Univ. Grenoble Alpes, CEA, CNRS, IRIG-SyMMES, F-38000 Grenoble, France; Univ. Grenoble Alpes, CEA, LETI-DTBS, F-38000 Grenoble, France.
Univ. Grenoble Alpes, CNRS, CEA, IRIG - Laboratoire de Chimie et Biologie des Métaux, F-38000 Grenoble, France.
Int J Pharm. 2021 Nov 20;609:121193. doi: 10.1016/j.ijpharm.2021.121193. Epub 2021 Oct 18.
Copper homeostasis is finely regulated in human to avoid any detrimental impact of free intracellular copper ions. Upon copper accumulation, biliary excretion is triggered in liver thanks to trafficking of the ATP7B copper transporter to bile canaliculi. However, in Wilson's disease this protein is mutated leading to copper accumulation. Current therapy uses Cu chelators acting extracellularly and requiring a life-long treatment with side effects. Herein, a new Cu(I) pro-chelator was encapsulated in long-term stable nanostructured lipid carriers. Cellular assays revealed that the pro-chelator protects hepatocytes against Cu-induced cell death. Besides, the cellular stresses induced by moderate copper concentrations, including protein unfolding, are counteracted by the pro-chelator. These data showed the pro-chelator efficiency to deliver intracellularly an active chelator that copes with copper stress and surpasses current and under development chelators. Although its biological activity is more mitigated, the pro-chelator nanolipid formulation led to promising results. This innovative approach is of outmost importance in the quest of better treatments for Wilson's disease.
铜稳态在人体中受到精细调控，以避免游离细胞内铜离子产生任何有害影响。当铜积累时，肝脏中 ATP7B 铜转运蛋白向胆小管的转运触发胆汁排泄。然而，在威尔逊病中，这种蛋白质发生突变导致铜积累。目前的治疗方法使用作用于细胞外的 Cu 螯合剂，需要终身治疗，并伴有副作用。本文将一种新型 Cu(I) 前螯合剂包封在长期稳定的纳米结构脂质载体中。细胞实验表明，该前螯合剂可保护肝细胞免受 Cu 诱导的细胞死亡。此外，前螯合剂还能抵抗由中等铜浓度引起的细胞应激，包括蛋白展开。这些数据表明，前螯合剂能够有效地将活性螯合剂递送至细胞内，以应对铜应激，优于当前和正在开发的螯合剂。尽管其生物活性较低，但前螯合剂纳米脂质制剂仍取得了有希望的结果。这种创新方法对于寻找威尔逊病更好的治疗方法至关重要。
