Carbon materials tailored for 225Ac/213Bi separation and their use in radionuclide generators

Cancer is a significant public health issue and one of the leading causes of death worldwide. Accordingly, developing effective cancer treatment strategies is of critical importance. One emerging approach involves targeted alpha therapy, which offers the potential of introducing highly cytotoxic effects on cancer cells and minimal damage to surrounding healthy cells. Bismuth-213 (213Bi) is a promising candidate for targeted alpha therapy. But its production, involving the separation from other radionuclides, on the required clinical scale is challenging. 213Bi is typically produced from the decay of 225Ac and is subsequently separated by radionuclide generators. Radionuclide generators can provide medical radionuclides locally, within hospitals, to circumvent the ongoing need for a dedicated production facility. However, the current sorbents used in the 225Ac/213Bi generators lack the separation performance to ensure a reliable and long-term production of 213Bi from 225Ac (e.g., 4 GBq) for large-scale clinical applications. The main reasons for this are the harsh conditions of the separation, and the strict set of requirements posed any material for clinical applications.

Carbon materials with polycyclic aromatic rings typically exhibit high radiation resistance and considerable chemical stability under highly acidic conditions (e.g., pH < 2), and have already been widely used in metal ions separation. As far as is known, there are currently no reports regarding the use of carbon materials or their derivatives to separate 225Ac and 213Bi. Typically, carbon materials possess insufficient functional groups due to the decomposition of heteroatoms, such as oxygen and hydrogen, at elevated temperatures. However, grafting functional groups directly onto carbon materials can tune the interaction mechanism of 225Ac and 213Bi, thereby improving the sorption capacity and separation factors of the isotope of interest.

This thesis reports on the design of carbon materials tailoring their porous architecture and the nature of the functional groups, aiming at an optimal separation performance. The synthesized sorbents were thoroughly characterized utilizing complementary techniques, including SEM, XRD, N2 adsorption-desorption, TGA-MS, XPS, DRIFT, elemental analysis, and NMR. Batch experiments and column chromatography were used to investigate the separation performance of these materials.

In a first stage, the influence of the nature and amount of carboxylic and sulfonic acid groups on the surface of an activated carbon was investigated. Therefore, the impact of the sulfonation conditions on the sorption performance was studied. The sulfonation treatment resulted in the grafting of substantial amounts of oxidized sulfur- and oxygen-containing groups, and a decrease in specific surface area due to the high density of functional groups, increased carbon sheet stacking, and the possible structural damage induced by the severe oxidation process. The comparison of the sorption performance revealed that the oxygen-containing groups are the primary active sorption sites for La3+, Ac3+, and Bi3+. La3+ was confirmed as a relevant surrogate for Ac3+ regarding its sorption behavior onto these carbon materials. The sorption and desorption properties of La3+/Ac3+/Bi3+ demonstrated the potential of such surface-modified activated carbon as sorbent materials in inverse generators.

Next, the gamma radiation stability of the sulfonated activated carbon materials was benchmarked with that of the commonly used AG MP-50 resin. The surface-modified activated carbon materials exhibited a higher radiation stability compared to the AG MP-50 resin, as indicated by a full material characterization and the unaltered sorption performance.

Despite the promising results of these materials, fine powders with high specific surface area pose some restrictions on their use in column chromatographic applications. To overcome this issue, shaping of the carbon materials in granulates or microspheres is an essential step towards their implementation in a generator. First, coarser, but irregularly shaped carbon materials were synthesized by an optimization of the pyrolysis conditions of a carbon precursor and the subsequent sulfonation. Classification of the pyrolyzed carbon material yielded different particle size distributions in the range between 25 and 300 µm. Based upon batch testing, column experiments were conducted, resulting in a high 213Bi yield (94%) with less than 0.04% 225Ac impurity under optimized conditions. The proof of concept of a multi-column selective 225Ac/213Bi inverse generator was established using the surface-modified carbon material in the primary column and AG MP-50 in the guard column.

A next step in the design of carbon sorbents consisted in the synthesis of spherical carbon particles, as column packing and the avoidance of preferential pathways in the column could even further improve the performance in column chromatography. The shaping route for spherical surface-modified carbon beads by pyrolysis of spherical cellulose beads and following sulfonation or oxidization treatments was preliminarily investigated.

In addition to sulfonic acid and carboxylic groups, phosphate groups were also investigated for 225Ac/213Bi separation. Commercially available bis(2-ethylhexyl) phosphate (BEHP) impregnated activated carbon was used as an example to explore the La3+ and Bi3+ separation mechanism. The phosphate groups adsorbed La3+ by electrostatic attraction and surface complexation. These results showed that the phosphate groups have a potential application in both direct and inverse generators for 225Ac and 213Bi separation. However, further studies, including column tests, are required to identify more appropriate eluents.

Overall, the studies reported herein elucidated the Bi3+/La3+/225Ac3+ separation mechanisms of three acidic functional groups on a carbon matrix. The potential use of surface-modified carbon materials for the separation of high-activity 213Bi from 225Ac in inverse generators, including the use of an AG MP-50 guard column, was validated. Based upon these results, an automated system for multi-column inverse generator setups can be envisioned to supply 213Bi in radiopharmaceutical applications. These comprehensive insights can guide future improvements in 225Ac/213Bi separation technologies and potentially open up new avenues for research.