Abstract:
The radionuclide therapy [177Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [177Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [177Lu]Lu-PSMA-617 to characterize its binding. Additionally, [177Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [177Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [177Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [177Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [177Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.
摘要:
放射性核素治疗[177Lu]Lu-PSMA-617最近被FDA批准用于治疗转移性去势抵抗性前列腺癌。唾液腺毒性目前被认为是主要的剂量限制性副作用。然而,其在唾液腺中的摄取和保留机制仍然难以捉摸。因此,我们的目的是通过进行细胞结合和放射自显影实验,阐明[177Lu]Lu-PSMA-617在唾液腺组织和细胞中的摄取模式。简而言之,A-253和PC3-PIP信元,小鼠肾脏和猪唾液腺组织,用5nM[177Lu]Lu-PSMA-617孵育以表征其结合。此外,[177Lu]Lu-PSMA-617与味精共孵育,离子型或代谢型谷氨酸受体拮抗剂。Low,在唾液腺细胞和组织中观察到非特异性结合。味精能够降低PC3-PIP细胞中的[177Lu]Lu-PSMA-617,小鼠肾脏和猪唾液腺组织。犬尿烯酸(离子型拮抗剂)将[177Lu]Lu-PSMA-617的结合降低至29.2±20.6%和63.4±15.4%,分别,在组织上观察到类似的效果。(RS)-MCPG(代谢拮抗剂)能够将[177Lu]Lu-PSMA-617与A-253细胞的结合降低至68.2±16.8%,将猪唾液腺组织降低至53.1±36.8%。最后,我们发现味精可以减少[177Lu]Lu-PSMA-617上的非特异性结合,犬尿氨酸和(RS)-MCPG。