Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Science for Life, Faculty of Science, Utrecht University, 3508 TB, Utrecht, the Netherlands; Radiation Science and Technology, Delft University of Technology, Mekelweg 15, 2629 JB, Delft, the Netherlands; Radboudumc, Department of Radiology and Nuclear Medicine, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, the Netherlands.
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Science for Life, Faculty of Science, Utrecht University, 3508 TB, Utrecht, the Netherlands.
Mater Sci Eng C Mater Biol Appl. 2020 Jan;106:110244. doi: 10.1016/j.msec.2019.110244. Epub 2019 Oct 14.
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 (Ho(AcAc)-ms) in NaHPO or NaOH solutions followed by 2 h incubation at room temperature. By exchange of acetylacetonate with phosphate or hydroxyl ions, holmium phosphate microspheres (HoPO-ms) and holmium hydroxide microspheres (Ho(OH)-ms) were formed respectively. The inorganic microspheres had a significantly smaller diameter (28.5 ± 4.4 μm (HoPO-ms) and 25.1 ± 3.5 μm (Ho(OH)-ms)) than those of Ho(AcAc)-ms (32.6 ± 5.2 μm). The weight percentage of holmium-165 in the microspheres increased significantly from 47% (Ho(AcAc)-ms) to 55% (HoPO-ms) and 73% (Ho(OH)-ms). After preparation of both HoPO-ms and Ho(OH)-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 (HoPO-ms) and from 28.8 to 79.9 MBq/mg (Ho(OH)-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 × 10 n m s. 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.
具有高放射性核素比活度的微球非常适合用于内部放射治疗。本工作重点研究了通过在 NaHPO 或 NaOH 溶液中分散固态钬乙酰丙酮微球（Ho(AcAc)-ms），并在室温下孵育 2 小时，得到两种新型无机微球的配方和特性。通过与磷酸根或氢氧根离子交换，分别形成了磷酸钬微球（HoPO-ms）和氢氧化钬微球（Ho(OH)-ms）。无机微球的直径明显小于 Ho(AcAc)-ms（28.5±4.4μm (HoPO-ms) 和 25.1±3.5μm (Ho(OH)-ms)）（32.6±5.2μm）。微球中钬-165 的重量百分比从 47%（Ho(AcAc)-ms）显著增加到 55%（HoPO-ms）和 73%（Ho(OH)-ms）。制备 HoPO-ms 和 Ho(OH)-ms 后，通过中子激活，稳定的钬-165 同位素部分转化为放射性钬-166，得到放射性微球。根据中子激活时间，实现了高达 21.7 至 59.9 MBq/mg（HoPO-ms）和 28.8 至 79.9 MBq/mg（Ho(OH)-ms）的高比活度。在热中子通量为 4.72×10 n m s 的情况下，两种微球的结构在长达 6 小时的中子激活下得以保留。激活后，两种微球在给药液（生理盐水和磷酸盐缓冲液）中均表现出优异的稳定性，在 72 小时孵育后，释放的钬不到 0.05%。最后，评估了这些无机微球的血液相容性，结果表明微球既不会引起溶血，也不会耗尽或抑制内源性血液凝固途径的凝血因子，这意味着微球具有良好的血液相容性。总体而言，这项工作表明，可以制备具有高比活度的放射性无机微球，有望用于内部放射性核素治疗。
