae

Paramagnetic Ultrasmall Gadolinium Oxide Nanoparticles as Advanced T1 MRI Contrast Agent: Account for Large Longitudinal Relaxivity, Optimal Particle Diameter, and In Vivo T1 MR Images

Paramagnetic ultrasmall gadolinium oxide (Gd(2)O(3)) nanoparticles with particle diameters (d) of approximately 1 nm were synthesized by using three kinds of Gd(III) ion precursors and by refluxing each of them in tripropylene glycol under an O(2) flow. A large longitudinal relaxivity (r(1)) of water proton of 9.9 s(-1) mM(-1) was estimated. As a result, high contrast in vivo T(1) MR images of the brain tumor of a rat were observed. This large r(1) is discussed in terms of the huge surface to volume ratio (S/V) of the ultrasmall gadolinium oxide nanoparticles coupled with the cooperative induction of surface Gd(III) ions for the longitudinal relaxation of a water proton. It is found from the d dependence of r(1) that the optimal range of d for the maximal r(1), which may be used as an advanced T(1) MRI contrast agent, is 1-2.5 nm.

A Facile Synthesis, In vitro and In vivo MR Studies of d-Glucuronic Acid-Coated Ultrasmall Ln2O3 (Ln = Eu, Gd, Dy, Ho, and Er) Nanoparticles as a New Potential MRI Contrast Agent

A facile one-pot synthesis of d-glucuronic acid-coated ultrasmall Ln(2)O(3) (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles is presented. Their water proton relaxivities were studied to address their possibility as a new potential MRI contrast agent. We focused on the d-glucuronic acid-coated ultrasmall Dy(2)O(3) nanoparticle because it showed the highest r(2) relaxivity among studied nanoparticles. Its performance as a T(2) MRI contrast agent was for the first time proved in vivo through its 3 T T(2) MR images of a mouse, showing that it can be further exploited for the rational design of a new T(2) MRI contrast agent at high MR fields.

Water-Soluble MnO Nanocolloid for a Molecular T1 MR Imaging: A Facile One-Pot Synthesis, In vivo T1 MR Images, and Account for Relaxivities

A facile one-pot synthesis of a water-soluble MnO nanocolloid (i.e., D-glucuronic acid-coated MnO nanoparticle) is presented. The MnO nanoparticle in the MnO nanocolloid was coated with a biocompatible and hydrophilic D-glucuronic acid, and its particle diameter was nearly monodisperse and ranged from 2 to 3 nm. The average hydrodynamic diameter of the MnO nanocolloid was estimated to be 5 nm. The MnO nanoparticle was nearly paramagnetic down to T=3 K. The MnO nanocolloid showed a high longitudinal water proton relaxivity of r1=7.02 s(-1) mM(-1) with the r2/r1 ratio of 6.83 due to five unpaired S-state electrons of Mn(II) ion (S=5/2) as well as a high surface to volume ratio of the MnO nanoparticle. High contrast in vivo T1 MR images were obtained for various organs, showing the capability of the MnO nanocolloid as a sensitive T1 MRI contrast agent. The suggested three key-parameters which control the r1 and r2 relaxivities of nanocolloids (i.e., the S value of a metal ion, the spin structure, and the surface to volume ratio of a nanoparticle) successfully accounted for the observed r1 and r2 relaxivities of the MnO nanocolloid.

NF-κB Activates Transcription of the RNA-Binding Factor HuR, via PI3K-AKT Signaling, to Promote Gastric Tumorigenesis

BACKGROUND & AIMS HuR is a RNA-binding factor whose expression is commonly upregulated in some human tumor types. We explored the molecular mechanism underlying HuR elevation and its role in gastric cancer tumorigenesis. METHODS HuR expression and subcellular localization were determined by polymerase chain reaction, immunoblot, and immunohistochemical analyses. Its effect on tumor growth was characterized using flow cytometry, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and soft agar analyses. Luciferase reporter, chromatin immunoprecipitation, and electrophoretic mobility shift assays were used to measure transcriptional activation by nuclear factor kappaB (NF-kappaB) signaling. RESULTS Compared with normal gastric tissues, HuR was expressed at higher levels in gastric tumors, particularly in advanced versus early tumors; this increase was associated with enhanced cytoplasmic translocation of HuR. HuR overexpression increased proliferation of tumor cells, activating the G(1) to S transition of the cell cycle, DNA synthesis, and anchorage-independent growth. Small interfering RNA-mediated knockdown of HuR expression reduced tumor cell proliferation and response to apoptotic stimuli. No genetic or epigenetic alterations of HuR were observed in gastric tumor cell lines or primary tumors; overexpression depended on phosphatidylinositol 3-kinase/AKT signaling and NF-kappaB activity. AKT activation increased p65/RelA binding to a putative NF-kappaB binding site in the HuR promoter, the stability of HuR target transcripts, and the cytoplasmic import of HuR. CONCLUSIONS HuR is a direct transcription target of NF-kappaB; its activation in gastric cancer cell lines depends on phosphatidylinositol 3-kinase/AKT signaling. HuR activation by this pathway has proliferative and antiapoptotic effects on gastric cancer cells.

Potential dual imaging nanoparticle: Gd2O3 nanoparticle

Gadolinium (Gd) is a unique and powerful element in chemistry and biomedicine which can be applied simultaneously to magnetic resonance imaging (MRI), X-ray computed tomography (CT), and neutron capture therapy for cancers. This multifunctionality can be maximized using gadolinium oxide (Gd2O3) nanoparticles (GNPs) because of the large amount of Gd per GNP, making both diagnosis and therapy (i.e., theragnosis) for cancers possible using only GNPs. In this study, the T1 MRI and CT dual imaging capability of GNPs is explored by synthesizing various iodine compound (IC) coated GNPs (IC-GNPs). All the IC-GNP samples showed stronger X-ray absorption and larger longitudinal water proton relaxivities (r1 = 26–38 s−1mM−1 and r2/r1 = 1.4–1.9) than the respective commercial contrast agents. In vivo T1 MR and CT images of mice were also acquired, supporting that the GNP is a potential dual imaging agent.

Paramagnetic dysprosium oxide nanoparticles and dysprosium hydroxide nanorods as T2 MRI contrast agents

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.

Gadolinium Oxide Nanoparticles as Potential Multimodal Imaging and Therapeutic Agents

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).

Mixed lanthanide oxide nanoparticles as dual imaging agent in biomedicine

There is no doubt that the molecular imaging is an extremely important technique in diagnosing diseases. Dual imaging is emerging as a step forward in molecular imaging technique because it can provide us with more information useful for diagnosing diseases than single imaging. Therefore, diverse dual imaging modalities should be developed. Molecular imaging generally relies on imaging agents. Mixed lanthanide oxide nanoparticles could be valuable materials for dual magnetic resonance imaging (MRI)-fluorescent imaging (FI) because they have both excellent and diverse magnetic and fluorescent properties useful for dual MRI-FI, depending on lanthanide ions used. Since they are mixed nanoparticles, they are compact, robust, and stable, which is extremely useful for biomedical applications. They can be also easily synthesized with facile composition control. In this study, we explored three systems of ultrasmall mixed lanthanide (Dy/Eu, Ho/Eu, and Ho/Tb) oxide nanoparticles to demonstrate their usefulness as dual T2 MRI–FI agents.

Fluorescein-polyethyleneimine coated gadolinium oxide nanoparticles as T1 magnetic resonance imaging (MRI)–cell labeling (CL) dual agents

We report the synthesis, characterization and application of highly water-soluble fluorescein-polyethyleneimine (PEI) coated gadolinium oxide (Gd2O3) nanoparticles to magnetic resonance imaging (MRI) and cell labeling (CL). The average particle diameter and average hydrodynamic diameter were estimated to be 3.92 and 7.5 nm, respectively. Fluorescein-PEI was prepared from EDC/NHS coupling method. The surface coating was characterized by the FT-IR absorption spectrum and the surface coating amount was estimated to be 22.42 wt% from a TGA analysis, corresponding to 0.65 nm−2 grafting density. The fluorescein-PEI coated gadolinium oxide nanoparticles showed r1 and r2 of 6.76 and 20.27 s−1mM−1, respectively, and a strong fluorescence at ∼527 nm. A pronounced positive contrast enhancement was clearly observed in 3 tesla T1 MR images of a rat with a liver tumor after injection of an aqueous sample solution into a rat tail vein. After treatment of DU145 cells with a sample solution, a strong fluorescence in confocal images was also observed. These two results together confirm the excellent MRI-CL dual functionality of fluorescein-PEI coated gadolinium oxide nanoparticles.

A T1, T2 magnetic resonance imaging (MRI)-fluorescent imaging (FI) by using ultrasmall mixed gadolinium–europium oxide nanoparticles

Multiple molecular imaging is a challenging subject. Water-soluble and biocompatible lactobionic acid coated ultrasmall mixed gadolinium–europium oxide nanoparticles with an average particle diameter of 1.75 nm and an average hydrodynamic diameter of 4.16 nm were synthesized and applied for T1, T2 MRI-FI in vitro and in vivo. They had r1 and r2 values of 11.9 and 38.7 s−1 mM−1, respectively, and showed clear dose-dependent contrast changes in both R1 and R2 map images. In addition, they showed both positive and negative contrast enhancements in 3 tesla T1 and T2 MR images in a mouse, respectively, and fluorescent confocal images in both DU145 cells and C. elegans (a small nematode). This study demonstrates the T1, T2 MRI-FI multi-functionality of lactobionic acid coated mixed gadolinium–europium oxide nanoparticles.