The prostate-specific membrane antigen holds potential as a vascular target for endogenous radiotherapy with [¹⁷⁷Lu]Lu-PSMA-I&T for triple-negative breast cancer

Introduction Overexpression of prostate-specific membrane antigen (PSMA) on the vasculature of triple-negative breast cancer (TNBC) presents a promising avenue for targeted endogenous radiotherapy with [Lu-177]Lu-PSMA-I&T. This study aimed to assess and compare the therapeutic efficacy of a single dose with a fractionated dose of [Lu-177]Lu-PSMA-I&T in an orthotopic model of TNBC. Methods Rj:NMRI-Foxn1(nu/nu) mice were used as recipients of MDA-MB-231 xenografts. The single dose group was treated with 1 x 60 +/- 5 MBq dose of [Lu-177]Lu-PSMA-I&T, while the fractionated dose group received 4 x a 15 +/- 2 MBq dose of [Lu-177]Lu-PSMA-I&T at 7 day intervals. The control group received 0.9% NaCl. Tumor progression was monitored using [F-18]FDG-PET/CT. Ex vivo analysis encompassed immunostaining, TUNEL staining, H&E staining, microautoradiography, and autoradiography. Results Tumor volumes were significantly smaller in the single dose (p < 0.001) and fractionated dose (p < 0.001) groups. Tumor growth inhibition rates were 38% (single dose) and 30% (fractionated dose). Median survival was notably prolonged in the treated groups compared to the control groups (31d, 28d and 19d for single dose, fractionated dose and control, respectively). [Lu-177]Lu-PSMA-I&T decreased the size of viable tumor areas. We further demonstrated, that [Lu-177]Lu-PSMA-I&T binds specifically to the tumor-associated vasculature. Conclusion This study highlights the potential of [Lu-177]Lu-PSMA-I&T for endogenous radiotherapy of TNBC.