In the last decade, the synthesis of VSOP has been refined in our laboratory, and VSOP have been explored for vascular imaging and other applications such as assessment of myocardial inflammation, sensitive detection of blood–brain barrier alterations, in vivo tracking of monocyte migration after intracerebral injection, and discrimination of different inflammatory events in an animal model of multiple sclerosis. Earlier versions of these IONP, produced as VSOP-C184 (Ferropharm, Teltow, Germany), were developed to the level of phase I and II as blood pool contrasts agent for MR angiography, but they are no longer available from the company. Very small iron oxide particles (VSOP), with a hydrodynamic diameter of 7 nm, combine high cellular uptake with low cytotoxicity due to their biocompatible citrate coating.
Therefore, the development of iron oxide-based contrast agents remains a topic of high experimental and clinical relevance.
Besides the use of IONP in MRI, the emerging technique of magnetic particle imaging (MPI) requires the development of new superparamagnetic IONP. Initially developed to treat iron anemia, ferumoxytol/feraheme ® is highly suitable for T1- and T2-weighted MRI. Recently, the safety concerns raised against some gadolinium-based contrast agents (GBCA) have motivated new attempts at off-label clinical used of magnetic IONP such as ferumoxytol. IONP was slowed down by the fast establishment of gadolinium-based contrast agents for clinical MRI and first-pass arterial MRI angiography. However, IONP that had early been approved by the US Food and Drug Administration (FDA) for liver imaging such as Endorem/Feridex ® (AMAG Pharmaceuticals, Inc., Walthman, MA, USA) and Resovist ® (Schering AG-now Bayer Pharma AG, Berlin, Germany) have not been further developed or have been withdrawn from the market.
The development of iron oxide nanoparticles (IONP) as contrast agents for magnetic resonance imaging (MRI) started about 4 decades ago. The fluorescent detection of Eu-doped very small iron oxide nanoparticles (Eu-VSOP) provides a straightforward tool to unambiguously characterize VSOP biodistribution and toxicology at tissue, and cellular levels, providing a sensitive analytical tool to detect Eu-doped IONP in dissolved organ tissue and biological fluids with fluorescence instruments. This enhancer solution allowed detection of Eu-VSOP using a standard fluorescence spectrophotometer and a fluorescence microscope equipped with a custom filter set with an excitation wavelength (λ ex) of 338 nm and an emission wavelength (λ em) of 616 nm. A customized enhancer solution with high buffer capacity and nearly neutral pH was developed to provide an antenna system that allowed fluorescent detection of Eu-VSOP in cells and histologic tissue slices as well as in solutions even under acidic conditions as frequently obtained from dissolved organic material. The resulting Eu-VSOP contained 0.7 to 2.7% Eu relative to iron, which was sufficient for fluorescent detection while not altering other important particle parameters such as size, surface charge, or relaxivity.
Here we report the full methodology for synthesizing very small iron oxide nanoparticles (VSOP) doped with europium (Eu) in their iron oxide core (Eu-VSOP) and their unambiguous qualitative and quantitative detection by fluorescence.
MktoForms2.loadForm("// iron in biological tissues frequently precludes unambiguous the identification of iron oxide nanoparticles when iron-based detection methods are used.