In vitro angiogenic performance and in vivo brain targeting of magnetized endothelial progenitor cells for neurorepair therapies.

Endothelial progenitor cells (EPCs) represent a promising approach for cell-based therapies to induce tissue repair; however, their effective delivery into the brain has remained a challenge. We loaded EPCs with superparamagnetic iron oxide nanoparticles (SPIONs), assessed their angiogenic potential and evaluated their guidance to the brain using an external magnet. SPIONs were stored in the cytoplasm within endosomes/lysosomes as observed by transmission electron microscopy (TEM) and could be visualized as hypointense signals by magnetic resonance imaging (MRI) T2-weighted images. In vitro SPION-loaded EPCs were fully functional, forming vessel-like structures in Matrigel®, and displayed enhanced migration and secretion of growth factors (VEGF and FGF), which was associated with a moderate increase in reactive oxygen species production. Furthermore, in vivo MRI of treated mice showed accumulated hypointense signals consistent with SPION-loaded EPCs engraftment. Thus, we demonstrate that loading EPCs with SPIONs represents a safe and effective strategy for precise cell guidance into specific brain areas. FROM THE CLINICAL EDITOR: This study investigates the potential role of endothelial progenitor cells in neuro-repair strategies of the central nervous system using SPION-loaded EPCs and magnetic guidance to the target organ. The authors demonstrate ex vivo cellular viability and maintained function following SPION load as well as successful guidance of the EPCs to the target site via MR imaging in a murine model.

Nitrogen dynamics and reactivity of chiral aziridines: generation of configurationally stable aziridinyllithium compounds.

Diastereomeric oxazolinylaziridines (R,R)-9 and (R,S)-9 have been regioselectively lithiated at the α-position with respect to the oxazolinyl ring. The resulting aziridinyllithium compounds proved to be chemically and configurationally stable under the experimental conditions used, thus furnishing, upon trapping with electrophiles, chiral 2,2-disubstituted aziridines, in contrast to the corresponding α-lithiated oxazolinyloxiranes that have been reported to be chemically stable but configurationally unstable. This peculiar behavior of the nitrogen-bearing heterocycle has been rationalized on the basis of DFT calculations and the observed dynamics of the aziridine nitrogen atom. The DFT analysis allowed the disclosure of a solvent-dependent differing stability of diastereomeric lithiated aziridines (R,R)-9-Li and (R,S)-9-Li, suggesting η(3)-coordinated oxazolinylaziridinyllithium compounds as likely intermediates. Such intermediates could be the result of a dynamically controlled lithiation that relies on the preliminary formation of a complex between the lithiating agent and the oxazolinyl ring. According to this model, the competing complexation of the lithiating agent by the lone pair of electrons on the aziridine nitrogen would cause addition to the oxazoline C=N bond, thus ending up with the formation of oxazolidines, which are precursors of useful chiral ketoaziridines. The proposed model has been also supported by estimating the nitrogen inversion barrier by dynamic NMR spectroscopic experiments.

Protective Effects of Bovine Serum Albumin on Superparamagnetic Iron Oxide Nanoparticles Evaluated in the Nematode Caenorhabditis elegans.

Nanomaterials give rise to unique biological reactivity that needs to be thoroughly investigated. The quest for enhanced magnetic nanomaterials of different shapes, magnetic properties, or surface coatings continues for applications in drug delivery, targeting therapies, biosensing, and magnetic separation. In this context, the use of simple in vivo models, such as Caenorhabditis elegans, to biologically evaluate nanoparticles is currently in increasing demand as it offers low-cost and information-rich experiments. In this work, we evaluated how surface modification (citrate- and protein-coated) of superparamagnetic iron oxide nanoparticles (C-SPIONs and BSA-SPIONs, respectively) induces changes in their toxicological profile and biodistribution using the animal model C. elegans and combining techniques from materials science and biochemistry. The acute toxicity and nanoparticle distribution were assessed in two populations of worms (adults and larvae) treated with both types of SPIONs. After 24 h treatment, nanoparticles were localized in the alimentary system of C. elegans; acute toxicity was stronger in adults and larvae exposed to C-SPIONs rather than BSA-SPIONs. Adult uptake was similar for both SPION types, whereas uptake in larvae was dependent on the surface coating, being higher for BSA-SPIONs. Nanoparticle size was evaluated upon excretion, and a slight size decrease was found. Interestingly, all results indicate the protective effects of the BSA to prevent degradation of the nanoparticles and decrease acute toxicity to the worms, especially at high concentrations. We argue that this relevant information on the chemistry and toxicity of SPIONs in vivo could not be gathered using more classical in vitro approaches such as cell culture assays, thus endorsing the potential of C. elegans to assess nanomaterials at early stages of their synthetic formulations.

Rapid synthesis of water-dispersible superparamagnetic iron oxide nanoparticles by a microwave-assisted route for safe labeling of endothelial progenitor cells.

We synthesize highly crystalline citrate-coated iron oxide superparamagnetic nanoparticles that are stable and readily dispersible in water by an extremely fast microwave-assisted route and investigate the uptake of magnetic nanoparticles by endothelial cells. Nanoparticles form large aggregates when added to complete endothelial cell medium. The size of the aggregates was controlled by adjusting the ionic strength of the medium. The internalization of nanoparticles into endothelial cells was then investigated by transmission electron microscopy, magnetometry and chemical analysis, together with cell viability assays. Interestingly, a sevenfold more efficient uptake was found for systems with larger nanoparticle aggregates, which also showed significantly higher magnetic resonance imaging effectiveness without compromising cell viability and functionality. We are thus presenting an example of a straightforward microwave synthesis of citrate-coated iron oxide nanoparticles for safe endothelial progenitor cell labeling and good magnetic resonance cell imaging with potential application for magnetic cell guidance and in vivo cell tracking.