In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T

PURPOSE: Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [(225)Ac]Ac-PSMA-I&T and [(177)Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy. METHODS AND RESULTS: The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [(225)Ac]Ac-PSMA-I&T and [(177)Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [(225)Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [(177)Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [(225)Ac]Ac-PSMA-I&T and [(177)Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [(225)Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [(177)Lu]Lu-PSMA-I&T. CONCLUSION: We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [(225)Ac]Ac-PSMA-I&T compared to [(177)Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [(225)Ac]Ac-PSMA-I&T compared to [(177)Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-05821-w.