Targeted Endoradiotherapy with Lu2O3-iPSMA/-iFAP Nanoparticles Activated by Neutron Irradiation: Preclinical Evaluation and First Patient Image

Pharmaceutics

Nallely Jiménez-Mancilla¹  Diana Trujillo-Benítez²  Blanca Ocampo-García²  Guillermina Ferro-Flores²  Tania Hernández-Jiménez²  Myrna Luna-Gutiérrez²  Clara Santos-Cuevas²  Gerardo Ramírez-Nava²  Alejandra Ancira-Cortez²  Rodrigo Hernández-Ramírez³ 

[1] Cátedras CONACyT, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico;Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico;Nuclear Medicine Department, Hospital Médica Sur, Mexico City 14080, Mexico;

关键词: lutetium oxide nanoparticles;    prostate-specific membrane antigen inhibitor;    fibroblast activation protein inhibitor;    lutetium-177;   

DOI  :  10.3390/pharmaceutics14040720

来源: DOAJ

【 摘 要 】

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 ¹⁷⁷Lu₂O₃ nanoparticles (<100 nm) functionalized with target-specific peptides. This research aimed to evaluate the dosimetry and therapeutic response of Lu₂O₃-iPSMA and Lu₂O₃-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 ([¹⁸F]FDG/micro-PET, SUV) in preclinical tumor tissues (athymic mice), following treatment with ¹⁷⁷Lu₂O₃-iPSMA, ¹⁷⁷Lu₂O₃-iFAP or ¹⁷⁷Lu₂O₃ nanoparticles, were assessed. One patient with multiple colorectal liver metastases (PSMA-positive) received ¹⁷⁷Lu₂O₃-iPSMA under a “compassionate use” protocol. Results indicated no significant difference (p < 0.05) between ¹⁷⁷Lu₂O₃-iPSMA and ¹⁷⁷Lu₂O₃-iFAP, regarding tumor radiation absorbed doses (105 ± 14 Gy, 99 ± 12 Gy and 58 ± 7 Gy for ¹⁷⁷Lu₂O₃-iPSMA, ¹⁷⁷Lu₂O₃-iFAP, and ¹⁷⁷Lu₂O₃, respectively) and tumor metabolic activity (SUV of 0.421 ± 0.092, 0.375 ± 0.104 and 1.821 ± 0.891 for ¹⁷⁷Lu₂O₃-iPSMA, ¹⁷⁷Lu₂O₃-iFAP, and ¹⁷⁷Lu₂O₃, respectively) in mice after treatment, which correlated with the observed therapeutic response. ¹⁷⁷Lu₂O₃-iPSMA and ¹⁷⁷Lu₂O₃-iFAP significantly inhibited tumor progression, due to the prolonged tumor retention and a combination of ¹⁷⁷Lu 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 ¹⁷⁷Lu₂O₃-iPSMA for treating colorectal liver metastases.

【 授权许可】

Unknown