With 30–40% of patients failing to respond to 177Lu PSMA or acquiring resistance, this bench study asks what actually separates α from β⁻ emitters. Across PSMA-positive and PSMA-negative cells lines, 177Lu required 100 fold the activity of 225Ac to achieve comparable DNA damage. With shorter range, 225Ac ideally needs to get inside the cell with rapid internalization and intracellular retention, and homogeneous target expression. 177Lu needs high affinity and high density membrane binding, which makes it more tolerable to heterogeneous target expression. 225Ac produced higher quality DNA damage per decay that remained unrepaired through 72 hours. Whereas 177Lu damage resolved within 24 hours and behaved essentially like photon damage. Both radionuclides showed damage accruing during continuous exposure, unlike the immediate-then-declining pattern after external beam. | Winter, Int J Radiat Oncol Biol Phys 2026
