Uniform and extremely small-sized iron oxide nanoparticles (ESIONs) of < 4 nm were synthesized via the thermal decomposition of iron-oleate complex in the presence of oleyl alcohol. Oleyl alcohol lowered the reaction temperature by reducing iron-oleate complex, resulting in the production of small-sized nanoparticles. XRD pattern of 3 nm-sized nanoparticles revealed maghemite crystal structure. These nanoparticles exhibited very low magnetization derived from the spin-canting effect. The hydrophobic nanoparticles can be easily transformed to water-dispersible and biocompatible nanoparticles by capping with the poly(ethylene glycol)-derivatized phosphine oxide (PO-PEG) ligands. Toxic response was not observed with Fe concentration up to 100 μg/mL in MTT cell proliferation assay of POPEG-capped 3 nm-sized iron oxide nanoparticles. The 3 nm-sized nanoparticles exhibited a high r(1) relaxivity of 4.78 mM(-1) s(-1) and low r(2)/r(1) ratio of 6.12, demonstrating that ESIONs can be efficient T(1) contrast agents. The high r(1) relaxivities of ESIONs can be attributed to the large number of surface Fe(3+) ions with 5 unpaired valence electrons. In the in vivo T(1)-weighted magnetic resonance imaging (MRI), ESIONs showed longer circulation time than the clinically used gadolinium complex-based contrast agent, enabling high-resolution imaging. High-resolution blood pool MR imaging using ESIONs enabled clear observation of various blood vessels with sizes down to 0.2 mm. These results demonstrate the potential of ESIONs as T(1) MRI contrast agents in clinical settings.

The theoretically predicted maximum r(2) relaxivity of iron oxide nanoparticles was achieved by optimizing the overall size of ferrimagnetic iron oxide nanocubes. Uniform-sized iron oxide nanocubes with an edge length of 22 nm, encapsulated with PEG-phospholipids (WFION), exhibited high colloidal stability in aqueous media. In addition, WFIONs are biocompatible and did not affect cell viability at concentrations up to 0.75 mg Fe/ml. Owing to the enhanced colloidal stability and the high r(2) relaxivity (761 mM(-1) s(-1)), it was possible to successfully perform in vivo MR imaging of tumors by intravenous injection of 22-nm-sized WFIONs, using a clinical 3-T MR scanner.

Dual-modal in vivo tumor imaging and photodynamic therapy using hexagonal NaYF(4):Yb,Er/NaGdF(4) core-shell upconverting nanoparticles combined with a photosensitizer, chlorin e6, is reported. Tumors can be clearly observed not only in the upconversion luminescence image but also in the magnetic resonance image. In vivo photodynamic therapy by systemic administration is demonstrated under 980 nm irradiation.

For ultrasensitive magnetic resonance imaging (MRI), magnetic nanoparticles with extremely high r2 relaxivity are strongly desired. Magnetosome-like nanoparticles were prepared by coating polyethylene glycol-phospholipid (PEG-phospholipid) onto ferrimagnetic iron oxide nanocubes (FIONs). FIONs exhibited a very high relaxivity (r2) of 324 mM −1 s −1 , allowing efficient labeling of various kinds of cells. The magnetic resonance (MR) imaging of single cells labeled with FIONs is demonstrated not only in vitro but also in vivo. Pancreatic islet grafts and their rejection could be imaged using FIONs on a 1.5 T clinical MRI scanner. The strong contrast effect of FIONs enabled MR imaging of transplanted islets in small rodents as well as in large animals. Therefore, we expect that MR imaging of pancreatic islet grafts using FIONs has the potentials for clinical applications. Furthermore, FIONs will enable highly sensitive noninvasive assessment after cell transplantation.cell tracking | contrast agent | molecular imaging | diabetes | islet transplantation

BACKGROUND AND PURPOSE:Dynamic contrast-enhanced T1-weighted perfusion MR imaging is much less susceptible to artifacts, and its high spatial resolution allows accurate characterization of the vascular microenvironment of the lesion. The purpose of this study was to test the predictive value of the initial and final area under the time signal-intensity curves ratio derived from dynamic contrastenhanced perfusion MR imaging to differentiate pseudoprogression from early tumor progression in patients with glioblastomas.

Vascular disrupting agents (VDAs) are new class of anti-cancer drugs targeting pre-existing tumor vasculature which lead to tumor ischemia and necrosis. An innovative tubulin polymerization inhibitor, CKD-516, was recently developed as a VDA. We attempted to evaluate its tubulin destabilizing effect using immunofluorescence staining on human endothelial cells (HUVECs) and to ascertain its antivascular effect in a rabbit VX2 tumor model using dynamic contrast-enhanced (DCE) MRI by measuring the changes in kinetic parameters such as K-trans and IAUGC. Immunofluorescence staining using anti-tubulin and anti-actin antibodies on HUVECs showed that CKD-516 selectively disrupted tubulin component of the endothelial cytoskeleton. Serial DCE-MRI showed a significant decrease in K-trans and IAUGC parameters from baseline at 4 h (39.9 % in K-trans; -45.0 % in IAUGC) and at 24 h (-32.2 % in K-trans; -36.5 % in IAUGC), and a significant recovery at 48 h (22.9 % in K-trans; 34.8 % in IAUGC) following administration of CKD-516 at a 0.7-mg/kg dose. When the tumors were stratified according to the initial K-trans value of 0.1, tumors with a high K-trans > 0.1 which was indicative of having well-developed pre-existing vessels, showed greater reduction in K-trans and IAUGC values. On histologic examination, the degree of necrosis of treated tumors was significantly greater than that of untreated tumors. In summary, CKD-516 is an effective VDA which results in rapid vascular shutdown by targeting the tubulin component of tumor vessels and thus leads to necrosis.

This study was undertaken to investigate the in vitro effect of islet labeling with iron oxide nanoparticles for MRI on islet viability, insulin secretion, and gene expression. Isolated rat islets were labeled with Resovist (25-200 microg Fe/mL, a clinically approved MRI contrast agent) in the presence or absence of poly-l-Lysine (PLL, 1.5 microg/mL) for 48 h. The iron content of labeled islets was found to increase in a dose-dependent manner. More than 90% of the islets were labeled with 100 microg Fe/mL. We confirmed the localizations of iron oxide nanoparticles within islet beta-cells by insulin immunostaining. As the concentration of Resovist increased, T(2) values as determined by T(2)-weighted MRI on a 1.5 Tesla MR scanner decreased. Labeling of 100 islets in a medium containing 100 microg Fe/mL of Resovist in the absence of PLL provided sufficient contrast for islet visualization on T(2)-weighted MRI. MTT assays showed that the viability of labeled islets was not different from that of unlabeled islets. No statistical difference was observed between labeled (2.91 +/- 0.36) and unlabeled islets (2.83 +/- 0.61) in terms of the ability to secrete insulin, as determined by the glucose stimulation index. We also evaluated the effect of iron oxide incorporation on the gene expressions in islet cells using RT-PCR (reverse transcriptase PCR). Insulin expression in labeled islets was significantly elevated (1.83 +/- 0.25 fold vs. unlabeled; p = 0.005), but not the expression of somatostatin (1.39 +/- 0.18 fold vs. unlabeled; p = 0.085) or glucagons (1.28 +/- 0.13 fold vs. unlabeled; p = 0.09). Expression of an important transcription factor for insulin gene transcription, BETA2 (beta-cell E-box trans-activator), was increased in labeled islets (1.67 +/- 0.15 fold vs. unlabeled; p = 0.029). The findings of this study indicate that Resovist provides a satisfactory means to image islets and has no deleterious effect on islet function or gene expression.

Gadolinium ethoxybenzyl dimeglumine (gadoxetate) is a recently developed hepatocyte-specific MRI contrast medium. Gadoxetate demonstrates unique pharmacokinetic and pharmacodynamic properties, because its uptake in hepatocytes occurs via the organic anion transporting polypeptide (OATP) transporter expressed at the sinusoidal membrane, and its biliary excretion via the multidrug resistance-associated proteins (MRPs) at the canalicular membrane. Based on these characteristics, gadoxetate-enhanced MRI can provide functional information on hepatobiliary diseases, including liver function estimation, biliary drainage evaluation and characterization of hepatocarcinogenesis. In addition, understanding its mode of action can provide an opportunity to use gadoxetate for cellular and molecular imaging. Radiologists and imaging scientists should be familiar with the basic mechanism of gadoxetate and OATP/MRP transporters.