The majority of contrast agents used in magnetic resonance imaging (MRI) is based on the rare-earth element gadolinium. Gadolinium-based nanoparticles could find promising applications in pre-clinical diagnostic procedures of certain types of cancer, such as glioblastoma multiforme. This is one of the most malignant, lethal and poorly accessible forms of cancer. Recent advances in colloidal nanocrystal synthesis have led to the development of ultra-small crystals of gadolinium oxide (US-Gd(2)O(3), 2-3 nm diameter). As of today, this is the smallest and the densest of all Gd-containing nanoparticles. Cancer cells labeled with a sufficient quantity of this compound appear bright in T(1)-weighted MRI images. Here we demonstrate that US-Gd(2)O(3) can be used to label GL-261 glioblastoma multiforme cells, followed by localization and visualization in vivo using MRI. Very high amounts of Gd are efficiently internalized and retained in cells, as confirmed with TEM and ICP-MS. Labeled cells were visualized in vivo at 1.5 T using the chicken embryo model. This is one more step toward the development of "positively contrasted" cell tracking procedures with MRI.
The performance of nanomaterials for biomedical applications is highly dependent on the nature and the quality of surface coatings. In particular, the development of functionalized nanoparticles for magnetic resonance imaging (MRI) requires the grafting of hydrophilic, nonimmunogenic, and biocompatible polymers such as poly(ethylene glycol) (PEG). Attached at the surface of nanoparticles, this polymer enhances the steric repulsion and therefore the stability of the colloids. In this study, phosphate molecules were used as an alternative to silanes or carboxylic acids, to graft PEG at the surface of ultrasmall gadolinium oxide nanoparticles (US-Gd(2)O(3), 2-3 nm diameter). This emerging, high-sensitivity "positive" contrast agent is used for signal enhancement in T(1)-weighted molecular and cellular MRI. Comparative grafting assays were performed on Gd(2)O(3) thin films, which demonstrated the strong reaction of phosphate with Gd(2)O(3) compared to silane and carboxyl groups. Therefore, PEG-phosphate was preferentially used to coat US-Gd(2)O(3) nanoparticles. The grafting of this polymer on the particles was confirmed by XPS and FTIR. These analyses also demonstrated the strong attachment of PEG-phosphate at the surface of Gd(2)O(3), forming a protective layer on the nanoparticles. The stability in aqueous solution, the relaxometric properties, and the MRI signal of PEG-phosphate-covered Gd(2)O(3) particles were also better than those from non-PEGylated nanoparticles. As a result, reacting PEG-phosphate with Gd(2)O(3) particles is a promising, rapid, one-step procedure to PEGylate US-Gd(2)O(3) nanoparticles, an emerging "positive" contrast agent for preclinical molecular and cellular applications.
The β-amyloid fragment peptide 25-35 (Aβ(25-35)) is recognized as the cytotoxic sequence of the parent peptide Aβ. However, it remains unclear whether its neurotoxicity originates from its fibrillar form, how it interacts with lipid membranes, and whether cholesterol modulates these interactions. These questions have been addressed at a molecular level using various microscopic and spectroscopic techniques. The data show that Aβ(25-35) forms protofilaments at pH 7.4 at a concentration of 5 mM in the absence and presence of DMPC/DMPG model membranes. The peptide adopts a predominant aggregated β-sheet conformation under these conditions. However, as the peptide concentration decreases, the β-sheet structure tends to disappear for the benefit of β-turns, suggesting that the peptide association is reversible. The β-sheet structure formed by Aβ(25-35) appears to be atypical and characterized by the absence of intermolecular dipolar coupling and by a parallel strand configuration. The data show that Aβ(25-35)-phospholipid interactions are characterized by an increase in the conformational order of the lipid acyl chains and a change in the fluidity/elasticity of the bilayers. Concomitantly, the peptide seems to lose a few β-sheet structures, which suggests that the interactions between Aβ(25-35) and DMPC/DMPG membranes are partly driven by peptide concentration. Interactions indeed seem to occur when part of the peptides is not involved in protofilaments and increase as the proportion of the free peptide species increases. The interactions are very similar in the presence of cholesterol, except that the concentration effect of Aβ(25-35) is cancelled, suggesting that Chol limits the penetration of the peptide inside the bilayers.
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