Investigation of the long-term micro-distribution, cellular dosimetry, and radiobiological effect of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T in LNCaP cells.

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Ziel/Aim: Current clinical dosimetry focuses on activity uptake at millimeter scales, measurable by SPECT or PET imaging. However, understanding the heterogeneous uptake distribution at the cellular level and its effect on dosimetry is essential for assessing response to radionuclide therapy. This study investigated the prolonged uptake kinetics of 177 Lu-PSMA-I&T and 177 Lu-PSMA-617 in LNCaP cells to determine cellular absorbed doses and correlate them with treatment effects. Methodik/Methods: For the uptake assay, 50,000 LNCaP cells were seeded in 6-well plates and incubated at 37°C with 5% CO 2 for 48 h. Cells were treated with an added activity (AA) of 300 kBq/mL of 177 Lu-PSMA-I&T or 177 Lu-PSMA-617 for 3/6/18/24 h. Membrane-bound and internalized activities were measured using a calibrated gamma counter. Cell counting was done via flow cytometry. Time-activity-curves were generated and cellular S values were calculated using MIRDcell. For the clonogenic assay, 50,000 cells were treated with varying concentrations (0-1.0 MBq/mL) of 177 Lu-PSMA-I&T and 177 Lu-PSMA-617 for 3 or 24 h. 1,000 cells were seeded in 6-well plates for 14 days before the staining. Immunofluorescence staining was performed to determine the DNA damage using DNA repair markers (53BP1 and γH2AX). Ergebnisse/Results: For 177 Lu-PSMA-I&T, internalized and membrane-bound fractions of activity varied over 24 hours, peaking at 18 hours (internalized: 3.9±1.6%AA/100,000 cells; membrane-bound: 2.2±0.6%AA/100,000 cells; total activity: 6.1±1.8%AA/100,000 cells). In contrast, 177 Lu-PSMA-617 exhibited higher uptake and more constant fractions of internalized and membrane-bound activity until 24 h (18 h: internalized: 1.2±0.6%AA/100,000 cells; membrane-bound: 6.1±0.8%AA/100,000 cells; total activity: 7.3-±1.3%AA/100,000 cells). The absorbed doses were 21 Gy for 177 Lu-PSMA-I&T and 26 Gy for 177 Lu-PSMA-617. Both radiopharmaceuticals demonstrated similar, dose-dependent reductions in clonogenic survival and number of DSB foci. Schlussfolgerungen/Conclusion: 177 Lu-PSMA-I&T shows a lower activity per cell and a higher internalized activity compared to 177 Lu-PSMA-617. Cellular absorbed doses were higher for 177 Lu-PSMA-617 for the same added activity. However, preliminary analysis shows a comparable DNA damage and cell survival for the same range of added activities. Publication History Article published online: 12 March 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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