急性和慢性暴露后，HEPG2和HEPARG HEPATOMA细胞中脂质纳米胶囊毒性的内在化和机制
Internalization and mechanisms of toxicity of lipid nanocapsules in HepG2 and HepaRG hepatoma cells upon acute and chronic exposures
影响因子:5.20000
发表日期:2024 Dec 25
作者:
Flavien Delaporte, Emilie Roger, Jérome Bejaud, Pascal Loyer, Frédéric Lagarce, Camille C Savary
摘要
已经开发出用作纳米医学的脂质纳米胶囊（LNC）来增强药代动力学并降低药物的副作用，尤其是用于癌症疗法。在静脉内给药后，LNC具有重要的肝疗法，但是，关于其毒性的数据很少，反复暴露后甚至更少。这项研究旨在评估HEPG2和HEPARG肝细胞系上未载的LNC的体外毒性和内在化，为50和100 nm。与100 nm LNC相比，50 nm LNC的内在化速度较慢，并且与分化的HEPARG细胞相比，两个LNC在癌性HEPG2细胞上的毒性更高。 LNC在两种细胞系中主要通过小窝蛋白介导的内吞作用进行内化。长期暴露后，尽管内在化的途径保持不变，但LNC对肝细胞的毒性增加。细胞死亡的研究表明，铁凋亡的参与，但没有凋亡。急性和反复暴露在Heparg细胞上后，100 nm LNC显示出良好的安全性。最后，与分化的HEPARG细胞相比，LNC在HEPG2癌模型中诱导的与更重要的内在化相关的毒性更重要。这为LNC提供了充分的证据，以使活性药物对肝癌细胞的细胞毒性作用潜在。
Abstract
Lipid nanocapsules (LNCs) used as nanomedicine have been developed to enhance pharmacokinetics and decrease side effects of drugs, particularly for cancer therapies. After intravenous administration, LNCs possess an important hepatic tropism however, few data exist about their toxicity and even less after repeated exposure. This study aimed to assess the in vitro toxicity and internalization of unloaded LNCs, of 50 and 100 nm size, on HepG2 and HepaRG liver cell lines. Internalization of the 50 nm LNCs was slower compared to the 100 nm LNCs and both LNCs exhibited a higher toxicity on cancerous HepG2 cells compared to differentiated HepaRG cells. LNCs were mainly internalized via caveolin-mediated endocytosis in both cell lines. Upon chronic exposure, the toxicity of LNCs on HepaRG cells increased, although the pathways of internalization remained unchanged. Cell death studies have demonstrated an involvement of ferroptosis, but not of apoptosis. After acute and repeated exposures on HepaRG cells, the 100 nm LNCs showed a good safety profile. Finally, LNCs induced a more significant toxicity associated with faster internalization in the HepG2 cancerous model than in the differentiated HepaRG cells. This provides good evidence for LNCs to potentialize the cytotoxic effects of an active drug on liver cancer cells.