Lénaïc Lartigue

Water-Dispersible Sugar-Coated Iron Oxide Nanoparticles. An Evaluation of their Relaxometric and Magnetic Hyperthermia Properties

Synthesis of functionalized magnetic nanoparticles (NPs) for biomedical applications represents a current challenge. In this paper we present the synthesis and characterization of water-dispersible sugar-coated iron oxide NPs specifically designed as magnetic fluid hyperthermia heat mediators and negative contrast agents for magnetic resonance imaging. In particular, the influence of the inorganic core size was investigated. To this end, iron oxide NPs with average size in the range of 4-35 nm were prepared by thermal decomposition of molecular precursors and then coated with organic ligands bearing a phosphonate group on one side and rhamnose, mannose, or ribose moieties on the other side. In this way a strong anchorage of the organic ligand on the inorganic surface was simply realized by ligand exchange, due to covalent bonding between the Fe(3+) atom and the phosphonate group. These synthesized nanoobjects can be fully dispersed in water forming colloids that are stable over very long periods. Mannose, ribose, and rhamnose were chosen to test the versatility of the method and also because these carbohydrates, in particular rhamnose, which is a substrate of skin lectin, confer targeting properties to the nanosystems. The magnetic, hyperthermal, and relaxometric properties of all the synthesized samples were investigated. Iron oxide NPs of ca. 16-18 nm were found to represent an efficient bifunctional targeting system for theranostic applications, as they have very good transverse relaxivity (three times larger than the best currently available commercial products) and large heat release upon application of radio frequency (RF) electromagnetic radiation with amplitude and frequency close to the human tolerance limit. The results have been rationalized on the basis of the magnetic properties of the investigated samples.

Water-Soluble Rhamnose-Coated Fe3O4 Nanoparticles

Water-soluble biocompatible rhamnose-coated Fe(3)O(4) nanoparticles of 4.0 nm are obtained by covalent anchorage of rhamnose on the nanoparticles surface via a phosphate linker. These nanoparticles present superparamagnetic behavior and nuclear relaxivities in the same order of magnitude as Endorem that make them potential magnetic resonance imaging (MRI) contrast agents of a second generation, where the saccharides represent also specific ligands able to target lectins on skin cells.

NMR-D study of the local spin dynamics and magnetic anisotropy in different nearly monodispersed ferrite nanoparticles

We present a systematic experimental comparison of the superparamagnetic relaxation time constants obtained by means of dynamic magnetic measurements and (1)H-NMR relaxometry, on ferrite-based nanosystems with different composition, various core sizes and dispersed in different solvents. The application of a heuristic model for the relaxivity allowed a comparison between the reversal time of magnetization as seen by NMR and the results from the AC susceptibility experiments, and an estimation of fundamental microscopic properties. A good agreement between the NMR and AC results was found when fitting the AC data to a Vogel-Fulcher law. Key parameters obtained from the model have been exploited to evaluate the impact of the contribution from magnetic anisotropy to the relaxivity curves and estimate the minimum approach distance of the bulk solvent.

Tuning the architectural integrity of high-performance magneto-fluorescent core-shell nanoassemblies in cancer cells.

High-density nanoarchitectures, endowed with simultaneous fluorescence and contrast properties for MRI and TEM imaging, have been obtained using a simple self-assembling strategy based on supramolecular interactions between non-doped fluorescent organic nanoparticles (FON) and superparamagnetic nanoparticles. In this way, a high-payload core-shell structure FON@mag has been obtained, protecting the hydrophobic fluorophores from the surroundings as well as from emission quenching by the shell of magnetic nanoparticles. Compared to isolated nanoparticles, maghemite nanoparticles self-assembled as an external shell create large inhomogeneous magnetic field, which causes enhanced transverse relaxivity and exacerbated MRI contrast. The magnetic load of the resulting nanoassemblies is evaluated using magnetic sedimentation and more originally electrospray mass spectrometry. The role of the stabilizing agents (citrate versus polyacrylate anions) revealed to be crucial regarding the cohesion of the resulting high-performance magneto-fluorescent nanoassemblies, which questions their use after cell internalization as nanocarriers or imaging agents for reliable correlative light and electron microcopy.

PEGylated Anionic Magnetofluorescent Nanoassemblies: Impact of Their Interface Structure on Magnetic Resonance Imaging Contrast and Cellular Uptake

Controlling the interactions of functional nanostructures with water and biological media represents high challenges in the field of bioimaging applications. Large contrast at low doses, high colloidal stability in physiological conditions, the absence of cell cytotoxicity, and efficient cell internalization represent strong additional needs. To achieve such requirements, we report on high-payload magnetofluorescent architectures made of a shell of superparamagnetic iron oxide nanoparticles tightly anchored around fluorescent organic nanoparticles. Their external coating is simply modulated using anionic polyelectrolytes in a final step to provide efficient magnetic resonance imaging (MRI) and fluorescence imaging of live cells. Various structures of PEGylated polyelectrolytes have been synthesized and investigated, differing from their iron oxide complexing units (carboxylic vs phosphonic acid), their structure (block- or comblike), their hydrophobicity, and their fabrication process [conventional or reversible addition-fragmentation chain transfer (RAFT)-controlled radical polymerization] while keeping the central magnetofluorescent platforms the same. Combined photophysical, magnetic, NMRD, and structural investigations proved the superiority of RAFT polymer coatings containing carboxylate units and a hydrophobic tail to impart the magnetic nanoassemblies (NAs) with enhanced-MRI negative contrast, characterized by a high r2/r1 ratio and a transverse relaxation r2 equal to 21 and 125 s-1 mmol-1 L, respectively, at 60 MHz clinical frequency (∼1.5 T). Thanks to their dual modality, cell internalization of the NAs in mesothelioma cancer cells could be evidenced by both confocal fluorescence microscopy and magnetophoresis. A 72 h follow-up showed efficient uptake after 24 h with no notable cell mortality. These studies again pointed out the distinct behavior of RAFT polyelectrolyte-coated bimodal NAs that internalize at a slower rate with no adverse cytotoxicity. Extension to multicellular tumor cell spheroids that mimic solid tumors revealed the successful internalization of the NAs in the periphery cells, which provides efficient deep-imaging labels thanks to their induced T2* contrast, large emission Stokes shift, and bright dotlike signal, popping out of the strong spheroid autofluorescence.

Small Molecule-Based Fluorescent Organic Nanoassemblies with Strong Hydrogen Bonding Networks for Fine Tuning and Monitoring Drug Delivery in Cancer Cells

Bright supramolecular fluorescent organic nanoassemblies (FONs), based on strongly polar red-emissive benzothiadiazole fluorophores containing acidic units, are fabricated to serve as theranostic tools with large colloidal stability in the absence of a polymer or surfactant. High architectural cohesion is ensured by the multiple hydrogen-bonding networks, reinforced by the dipolar and hydrophobic interactions developed between the dyes. Such interactions are harnessed to ensure high payload encapsulation and efficient trapping of hydrophobic and hydrogen-bonding drugs like doxorubicin, as shown by steady state and time-resolved measurements. Fine tuning of the drug release in cancer cells is achieved by adjusting the structure and combination of the fluorophore acidic units. Notably delayed drug delivery is observed by confocal microscopy compared to the entrance of hydrosoluble doxorubicin, demonstrating the absence of undesirable burst release outside the cells by using FONs. Since FON-constituting fluorophores exhibit a large emission shift from red to green when dissociating in contact with the lipid cellular content, drug delivery could advantageously be followed by dual-color spectral detection, independently of the drug staining potentiality.