PDF(Pubmed)
Abstract：
[177Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-3H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities.
摘要：
[177Lu]Lu-PSMA-617最近成功获得FDA批准，MHRA,加拿大卫生部和EMA作为Plovicto®。然而,唾液腺（SG）和肾脏毒性是其主要的剂量限制性副作用，而其相应的吸收和保留机制仍然难以捉摸。最近,存在不同的ATP结合盒（ABC）转运蛋白，如人类乳腺癌耐药蛋白（BCRP），多药耐药蛋白（MDR1），多药耐药相关蛋白（MRP1，MRP4）和溶质盒（SLC）转运体，如多药和毒素挤出蛋白（MATE1，MATE2-K），有机阴离子转运蛋白（OAT1，OAT2v1，OAT3，OAT4）和肽转运蛋白（PEPT2），已在人类SGs和肾脏中的不同丰度得到验证。因此,我们的目的是评估[177Lu]Lu-PSMA-617和[225Ac]Ac-PSMA-617是否是这些ABC和SLC转运蛋白的底物。对于体外研究，新型同位素([α，β-3H]Nal）Lu-PSMA-617用于表达上述人ABC和SLC转运蛋白的细胞系或囊泡，用于抑制和摄取研究，分别。相应的探针底物和参考抑制剂用作对照。我们的结果表明[177Lu]Lu-PSMA-617和[225Ac]Ac-PSMA-617既不是所检查转运蛋白的抑制剂也不是底物。因此,我们的结果表明，人类ABC和SLC转运蛋白在SGs和肾脏中吸收和保留[177Lu]Lu-PSMA-617和[225Ac]Ac-PSMA-617以及观察到的毒性中没有核心作用。
