Polymeric micelles loaded with magnetic iron oxides (e.g. Fe3O4, magnetite or γ-Fe2O3, maghemite) are being investigated in a number of biomedical applications including Magnetic Resonance Imaging (MRI) contrast agents and for the radio frequency wave-induced destruction of cancer cells.[1] These can be obtained by the adsorption of amphiphilic block copolymers onto preformed nanoparticles,[2] or through the self-assembly of block copolymers into micelles and complexation with iron salts.[3] Both approaches have limitations: For example spherical micelles are only formed over a narrow block copolymer composition range, and they can dissociate if the solvency conditions (solvent type, pH, temperature, etc.) change; their size is also difficult to vary over a wide range.

We now propose a new strategy for the preparation of polymer-stabilized magnetic nanoparticles with stealth properties (invisible to the immune system) in biological media, potentially useful as MRI contrast agents and for cancer treatment by magnetic hyperthermia. We will use amphiphilic branched copolymers with a dendritic architecture (arborescent polymers) both as template for the iron cores’ synthesis and to provide a repulsive (stabilizing) shell around the nanoparticles. The challenge for MRI and hyperthermia applications consists in maintaining large (e.g. 15–25 nm) nanoparticles dispersed in blood serum, i.e. in a high ionic strength and protein content environment. These macromolecules are derived from successive grafting reactions of linear polymer segments.[4] Unimolecular water-soluble micelles in a size range from 5-200 nm can be derived from these materials by adding polar polymer segments in the last grafting cycle to form a hydrophilic shell.[5] This unique approach will provide stable micelles independently of the solvency conditions used, and whose characteristics (size, flexibility) are predetermined in their synthesis. We will explore the use of amphiphilic arborescent copolymers (synthesized in Waterloo) to generate magnetic nanoparticles of uniform yet controllable size, as shown schematically below. These copolymers will incorporate side-chains acting as ligands for iron salts such as poly(2-vinylpyridine), poly(acrylic acid), and poly(glutamic acid), and a shell of biocompatible poly(ethylene oxide), polyglycidol, or polyoxazoline chains to provide steric stabilization. The magnetic properties of the nanoparticles will be investigated in Bordeaux with TEM, XRD, and magnetometry measurements to evaluate their potential in MRI diagnostic applications. The hyperthemic properties in radio-frequency fields will be studied in collaboration with the company COLLOROBIA, which  owns the equipment and knowledge to characterize the energy absorption rate of magnetic nanoparticles subjected to ac magnetic fields.

The project will require alternating 6-9 month stays in Waterloo and in Bordeaux for the synthetic and the characterization portions of the work, respectively.

 

 


[1](a) A. Aqil, S. Vasseur, E. Duguet, C. Passiranic, J-P. Benoît, A. Roch, R. N. Muller, R. Jérôme, C. Jérôme Eur. Polym. J. 2008, 44, 3191-3199. (b) J-P. Fortin, F. Gazeau, C. Wilhelm Eur. Biophys. J. 2008, 37, 223-228

[2](a) J-F. Berret, N. Schonbeck, F. Gazeau, D. El Kharrat, O. Sandre, A. Vacher, M Airiau JACS 2006, 128, 1755. (b) S. Lecommandoux, O. Sandre, F. Chécot, J. Rodriguez-Hernandez, R.; Perzynski Adv. Mater. 2005, 17, 712

[3]J. I. Abes, R. E. Cohen, C. A. Ross Mater. Sci. Eng. 2003, C23, 641

[4]S. J. Teertstra, M. Gauthier Prog. Polym. Sci. 2004, 29, 277

[5](a) M. Gauthier, L. Tichagwa, J.S. Downey, S. Gao Macro 1996, 29, 519. (b) Gauthier et al. Macro 2003, 36, 2642

Project Partners

Department of Chemistry, University of Waterloo, Canada

LCPO, Université Bordeaux 1, France

COLOROBBIA ITALIA S.p.A, Vinci (Firenze), Italy