Microbrachytherapy with radioactive holmium-166 (166Ho) microspheres (MS) has the potential to be an effective treatment method for brain malignancies. Direct intratumoural delivery of 166Ho-MS and dose coverage of the whole tumour are crucial requirements. However, currently no dedicated instruments for controlled intratumoural delivery exist. This study presents an administration device that facilitates this novel magnetic resonance imaging (MRI) -guided intervention. The bioceramic alumina oxide cannula creates a straight channel for a superelastic nitinol precurved stylet to control spatial deposition of Ho-MS. End-point accuracy of the stylet was measured during insertions in phantoms. Imaging tests were performed in a 3 Tesla MRI-scanner to quantify instrument-induced artefacts. Additionally, the feasibility of non-radioactive holmium-165 (165Ho)-MS delivery with the administration device was evaluated in a brain tumour simulant. Absolute stylet tip error was 0.88 ± 0.61 mm, instrument distortion in MRI depended on needle material and orientation and dose delivery of 165Ho-MS in a brain tumour phantom was possible. This study shows that the administration device can accurately place the stylet for injection of Ho-MS and that visualization can be performed with MRI.

Microspheres with high specific activities of radionuclides are very interesting for internal radiotherapy treatments. This work focuses on the formulation and characterization of inorganic microspheres with a high content of holmium and therefore a high specific radioactivity of holmium-166. Two novel formulations of inorganic microspheres were obtained by dispersing solid holmium acetylacetonate microspheres (Ho₂(AcAc)₃-ms) in NaH₂PO₄ or NaOH solutions followed by 2 h incubation at room temperature. By exchange of acetylacetonate with phosphate or hydroxyl ions, holmium phosphate microspheres (HoPO₄-ms) and holmium hydroxide microspheres (Ho(OH)₃-ms) were formed respectively. The inorganic microspheres had a significantly smaller diameter (28.5 ± 4.4 μm (HoPO₄-ms) and 25.1 ± 3.5 μm (Ho(OH)₃-ms)) than those of Ho₂(AcAc)₃-ms (32.6 ± 5.2 μm). The weight percentage of holmium-165 in the microspheres increased significantly from 47% (Ho₂(AcAc)₃-ms) to 55% (HoPO₄-ms) and 73% (Ho(OH)₃-ms). After preparation of both HoPO₄-ms and Ho(OH)₃-ms, the stable holmium-165 isotope was partly converted by neutron activation into radioactive holmium-166 to yield radioactive microspheres. High specific activities were achieved ranging from 21.7 to 59.9 MBq/mg (¹⁶⁶HoPO₄-ms) and from 28.8 to 79.9 MBq/mg (¹⁶⁶Ho(OH)₃-ms) depending on the neutron activation time. The structure of both microspheres was preserved up to neutron activations of 6 h in a thermal neutron flux of 4.72 × 10¹⁶ n m⁻² s⁻¹. After activation, both microspheres revealed excellent stability in administration fluids (saline and phosphate buffer) having less than 0.05% of holmium released after 72 h incubation. Finally, the hemocompatibility of these inorganic microspheres was evaluated and it was shown that the microspheres did cause neither hemolysis nor depletion or inhibition of the coagulation factors of the intrinsic blood coagulation pathway meaning that the microspheres have a good hemocompatibility. Overall, this work shows that radioactive inorganic microspheres with high specific activities of holmium-166 can be prepared which potentially can be used for internal radionuclide therapy.

The aim of this study was the development of radioactive holmium phosphate microspheres (HoPO₄-MS) with a high holmium content and that are stable in human serum for selective internal radiation therapy (SIRT) of liver cancer. To this end, holmium acetylacetonate microspheres (HoAcAc-MS) were prepared (34.2 ± 1.0 µm in diameter, holmium content of 46.2 ± 0.8 and density of 1.7 g/cm³) via an emulsification and solvent evaporation method. The concentration of HoAcAc in the organic solvent, the temperature of emulsification and the stirring speed were varied for the preparation of the HoAcAc-MS to obtain microspheres with different diameters ranging from 11 to 35 µm. Subsequently, the AcAc ligands of the HoAcAc-MS were replaced by phosphate ions by simply incubating neutron irradiated HoAcAc-MS in a phosphate buffer solution (0.116 M, pH 4.2) to yield radioactive HoPO₄-MS. The obtained microspheres were analyzed using different techniques such as SEM-EDS, ICP-OES and HPLC. The prepared HoPO₄-MS (29.5 ± 1.2 µm in diameter and a density of 3.1 g/cm³) present an even higher holmium content (52 wt%) than the HoAcAc-MS precursor (46 wt%). Finally, the stability of the HoPO₄-MS was tested by incubation in human serum at 37 °C which showed no visible changes of the microspheres morphology and only 0.1% of holmium release was observed during the 2 weeks period of incubation. In conclusion, this study shows that stable radioactive HoPO₄-MS can be prepared with suitable properties to be used for cancer therapy.