Kurzbeschreibung
(Englisch)
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We will exploit novel approaches of immobilizing functional molecules through bioinspired (cyanobacterial iron chelator, mussel adhesive proteins) anchorage chemistry to iron oxide nanoparticles. Biotinylated, adhesive PEG constructs will be assembled on Superparamagnetic Iron Oxide Nanoparticles (SPION) and assembly protocols optimized. Further functionalization includes sequential immobilization of streptavidin (or neutravidin) and biotinylated targeting ligands or alternatively direct coupling of such ligands. As a model application, the novel multifunctional SPIO particles - presenting specific targeting ligands - will be used for the non-invasive detection of early stages of vulnerable plaque in blood vessels by Magnetic Resonance Imaging (MRI) using suitable animal models.
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Partner und Internationale Organisationen
(Englisch)
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AT, BG, CH, CY, CZ, DE, ES, FI, FR, GR, HR, HU, IE, IL, IT, LT, LV, NL, NO, PL, PT, RO, RS, SE, SI, SK, TR, UK
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Abstract
(Englisch)
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The good biocompatibility and magnetic properties of iron oxide nanoparticles render them well suited for many different biomedical applications. They can be used for diagnostic purposes as magnetic resonance (MR) contrast agents, for cell labelling and separations and for therapeutic reasons in hyperthermia and drug delivery vehicles. If assembled in drug delivery vehicles, iron oxide nanoparticles can be used to visualize these vehicles using MR imaging and as actuators to trigger release of encapsulated cargo. Key to successful applications of superparamagnetic iron oxide nanoparticles in the biomedical field are good colloidal stability under physiologic conditions and a close control over the surface presentation of functionalities. We synthesized superparamagnetic iron oxide nanoparticles for which we could controllably vary the average core diameter between 5 and 10 nm. As-synthesized iron oxide nanoparticles were sterically stabilized with dispersants consisting of a high affinity catechol derived anchor that was covalently linked to poly(ethylene glycol) (PEG). The latter is known to render nanoparticles stealth such that protein adsorption on nanoparticle surfaces is minimized. PEG thus significantly prolongs the circulation time of nanoparticles if applied in vivo. However, PEG can only minimize protein adsorption if it is firmly bound to nanoparticle surfaces. We found that electronegatively substituted catechol derivatives such as nitrocatechols are particularly well suited anchors to irreversibly bind dispersant spacers such as PEG to Fe3O4 nanoparticle surfaces. The irreversible binding of nitrocatechol anchors allowed us to tune the dispersant shell thickness by varying the PEG molecular weight. Therefore, we gained close control over the hydrodynamic size of individually stabilized iron oxide nanoparticles by independently tuning the core size and shell thickness. The core size determines the magnetic properties of the resulting superparamangetic core-shell nanoparticles and the shell thickness determines the colloidal stability and the fate of the nanoparticles if applied in vivo. Furthermore, we could closely control the density of functionalities such as fluorophores and targeting ligands presented at the nanoparticle interphase rendering these nanoparticles multifunctional. A second emerging application of iron oxide nanoparticles is their use in drug delivery vehicles. Drug delivery vehicles should have a low passive leakage of encapsulated cargo at body temperature. At the same time, it would be highly beneficial to be able to externally trigger release of cargo which would open up the possibility to closely and externally control the timing and dose of released cargo. We could show that iron oxide nanoparticles are well suited actuators to trigger cargo release if hydrophobic iron oxide nanoparticles are self-assembled in liposome membranes. We found that liposomes containing iron oxide nanoparticles in their membranes have a much higher efficiency to release encapsulated cargo compared to liposomes containing hydrophilic nanoparticles in their lumen. After we established a protocol to assemble liposomes hosting iron oxide nanoparticles in their membrane, we developped a protocol to efficiently release cargo that was encapsulated in the liposome lumen. This allowed us to closely control the timing and dose of cargo encapsulated in the lumen of liposomes functionalized with hydrophobic iron oxide nanoparticles in their membranes.
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