Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.220277v1?rss=1 Authors: PILLARSETTY, N., Kalidindi, T. M., Lee, S. G., Jou, K., Chakraborty, G., Skafida, M., Tagawa, S. T., Bander, N. H., Schoder, H., Bodei, L., Pandit-Taskar, N., Lewis, J. S., Larson, S. M., Osborne, J. R. Abstract: The past five years have seen an increasing acceptance of peptide-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) agents for treatment of metastatic castration-resistant prostate cancer (mCRPC), with [177Lu]-DKFZ-PSMA-617 ([177Lu]-PSMA-617) emerging as the leading candidate. [177Lu]-PSMA-617 and other PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to salivary gland and kidneys is a concern and dose limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Here, we report the effects of the addition of the cold PSMA ligand DKFZ-PSMA-11 (PSMA-11) on the uptake of [177Lu]-PSMA-617 in tumor, salivary glands and kidneys. Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [177Lu]-PSMA-617 along with 0, 5, 100, 500, 1000 and 2000 pmoles of PSMA-11. Biodistribution studies 1 h post-administration revealed that [177Lu]-PSMA-617 uptake in PSMA-expressing PC3-PIP tumors was 21.71{+/-}6.13, 18.7{+/-}2.03, 26.44{+/-}2.94, 16.21{+/-}3.5, 13.52{+/-}3.68, and 12.03{+/-}1.96 %ID/g when 0, 5, 100, 500, 1000 and 2000 pmoles of PSMA-11 were added, respectively. Corresponding kidney uptake values were 123.14{+/-}52.52, 132.31{+/-}47.4, 84.29{+/-}78.25, 2.12{+/-}1.88, 1.16{+/-}0.36, 0.64{+/-}0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48{+/-}0.11, 0.45{+/-}0.15, 0.38{+/-}0.3, 0.08{+/-}0.03, 0.09{+/-}0.07, 0.05{+/-}0.02 % ID/g, respectively. Thus, uptake of PSMA TRT agents in salivary gland and kidney can be substantially reduced without impact on tumor uptake by adding cold PSMA-11. Our data provides proof-of-concept and we propose that similar strategy be pursued in future clinical trials to prevent xerostomia and renal toxicity arising from [177Lu]-PSMA-617. Copy rights belong to original authors. Visit the link for more info