Lanthanide bearing radioactive particles for cancer therapy and multimodality imaging (2006)

Local radionuclide therapy using radioactive microspheres is a promising therapy for patients suffering from liver malignancies. In contrast to normal liver tissue, which receives most of its blood flow from the portal vein, liver malignancies are almost exclusively dependent on arterial blood supply. Based on this difference in blood supply, it has been demonstrated that radioactive microspheres with a diameter between 20 and 50 mm that are injected into the hepatic artery, selectively lodge in and around the tumours and thereby irradiate the surrounding tissue. The treatment of cancer with holmium-166 loaded microspheres has obvious advantages over the use of other radionuclides, because holmium is the only element, which can be easily neutron-activated to a beta- and gamma-emitter with a logistically favourable half-life (26.8 h), and it can also be visualized by magnetic resonance imaging (MRI). Using a solvent evaporation technique, non-radioactive holmium-165 can be incorporated into poly(L-lactic acid) (PLLA) microspheres as its acetylacetonate complex (HoAcAc). In a subsequent step, the microspheres (Ho-PLLA-MS) can be neutron activated. Before Ho-PLLA-MS can be clinically applied in patients, the pharmaceutical quality of the microspheres must be well defined, and in addition, the entire production procedure should be in compliance with the Good Manufacturing Practice (GMP) regulations. The setup of a GMP production process resulted in Ho-PLLA-MS batches of which the pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) were in compliance with the requirements of the European Pharmacopoeia. Moreover, the administration of Ho-PLLA-MS must not lead to toxic effects. A biocompatibility study in healthy rats showed that neutron-irradiated Ho-PLLA-MS had a good biocompatibility. An in vitro degradation study showed that the degradation of Ho-PLLA-MS resulted in the formation of holmium lactate. Lanthanides, among which holmium, offer great opportunities for new anticancer therapies that can be visualized with different imaging modalities. Therefore, also other lanthanide-loaded particles have been designed. Holmium-loaded alginate microspheres with a mean size of 160 mm can be used therapeutically for embolization and, when radioactive, for local radiotherapy of tumours. The preparation and characterisation of holmium-loaded liposomes for was investigated and showed that these liposomes could be used for multilimodality imaging and cancer therapy. Liposomes formulations were successfully labelled with radioactive holmium, allowing local radionuclide therapy and visualisation with a gamma camera. The incorporation of gadolinium acetylacetonate resulted in a strong effect on the relaxivity of the liposomes, allowing their detection with MRI. In conclusion, the preclinical research described in this thesis demonstrates that regarding the pharmaceutical quality and biocompatibility of Ho-PLLA-MS clinical research can be initiated. Furthermore, the possibility to image therapeutic radionuclides like holmium with different modalities such as gamma cameras and MRI offers great opportunities for the development of other advanced radionuclide cancer therapies.