CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the U.S. national phase of International Application No. PCT/EP2016/068756, filed on Aug. 5, 2016, which claims the benefit of German Patent Application No. 10 2015 215 736.9, filed Aug. 18, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

The present invention relates to magnetic, single-core nanoparticles, in particular stably dispersible, magnetic, single-core nanoparticles (e.g. single-core, magnetite nanoparticles) with a diameter between 20 and 200 nm with different morphology, and the continuous, aqueous synthesis thereof, in particular with the help of micromixers. The method can be implemented easily, rapidly and economically and does not require organic solvents. The single-core nanoparticles produced by the method form stable dispersions in aqueous media, i.e. they do not have a tendency to assembling or aggregation. Furthermore, the method offers the possibility of producing anisotropic, super-paramagnetic, plate-like nanoparticles which, because of their shape anisotropy, are outstandingly suited for use in polymer matrices for magnetic field-controlled release of active substances.

At present, there is no possibility of producing economically individually stabilised, single-core iron oxide nanoparticles, the diameter of which is greater than 20 nm. However, there are various applications for which in particular nanoparticulate, magnetic, single-core iron oxides, which are greater than 20 nm in diameter, must be present individually stabilised in the dispersion medium, i.e. aggregation of the nanoparticles must not take place. These applications concern, for example, magnetic fluid hyperthermia, magnetic separation, magnetic active substance transport, magnetic active substance release, immunoassays, diagnostics applications and so-called “magnetic particle imaging”.

One production method of magnetic, iron oxide nanoparticles is the standard method of co-precipitation according to the method by Massart (see DE 10 2008 015365 A1) which is used also for the industrial production of ferrofluids. However, this does not provide any single-core, iron oxide nanoparticles which have a size of at least 20 nm. Therefore, it is unsuitable for preparation of nanoparticles with a size of 20 to 200 nm.

Current production methods of magnetic, iron oxide, single-core particles with a size of at least 20 nm are based on the thermal decomposition of organic precursor molecules in high-boiling organic solvents. These methods are very energy-intensive and consume large quantities of organic solvents (see e.g. US 2006/0133990 A1). Firstly, these methods cannot be transferred easily to an industrial scale. Secondly, the nanoparticles produced in boiling organic solvents have hydrophobic properties. Consequently, transfer thereof into an aqueous medium is accompanied by the formation of nanoparticle aggregates (hydrophobic effect), which represents a problem which to date has only been solved inadequately.

It is known that iron oxide nanoparticles with a size of more than 50 nm and hydrophilic properties can be produced by the oxidation method of Sugimoto. Firstly, Fe(OH)2is hereby precipitated from an Fe(II) solution in an alkaline medium and subsequently is oxidised to magnetite by an added oxidant and temperature effects (Sugimoto & Matijevic, J. Colloid Interface Sci. 1980, 74 (1), 227-243). The particles produced in this way have, however, because of their size, already ferromagnetic properties and, in addition, have a tendency to aggregation.

In summary, it must be emphasised that neither with the method according to Massart nor with the oxidation method of Sugimoto, are there accessible individually stabilised, single-core iron oxide nanoparticles in the size between 20 and 200 nm, which have super-paramagnetic to ferromagnetic properties and a low aggregation tendency and hence are suitable also for demanding medical applications (e.g. hyperthermia or “magnetic particle imaging”).

The only known possibility to date of producing stably dispersible, single-core iron oxide nanoparticles in aqueous media in this size range is a production by a biotechnological route with the help of microorganisms (Lang et al. Macromol. Biosci. 2007, 7, 144-151). The hereby produced single-core, iron oxide nanoparticles are termed magnetosomes and actually have very good physical properties (e.g. for “magnetic particle imaging”). The magnetosomes have, however, the crucial disadvantage that, because of their bacterial origin, they still include bacterial antigens and hence are strongly immunogenic. They are hence unsuitable for medical application. In addition, they have to date been able to be produced only very elaborately and in small quantities.

Starting herefrom, it was the object of the present invention to provide a method for the production of nanoparticles which are not immunogenic, have preferably super-paramagnetic properties and a comparatively high magnetic moment and do not have a tendency to aggregation formation in aqueous media.

The object is achieved by the method described herein, the features of the magnetic, single-core nanoparticles described herein, and the advantageous developments thereof. Uses of the magnetic, single-core nanoparticles according to the invention are also described.

