Luna-Gutiérrez Myrna, Ocampo-García Blanca, Jiménez-Mancilla Nallely, Ancira-Cortez Alejandra, Trujillo-Benítez Diana, Hernández-Jiménez Tania, Ramírez-Nava Gerardo, Hernández-Ramírez Rodrigo, Santos-Cuevas Clara, Ferro-Flores Guillermina
Department of Radioactive Materials, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico.
Cátedras CONACyT, Instituto Nacional de Investigaciones Nucleares, Ocoyoacac 52750, Mexico.
Pharmaceutics. 2022 Mar 27;14(4):720. doi: 10.3390/pharmaceutics14040720.
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.
前列腺特异性膜抗原（PSMA）在多种癌细胞中表达，而成纤维细胞活化蛋白（FAP）在肿瘤微环境中表达。此前，我们报道了iPSMA和iFAP配体特异性靶向PSMA和FAP蛋白的能力，以及用靶向特异性肽功能化的稳定177Lu2O3纳米颗粒（<100 nm）的制备。本研究旨在评估经中子辐照激活的Lu2O3-iPSMA和Lu2O3-iFAP纳米颗粒的剂量学和治疗反应，以证明它们在核医学诊疗应用中的潜力。在用177Lu2O3-iPSMA、177Lu2O3-iFAP或177Lu2O3纳米颗粒治疗后，评估了临床前肿瘤组织（无胸腺小鼠）中的生物动力学行为、辐射吸收剂量和代谢活性（[18F]FDG/微型PET，SUV）。一名患有多发性结直肠癌肝转移（PSMA阳性）的患者在“同情用药”方案下接受了177Lu2O3-iPSMA治疗。结果表明，177Lu2O3-iPSMA和177Lu2O3-iFAP在肿瘤辐射吸收剂量（177Lu2O3-iPSMA、177Lu2O3-iFAP和177Lu2O3分别为105±14 Gy、99±12 Gy和58±7 Gy）和治疗后小鼠的肿瘤代谢活性（177Lu2O3-iPSMA、177Lu2O3-iFAP和177Lu2O3的SUV分别为0.421±0.092、0.375±0.104和1.821±0.891）方面无显著差异（p<0.05），这与观察到的治疗反应相关。由于肿瘤滞留时间延长以及177Lu放疗与iPSMA或iFAP分子识别的结合，177Lu2O3-iPSMA和177Lu2O3-iFAP显著抑制了肿瘤进展。非靶组织中的摄取值可忽略不计，且无肝毒性和肾毒性证据。患者肝转移灶接受的剂量（42−210 Gy）证明了177Lu2O3-iPSMA治疗结直肠癌肝转移的潜力。
