Characterization of holmium loaded alginate microspheres for multimodality imaging and therapeutic applications

In this paper the preparation and characterization of holmium‐loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug‐loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron‐activated resulting in the emission of gamma‐radiation, allowing visualisation with gamma cameras, and beta‐radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho3+ binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 μm and a holmium loading of 1.3 ± 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 ± 0.3% (w/w)). The binding capacity of the alginate polymer for Ho3+ (expressed in molar amounts) is equal to that for Ca2+, which is commonly used for the hardening of alginate. This indicates that Ho3+ has the same binding affinity as Ca2+. In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca2+ or Ho3+ had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R2* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium‐166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after 48 h incubation in human serum), allowing therapeutic applications for treatment of cancer. The potential in vivo application of the microspheres for a MR‐guided renal embolization procedure was illustrated by selective administration of microspheres to the left kidney of a pig. Anatomic MR‐imaging showed the presence of holmium‐loaded microspheres in the kidney. In conclusion, this study demonstrates that the incorporation of holmium into alginate microspheres allows their visualisation with a gamma camera and MRI. Hol