Non-Specific Zn2+ Ion Sensing Using Ultrasmall Gadolinium Oxide Nanoparticle as a Magnetic Resonance Imaging Contrast Agent.

The gadolinium oxide (Gd2O3) nanoparticles are well-known potential candidates for a positive magnetic resonance imaging (MRI) contrast agent owing to their large longitudinal water proton relaxivity (r1) value with r2/r1 ratio close to one (r2 = transverse water proton relaxivity). In addition they may be used to sense metal ions because their r1 and r2 values can be altered in the presence of metal ions. This may allow us to study metabolic processes involving metal ions and to diagnose disease related to abnormal concentrations of metal ions in the body in a non-invasive way. In this study ultrasmall Gd2O3 nanoparticles were for the first time applied to non-specifically sense Zn2+ ions in aqueous solution. We explored this by measuring r1 and r2 values in the presence of Zn2+ ions in solution.

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.

Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier.

Aging-induced alterations to the blood-brain barrier (BBB) are increasingly being seen as a primary event in chronic progressive neurological disorders that lead to cognitive decline. With the goal of increasing delivery into the brain in hopes of effectively treating these diseases, a large focus has been placed on developing BBB permeable materials. However, these strategies have suffered from a lack of specificity toward regions of disease progression. Here, we report on the development of a nanoparticle (C1C2-NP) that targets regions of increased claudin-1 expression that reduces BBB integrity. Using dynamic contrast enhanced magnetic resonance imaging, we find that C1C2-NP accumulation and retention is significantly increased in brains from 12 month-old mice as compared to nontargeted NPs and brains from 2 month-old mice. Furthermore, we find C1C2-NP accumulation in brain endothelial cells with high claudin-1 expression, suggesting target-specific binding of the NPs, which was validated through fluorescence imaging, in vitro testing, and biophysical analyses. Our results further suggest a role of claudin-1 in reducing BBB integrity during aging and show altered expression of claudin-1 can be actively targeted with NPs. These findings could help develop strategies for longitudinal monitoring of tight junction protein expression changes during aging as well as be used as a delivery strategy for site-specific delivery of therapeutics at these early stages of disease development.

Smooth muscle cells affect differential nanoparticle accumulation in disturbed blood flow-induced murine atherosclerosis.

Atherosclerosis is a lipid-driven chronic inflammatory disease that leads to the formation of plaques in the inner lining of arteries. Plaques form over a range of phenotypes, the most severe of which is vulnerable to rupture and causes most of the clinically significant events. In this study, we evaluated the efficacy of nanoparticles (NPs) to differentiate between two plaque phenotypes based on accumulation kinetics in a mouse model of atherosclerosis. This model uses a perivascular cuff to induce two regions of disturbed wall shear stress (WSS) on the inner lining of the instrumented artery, low (upstream) and multidirectional (downstream), which, in turn, cause the development of an unstable and stable plaque phenotype, respectively. To evaluate the influence of each WSS condition, in addition to the final plaque phenotype, in determining NP uptake, mice were injected with NPs at intermediate and fully developed stages of plaque growth. The kinetics of artery wall uptake were assessed in vivo using dynamic contrast-enhanced magnetic resonance imaging. At the intermediate stage, there was no difference in NP uptake between the two WSS conditions, although both were different from the control arteries. At the fully-developed stage, however, NP uptake was reduced in plaques induced by low WSS, but not multidirectional WSS. Histological evaluation of plaques induced by low WSS revealed a significant inverse correlation between the presence of smooth muscle cells and NP accumulation, particularly at the plaque-lumen interface, which did not exist with other constituents (lipid and collagen) and was not present in plaques induced by multidirectional WSS. These findings demonstrate that NP accumulation can be used to differentiate between unstable and stable murine atherosclerosis, but accumulation kinetics are not directly influenced by the WSS condition. This tool could be used as a diagnostic to evaluate the efficacy of experimental therapeutics for atherosclerosis.

Ultrasmall Mixed Eu-Gd Oxide Nanoparticles for Multimodal Fluorescence and Magnetic Resonance Imaging of Passive Accumulation and Retention in TBI.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI can have a long-term impact on the quality of life for survivors of all ages. However, there remains no approved treatment that improves outcomes following TBI, which is partially due to poor delivery of therapies into the brain. Therefore, there is a significant unmet need to develop more effective delivery strategies that increase the accumulation and retention of potentially efficacious treatments in the injured brain. Recent work has revealed that nanoparticles (NPs) may offer a promising approach for site-specific delivery; however, a detailed understanding of the specific NP properties that promote brain accumulation and retention are still being developed. Multimodal imaging plays a vital role in the understanding of physicochemical properties that initiate the uptake and accumulation of NPs in the brain at both high spatial (e.g., fluorescence imaging) and temporal (e.g., magnetic resonance imaging, MRI) frequency. However, many NP systems that are currently used in TBI only provide contrast in a single imaging modality limiting the imaging data that can be obtained, and those that offer multimodal imaging capabilities have complicated multistep synthesis methods. Therefore, the goal of this work was to develop an ultrasmall NP with simple fabrication capable of multimodal imaging. Here, we describe the development, characterization, accumulation, and retention of poly(ethylene glycol) (PEG)-coated europium-gadolinium (Eu-Gd) mixed magnetic NPs (MNPs) in a controlled cortical impact mouse model of TBI. We find that these NPs having an ultrasmall core size of 2 nm and a small hydrodynamic size of 13.5 nm can be detected in both fluorescence and MR imaging modalities and rapidly accumulate and are retained in injured brain parenchyma. These NPs should allow for further testing of NP physicochemical properties that promote accumulation and retention in TBI and other disease models.

Water-soluble d-glucuronic acid coated ultrasmall mixed Ln/Mn (Ln = Gd and Dy) oxide nanoparticles and their application to magnetic resonance imaging.

Ultrasmall lanthanide oxide nanoparticles are promising materials as new magnetic resonance imaging (MRI) contrast agents because of their appreciable longitudinal (r1) or transverse (r2) water proton relaxivities at ultrasmall particle diameters. Two systems of d-glucuronic acid coated ultrasmall Ln/Mn (Ln = Gd and Dy) oxide nanoparticles with an average particle diameter of 2.0 nm were explored. The d-glucuronic acid coated ultrasmall Gd/Mn oxide nanoparticles showed strong positive contrast enhancements in 1.5 tesla T1 MR images while the d-glucuronic acid coated ultrasmall Dy/Mn oxide nanoparticles showed appreciable negative contrast enhancements in 1.5 tesla T2 MR images, proving their potential as T1 and T2 MRI contrast agents, respectively.

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.

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.

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.