Targeted Endoradiotherapy with Lu(2)O(3)-iPSMA/-iFAP Nanoparticles Activated by Neutron Irradiation: Preclinical Evaluation and First Patient Image

Prostate-specific membrane antigen (PSMA) is expressed in a variety of cancer cells, while the fibroblast activation protein (FAP) is expressed in the microenvironment of tumors. Previously, we reported the ability of iPSMA and iFAP ligands to specifically target PSMA and FAP proteins, as well as the preparation of stable (177)Lu(2)O(3) nanoparticles (<100 nm) functionalized with target-specific peptides. This research aimed to evaluate the dosimetry and therapeutic response of Lu(2)O(3)-iPSMA and Lu(2)O(3)-iFAP nanoparticles activated by neutron irradiation to demonstrate their potential for theranostic applications in nuclear medicine. The biokinetic behavior, radiation absorbed dose, and metabolic activity ([(18)F]FDG/micro-PET, SUV) in preclinical tumor tissues (athymic mice), following treatment with (177)Lu(2)O(3)-iPSMA, (177)Lu(2)O(3)-iFAP or (177)Lu(2)O(3) nanoparticles, were assessed. One patient with multiple colorectal liver metastases (PSMA-positive) received (177)Lu(2)O(3)-iPSMA under a “compassionate use” protocol. Results indicated no significant difference (p < 0.05) between (177)Lu(2)O(3)-iPSMA and (177)Lu(2)O(3)-iFAP, regarding tumor radiation absorbed doses (105 ± 14 Gy, 99 ± 12 Gy and 58 ± 7 Gy for (177)Lu(2)O(3)-iPSMA, (177)Lu(2)O(3)-iFAP, and (177)Lu(2)O(3), respectively) and tumor metabolic activity (SUV of 0.421 ± 0.092, 0.375 ± 0.104 and 1.821 ± 0.891 for (177)Lu(2)O(3)-iPSMA, (177)Lu(2)O(3)-iFAP, and (177)Lu(2)O(3), respectively) in mice after treatment, which correlated with the observed therapeutic response. (177)Lu(2)O(3)-iPSMA and (177)Lu(2)O(3)-iFAP significantly inhibited tumor progression, due to the prolonged tumor retention and a combination of (177)Lu radiotherapy and iPSMA or iFAP molecular recognition. There were negligible uptake values in non-target tissues and no evidence of liver and renal toxicity. The doses received by the patient’s liver metastases (42–210 Gy) demonstrated the potential of (177)Lu(2)O(3)-iPSMA for treating colorectal liver metastases.