Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

Purpose The radiolanthanide Tb-161 (T (1/2) = 6.90 days, E beta(-) (av) = 154 keV) was recently proposed as a potential alternative to Lu-177 (T (1/2) = 6.71 days, E beta(-) (av) = 134 keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare Tb-161 and Lu-177 in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods Tb-161-cm09 and Lu-177-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo Tb-161-cm09 and Lu-177-cm09 (10 MBq, 0.5 nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6 months by determination of plasma parameters and examination of kidney function with quantitative SPECT using Tc-99m-dimercaptosuccinic acid (DMSA). Results To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for Tb-161-cm09 (IC50 similar to 0.014 MBq/ml and similar to 2.53 MBq/ml) compared to Lu-177-cm09 (IC50 similar to 0.063 MBq/ml and similar to 4.52 MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies Tb-161-cm09 reduced tumour growth more efficiently than Lu-177-cm09. These findings were in line with the higher absorbed tumour dose for Tb-161-cm09 (3.3 Gy/MBq) compared to Lu-177-cm09 (2.4 Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion Compared to Lu-177-cm09 we demonstrated equal imaging features for Tb-161-cm09 but an increased therapeutic efficacy for Tb-161-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of Tb-161.