Therapeutic efficacy of heterogeneously distributed radiolabelled peptides: Influence of radionuclide choice

Purpose: To model dose-response relationships for in vivo experiments with radiolabelled peptides enabling maximum therapeutic efficacy while limiting toxicity to kidney and bone marrow. Methods: A multiregional murine kidney phantom, with a kinetic model for cortex and outer medulla distribution, were used to predict renal toxicity. Maximum tolerated activities to avoid nephrotoxicity (at 40 Gy Biological Effective Dose BED) and hematologic toxicity (at 2 Gy) were compared. The therapeutic efficacy of ⁹⁰Y, ¹⁶¹Tb, ¹⁷⁷Lu and ²¹³Bi was assessed at their respective maximum tolerated activities based on cellular-level dosimetry accounting for activity and tumor heterogeneity. These results were compared with average tumor-dosimetry-based predictions. Results: The kidney was found to be the dose-limiting organ for all radionuclides, limiting the administered activity to 44 MBq ¹⁷⁷Lu, 34 MBq ¹⁶¹Tb, 19 MBq ⁹⁰Y and 13 MBq ²¹³Bi, respectively. The average S-values for the initial heterogeneous activity distribution in the tumor volume are not significantly different from the homogeneous ones. The in vivo tumor cell survivals predicted by assuming uniform dose rate-distributions are not significantly different from those for heterogeneous dose rate-based predictions. The lowest in vivo survival was found for ²¹³Bi (2%) followed by ¹⁶¹Tb (30%), ¹⁷⁷Lu (37%) and ⁹⁰Y (60%). The minimal effective dose rate for cell kill is 13–14 mGy/h for β-emitters and 2.2 mGy/h for the α-particle emitter ²¹³Bi, below these values proliferation takes over. Conclusions: Radionuclides emitting α-particles have the highest potential for improving therapeutic efficacy in tumors and metastases with uniform receptor expression, after careful evaluation of their burden to the healthy organs.