Comparison of the dosimetry and cell survival effect of 177Lu and 161Tb somatostatin analog radiopharmaceuticals in cancer cell clusters and micrometastases.

Background: ¹⁷⁷Lu-based radiopharmaceuticals (RPs) are the most used for targeted radionuclide therapy (TRT) due to their good response rates. However, the worldwide availability of ¹⁷⁷Lu is limited. ¹⁶¹Tb represents a potential alternative for TRT, as it emits photons for SPECT imaging, β^--particles for therapy, and also releases a significant yield of internal conversion (IE) and Auger electrons (AE). This research aimed to evaluate cell dosimetry with the MIRDcell code considering a realistic localization of three ¹⁶¹Tb- and ¹⁷⁷Lu-somatostatin (SST) analogs in different subcellular regions as reported in the literature, various cell cluster sizes (25-1000 µm of radius) and percentage of labeled cells. Experimental values of the α- and β-survival coefficients determined by external beam photon irradiation were used to estimate the survival fraction (SF) of AR42J pancreatic cell clusters and micrometastases.

Results: The different localization of RPs labeled with the same radionuclide within the cells, resulted in only slight variations in the dose absorbed by the nuclei (AD_N) of the labeled cells with no differences observed in either the unlabeled cells or the SF. AD_N of labeled cells (MDLC) produced by ¹⁶¹Tb-RPs were from 2.8-3.7 times higher than those delivered by ¹⁷⁷Lu-RPs in cell clusters with a radius lower than 0.1 mm and 10% of labeled cells, due to the higher amount of energy emitted by ¹⁶¹Tb-disintegration in form of IE and AE. However, the ¹⁶¹Tb-RPs/¹⁷⁷Lu-RPs MDLC ratio decreased below 1.6 in larger cell clusters (0.5-1 mm) with > 40% labeled cells, due to the significantly higher ¹⁷⁷Lu-RPs cross-irradiation contribution. Using a fixed number of disintegrations, SFs of ¹⁶¹Tb-RPs in clusters with > 40% labeled cells were lower than those of ¹⁷⁷Lu-RPs, but when the same amount of emitted energy was used no significant differences in SF were observed between ¹⁷⁷Lu- and ¹⁶¹Tb-RPs, except for the smallest cluster sizes.

Conclusions: Despite the emissions of IE and AE from ¹⁶¹Tb-RPs, their localization within different subcellular regions exerted a negligible influence on the AD_N. The same cell damage produced by ¹⁷⁷Lu-RPs could be achieved using smaller quantities of ¹⁶¹Tb-RPs, thus making ¹⁶¹Tb a suitable alternative for TRT.