Holmium-lipiodol-alginate microspheres for fluoroscopy-guided embolotherapy and multimodality imaging

Oerlemans, Chris, Seevinck, Peter R, Smits, Maarten L, Hennink, Wim E, Bakker, Chris J G, van den Bosch, Maurice A A J, Nijsen, JFW


International Journal of Pharmaceutics 482 (1-2), p. 47-53


Embolotherapy is a minimally invasive transcatheter technique aiming at reduction or complete obstruction of the blood flow by infusion of micro-sized particles in order to induce tumor regression. A major drawback of the current commercially available and clinically used microspheres is that they cannot be detected in vivo with medical imaging techniques, impeding intra- and post-procedural feedback. It can be expected that real-time monitoring of microsphere infusion and post-procedural imaging will result in better predictability and higher efficacy of the treatment. In this study, a novel microsphere formulation has been developed that can be visualized with fluoroscopy, X-ray computed tomography (CT) and magnetic resonance imaging (MRI). The microspheres were prepared with the JetCutter technique and consist of alginate (matrix-forming polymer), holmium (cross-linking and MRI contrast agent), lipiodol (radiopaque contrast agent) and Pluronic F-68 (surfactant). The mean size (±SEM) of the hydrated holmium-lipiodol-alginate microspheres (Ho-lip-ams) was 570±12 μm with a holmium content of 0.38±0.01% (w/w). Stability studies showed that the microspheres remained intact during incubation for two weeks in fetal calf serum (FCS) at 37 °C. The inclusion of lipiodol in the microspheres rendered excellent visualization capabilities for fluoroscopy and CT, whereas the holmium ions, which keep the alginate network together, also allow MR imaging. In this study it was shown that single sphere detection was possible by fluoroscopy, CT and MRI. The Ho-lip-ams were visualized in real-time, during infusion in a porcine kidney using fluoroscopy, and post-procedural, the deposition of the microspheres was examined with fluoroscopy, (cone beam rotational) CT and MRI. The different imaging modalities showed similar deposition patterns of the microspheres within the organ. The combination of intra-procedural visualization, multimodality imaging for patient follow-up and the possibility of quantification offers a new and promising method for more safe, efficient and successful embolization treatment.