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.