Luce Vander Elst

Hydrogels incorporating GdDOTA: towards highly efficient dual T1/T2 MRI contrast agents.

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA NPs) exhibited high relaxivity (r(1) =101.7 s(-1) mM(-1) per Gd(3+) ion at 37 °C and 20 MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1)/T(2) dual-mode contrast agent was studied in C6 cells.

How to quantify iron in an aqueous or biological matrix: a technical note

Iron oxide (nano)particles are powerful contrast agents for MRI and tags for magnetic cellular labeling. The need for quantitative methods to evaluate the iron content of contrast media solutions and biological matrixes is thus obvious. Several convenient methods aiming at the quantification of iron from iron oxide nanoparticle-containing samples are presented.

High Relaxivities and Strong Vascular Signal Enhancement for NaGdF4 Nanoparticles Designed for Dual MR/Optical Imaging

Near-infrared (NIR)-to-NIR upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) paramagnetic nanoparticles (NPs) are efficiently detected by NIR imaging techniques. As they contain Gd(3+) ions, they also provide efficient positive contrast in magnetic resonance imaging (MRI). Water-dispersible small (≈25 nm, S-) and ultrasmall (<5 nm diam., US-) NaY(Gd)F4 :Tm(3+) ,Yb(3+) NPs are synthesized by thermal decomposition and capped with citrate. The surface of citrate-coated US-NPs shows sodium depletion and high Gd elemental ratios, as confirmed by a comparative X-ray photoelectron spectroscopy (XPS)/neutron absorption analysis study. US-NaGd0.745 F4 :Tm0.005 ,Yb0.25 NPs have hydrodynamic diameters close to that measured by TEM, with the lowest relaxometric ratios (r2 /r1 = 1.18) reported for NaGdF4 nanoparticle suspensions (r1 = 3.37 mM(-1) s(-1) at 1.4 T and 37 °C). Strong relaxivity peaks in the range of 20 (0.47 T) - 300 MHz (7.05 T) are revealed in nuclear magnetic resonance dispersion profiles, with high r2 /r1 ratios at increasing field strengths for S-NPs. This indicates the superiority of US-NPs over S-NPs for achieving high positive contrast at clinical MRI field strengths. I.-v. injected citrate-coated US-NPs evidence long blood retention times (>90 min) in mice. Biodistribution studies (48 h, 8 d) show elimination through the reticuloendothelial and urinary systems, similarly to other citrate-capped US-NP systems. In summary, upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) nanoparticles have promising luminescent, relaxometric and blood-retention properties for dual MRI/optical imaging.

Polyglycerol-grafted superparamagnetic iron oxide nanoparticles: highly efficient MRI contrast agent for liver and kidney imaging and potential scaffold for cellular and molecular imaging.

Polyglycerol as a water-soluble and biocompatible hyperbranched polymer was covalently grafted on the surface of superparamagnetic iron oxide nanoparticles. With this aim, superparamagnetic magnetite nanoparticles were prepared by coprecipitation in aqueous media, then the surface of nanoparticles was modified to introduce the reactive groups on the surface of nanoparticles. After that, polyglycerol was grafted on the surface of nanoparticles by ring-opening anionic polymerization of glycidol using n-bulyllithium as initiator. The magnetometry, relaxometry and phantom MRI experiments of this highly stable ferrofluid showed its high potential as a negative MRI contrast agent. Calculated r(1) and r(2) relaxivities at different magnetic fields were higher than the values reported for commercially available iron oxide contrast agents. The in vivo MRI studies showed that, after intravenous injection into mice, the particles produced a strong negative contrast in liver and kidneys, which persisted for 80u2009min (in liver) to 110u2009min (in kidneys). The negative contrast of the liver and kidneys weakened over the time, suggesting that polyglycerol coating renders the nanoparticles stealth and possibly optimal for renal excretion.

Potential amyloid plaque-specific peptides for the diagnosis of Alzheimer's disease.

Amyloid plaques (AP) represent one of the main molecular hallmarks of Alzheimers disease (AD). In order to develop new AP-specific contrast agents for AD molecular imaging, the phage display technology was used to identify peptides specific to amyloid-beta (A beta(42)). A random disulfide constrained heptapeptide phage display library was screened against A beta(42). After biopanning, 72 phage clones were isolated and their binding affinity to A beta(42) was evaluated by enzyme-linked immunosorbent assay (ELISA). The final library was enriched in two peptide sequences. The K(d) of candidate phage clones for binding to A beta(42) are in the picomolar range. The binding affinity for A beta(42) of two selected peptides was confirmed by ELISA, and the specific interaction with AP was validated by immunohistochemistry on brain sections. The preliminary MRI in vivo study, which was performed with a peptide functionalized contrast agent on AD transgenic mouse, showed encouraging results. To conclude, low molecular weight peptides presenting a specific affinity for A beta(42) were identified by phage display. As specific carriers, they have a real potential for molecular imaging of AD thanks to AP binding.

Glucose-, pH- and thermo-responsive nanogels crosslinked by functional superparamagnetic maghemite nanoparticles as innovative drug delivery systems

Reversibly crosslinked (RCL) nanogels made of thermo-responsive poly(vinyl alcohol)-b-poly(N-vinylcaprolactam) copolymers were combined with maghemite nanoparticles and developed as new drug delivery systems (DDS). The crosslinking was formed via boronate/diol bonding from the surface-functionalized superparamagnetic maghemite nanoparticles, endowing the DDS with thermo-, pH- and glucose-responsiveness. The capability to load a hydrophobic drug model Nile red (NR) within the RCL nanogels was evaluated, and stimuli-triggered drug release behaviours under different conditions were tested. Zero premature release behaviour was detected at physiological pH in the absence of glucose, whereas triggered release was observed upon exposure to acidic pH (5.0) and/or in the presence of glucose. In light of the superparamagnetic properties of the maghemite nanoparticles and RCL nanogels, magnetically-induced heating, MR imaging performance, as well as remotely magnetically-triggered drug release under alternating magnetic field (AMF), were investigated. Cytotoxicity against fibroblast-like L929 and human melanoma MEL-5 cell lines was assessed via the MTS assay. In vitro stimuli-triggered release of tamoxifen, a chemotherapeutic drug, was also studied within MEL-5 cell cultures under different conditions. These innovative RCL nanogels, integrating different stimuli-responsive components, hydrophobic chemotherapeutic moieties and also diagnostic agents together via reversible crosslinking, are promising new theranostic platforms.

Nanoparticles based on star polymers as theranostic vectors: endosomal-triggered drug release combined with MRI sensitivity

Dual-functional star polymers (diameters 15 nm) are synthesized producing nanoparticles with excellent colloidal stability in both water and serum. The nanoparticles are built with aldehyde groups in the core and activated esters in the arms. The different reactivity of the two functional groups to sequentially react with different amino compounds is exploited; doxorubicin (DOX) and 1-(5-amino-3-aza-2-oxypentyl)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO3A-tBu-NH2 )-a chelating agent effective for the complexation of Gadolinium ions (Gd). The activated ester group is employed to attach the DO3A chelating agent, while the aldehyde groups are exploited for DOX conjugation, providing a controlled release mechanism for DOX in acidic environments. DOX/Gd-loaded nanoparticles are rapidly taken up by MCF-7 breast cancer cells, subsequently releasing DOX as demonstrated using in vitro fluorescence lifetime imaging microscopy (FLIM). Endosomal, DOX release is observed, using a phasor plot representation of the fluorescence lifetime data, showing an increase of native DOX with time. The MRI properties of the stars are assessed and the relaxivity of Gd loaded in stars is three times higher than conventional organic Gd/DO3A complexes. The DOX/Gd-conjugated nanoparticles yield a similar IC50 to native DOX for breast cancer cell lines, confirming that DOX integrity is conserved during nanoparticle attachment and release.

Poly(acrylic acid)-block-poly(vinyl alcohol) anchored maghemite nanoparticles designed for multi-stimuli triggered drug release

Original core/corona nanoparticles composed of a maghemite core and a stimuli-responsive polymer coating made of poly(acrylic acid)-block-poly(vinyl alcohol) macromolecules were fabricated for drug delivery system (DDS) application. This kind of DDS aims to combine the advantage of stimuli-responsive polymer coating, in order to regulate the drug release behaviours under different conditions and furthermore, improve the biocompatibility and in vivo circulation half-time of the maghemite nanoparticles. Drug loading capacity was evaluated with methylene blue (MB), a cationic model drug. The triggered release of MB was studied under various stimuli such as pH, ionic strength and temperature. Local heating generated under alternating magnetic field (AMF) application was studied, and remotely AMF-triggered release was also confirmed, while a mild heating-up of the release medium was observed. Furthermore, their potential application as magnetic resonance imaging (MRI) contrast agents was explored via relaxivity measurements and acquisition of T2-weighted images. Preliminary studies on the cytotoxicity against mouse fibroblast-like L929 cell line and also their cellular uptake within human melanoma MEL-5 cell line were carried out. In conclusion, this kind of stimuli-responsive nanoparticles appears to be promising carriers for delivering drugs to some tumour sites or into cellular compartments with an acidic environment.

In vitro biomedical applications of functionalized iron oxide nanoparticles, including those not related to magnetic properties.

Superparamagnetic iron oxide nanoparticles (SPION) are very promising contrast media, especially for molecular imaging, due to their superior NMR efficacy. They even have wider biomedical applications such as in drug and gene delivery, tissue engineering and bioseparation, or as sensitive biological nanosensors. By coupling them to affinity ligands, SPION can bind to drugs, proteins, enzymes, antibodies or nucleotides. For in vitro biomedical applications, the detection of molecular interaction is possible by using a diversity of systems capable of sensing the magnetic properties of these materials. The goal of the present work was to develop and validate various in vitro biomedical applications of ultrasmall superparamagnetic particles of iron oxide (USPIO), including some that are not related to their magnetic properties. USPIO coated with dextran, starch or bisphosphonate exposing carboxylate groups were synthesized and some of them were functionalized by conjugating various biomolecules, such as biotin, streptavidin and apoptosis, or VCAM-1 specific peptides. The in vitro biomedical applications assessed in the present work included: (1) the relaxometric measurement of antibody concentration, cell receptor expression, molecular interaction, and enzymatic activity in aqueous suspensions; (2) MRI visualization of cells and detection of molecular interaction in an ELISA system; (3) ELISA applications of USPIO derivatives; and (4) detection of specific biomolecules by histochemistry. Our results confirm that rapid and simple in vitro detection of a diversity of functionalized SPION with relevance in medicine is possible by the existing NMR techniques and by chemical staining reactions. The protocols can be applied to minimally prepared biological samples (e.g. whole blood, blood plasma or serum, cell suspensions, biopsies, histological preparations, etc.), and often do not need complicated systems of signal amplification. The use of SPION labeled compounds could furthermore contribute to cost reductions in the diagnosis and in patient care.

A new approach to follow the formation of iron oxide nanoparticles synthesized by thermal decomposition.

A novel way has been proposed to follow the formation of nanocrystalline magnetite. Iron oxide nanoparticles were synthesized by the thermal decomposition of Fe(acac)(3) in the presence of oleic acid and oleylamine surfactants at high temperature. The species produced during the synthetic process are characterized through their effects on the proton nuclear magnetic relaxation of the reaction medium and their sizes. As shown by transmission electron microscopy, photon correlation spectroscopy and x-ray diffraction, the diameter of nano-objects increases when the time synthesis is longer. Magnetic properties evaluated by nuclear magnetic resonance (NMRD profiles, T(1) and T(2) measurements) were correlated with the size parameters.