Christine Ménager

Doxorubicin release triggered by alginate embedded magnetic nanoheaters: a combined therapy.

www.MaterialsViews.com C O M M Doxorubicin Release Triggered by Alginate Embedded Magnetic Nanoheaters: A Combined Therapy U N IC A T Séverine Brulé , Michael Levy , Claire Wilhelm , Didier Letourneur , Florence Gazeau , Christine Ménager , and Catherine Le Visage * IO N In recent years, local heat generation (hyperthermia) has been tested as a means of destroying malignant tumors. Hyperthermia is a very promising treatment for cancer based on the hypothesis that cancerous cells are more sensitive to an increase of temperature than normal cells. When exposed to a high-frequency magnetic fi eld, magnetic nanoparticles generate heat through oscillation of their magnetic moment due to Neel and Brownian relaxations. [ 1 ] Direct injection of magnetic nanoparticles into solid tumors, followed by exposure to an alternating magnetic fi eld, has been shown to be capable of inducing tumor regression. [ 2 , 3 ] Ideally, the particle-induced magnetic heating should be precisely controlled, highly localized, and should result in no systemic effects and signifi cantly reduced side effects in patients. [ 4–6 ] On the other side, nanotechnology applications for anticancer drug delivery have been extensively explored, hoping to improve the effi cacy and to reduce side effects of chemotherapy. Once at the target site, the drug is released from the carrier creating a high local concentration in the tumor tissue. Nanoparticles can stimulate drug uptake by cancer cells by locally providing high extracellular concentrations of the drug and/or by direct action on the permeability of cell membranes. [ 7 ] Recently, Ciofani and coauthors hypothesized that polymeric nanoparticles with a core of magnetite and carrying specifi c drugs could be investigated for simultaneous drug targeting and hyperthermia application but they did not investigate the potential application of this system. [ 8 ] Remote-controlled degradation of degradable nanocomposite hydrogels was also obtained by application of an alternating magnetic fi eld. [ 9 ] Here, we designed microbeads loaded with both magnetic nanoparticles (or nanoheaters) and doxorubicin to combine magnetic control of heating and drug delivery. We demonstrate that this new nano-in-micro platform greatly enhances the performance of encapsulated doxorubicin

Magnetic micro-manipulations to probe the local physical properties of porous scaffolds and to confine stem cells

The in vitro generation of engineered tissue constructs involves the seeding of cells into porous scaffolds. Ongoing challenges are to design scaffolds to meet biochemical and mechanical requirements and to optimize cell seeding in the constructs. In this context, we have developed a simple method based on a magnetic tweezer set-up to manipulate, probe, and position magnetic objects inside a porous scaffold. The magnetic force acting on magnetic objects of various sizes serves as a control parameter to retrieve the local viscosity of the scaffolds internal channels as well as the stiffness of the scaffolds pores. Labeling of human stem cells with iron oxide magnetic nanoparticles makes it possible to perform the same type of measurement with cells as probes and evaluate their own microenvironment. For 18 microm diameter magnetic beads or magnetically labeled stem cells of similar diameter, the viscosity was equivalently equal to 20 mPa s in average. This apparent viscosity was then found to increase with the magnetic probes sizes. The stiffness probed with 100 microm magnetic beads was found in the 50 Pa range, and was lowered by a factor 5 when probed with cells aggregates. The magnetic forces were also successfully applied to the stem cells to enhance the cell seeding process and impose a well defined spatial organization into the scaffold.

Can Magnetic Targeting of Magnetically Labeled Circulating Cells Optimize Intramyocardial Cell Retention

Therapeutic intracavitary stem cell infusion currently suffers from poor myocardial homing. We examined whether cardiac cell retention could be enhanced by magnetic targeting of endothelial progenitor cells (EPCs) loaded with iron oxide nanoparticles. EPCs were magnetically labeled with citrate-coated iron oxide nanoparticles. Cell proliferation, migration, and CXCR4 chemokine receptor expression were assessed in different labeling conditions and no adverse effects of the magnetic label were observed. The magnetophoretic mobility of labeled EPCs was determined in vitro, with the same magnet as that subsequently used in vivo. Coronary artery occlusion was induced for 30 min in 36 rats (31 survivors), followed by 20 min of reperfusion. The rats were randomized to receive, during brief aortic cross-clamping, direct intraventricular injection of culture medium (n = 7) or magnetically labeled EPCs (n = 24), with (n = 14) or without (n = 10) subcutaneous insertion of a magnet over the chest cavity (n = 14). The hearts were explanted 24 h later and engrafted cells were visualized by magnetic resonance imaging (MRI) of the heart at 1.5 T. Their abundance in the myocardium was also analyzed semiquantitatively by immunofluorescence, and quantitatively by real-time polymerase chain reaction (RT-PCR). Although differences in cell retention between groups failed to be statistically significant using RT-PCR quantification, due to the variability of the animal model, immunostaining showed that the average number of engrafted EPCs was significantly ten times higher with than without magnetic targeting. There was thus a consistent trend favoring the magnet-treated hearts, thereby suggesting magnetic targeting as a potentially new mean of enhancing myocardial homing of intravascularly delivered stem cells. Magnetic targeting has the potential to enhance myocardial retention of intravascularly delivered endothelial progenitor cells.

Polyvalent catanionic vesicles: Exploring the drug delivery mechanisms

Among drug delivery systems, catanionic vesicles now appear as powerful candidates for pharmaceutical applications because they are relatively cheap and easy to use, thus well corresponding to industrial requirements. Using labelled vesicles made of a tricatenar catanionic surfactant, the work reported here aims at exploring the mechanisms by which internalisation into a cell occurs. The study was performed on various cell types such as phagocytic as well as non-phagocytic cells using confocal laser scanning microscopy and flow cytometry. Using various inhibitors, endocytosis and also a passive process, as probably fusion, were highlighted as interaction phenomena between catanionic vesicles and cell membranes. Finally, the interaction modelled with giant liposomes as membrane models confirmed the hypothesis of the occurrence of a fusion phenomenon between the nanovectors and cell membranes. This process highlights the potential of catanionic vesicles for a future pharmaceutical application as a universal drug delivery system.

Strong and specific interaction of ultra small superparamagnetic iron oxide nanoparticles and human activated platelets mediated by fucoidan coating

Activated platelets play a pivotal role in cardiovascular diseases such as atherothrombosis. Therefore, strategies enabling activated platelet molecular imaging are of great interest. Herein, a chemical protocol was investigated for coating superparamagnetic iron oxide nanoparticles with low molecular weight fucoidan, a ligand of P-selectin expressed on the surface of activated platelets. The physico–chemical characterization of the obtained product demonstrated successful fucoidan coating and its potential as a T2 MRI contrast agent. The specificity and the strength of the interaction between fucoidan-coated iron oxide nanoparticles and human activated platelets was demonstrated by flow cytometry. Micromagnetophoresis experiments revealed that platelets experience magnetically-induced motion in the presence of a magnetic field gradient created by a micromagnet. Altogether, these results indicate that superparamagnetic iron oxide nanoparticles coated with low molecular weight fucoidan may represent a promising molecular imaging tool for activated platelets in human diseases.

Multifunctional nanovectors based on magnetic nanoparticles coupled with biological vesicles or synthetic liposomes

The combination of synthetic liposomes or cell-derived biological vesicles with magnetic nanoparticles creates multifunctional nanovectors with promising potential for diagnosis and therapy. First, the magnetic properties exported from the nanoparticles to the vesicles make them efficient tracers for Magnetic Resonance Imaging and mediators for therapeutic magnetic hyperthermia. Second, the vesicles are magnetic and can be manipulated by an external magnet. This ‘action at a distance’, opens up many applications involving the induced magnetic mobility, from magnetically promoted cell internalisation to magnetic targeting in vivo. Finally, due to their vesicular structure enabling drug encapsulation, the magnetic vesicles are considered as drug delivery systems.