脂质纳米胶囊在HepG2和HepaRG肝癌细胞中急性和慢性暴露后的内吞机制及毒性机制研究
Internalization and mechanisms of toxicity of lipid nanocapsules in HepG2 and HepaRG hepatoma cells upon acute and chronic exposures
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发表日期:2024 Dec 25
作者:
Flavien Delaporte, Emilie Roger, Jérome Bejaud, Pascal Loyer, Frédéric Lagarce, Camille C Savary
DOI:
10.1016/j.ijpharm.2024.124815
摘要
脂质纳米胶囊（LNCs）作为纳米药物已被开发用以增强药物的药代动力学特性并减少副作用，尤其是在癌症治疗中。静脉注射后，LNCs具有重要的肝脏靶向性，但关于其毒性以及反复暴露后的影响资料较少。本研究旨在评估未加载的50和100 nm尺寸LNCs在HepG2和HepaRG肝细胞系中的体外毒性和内吞情况。结果显示，50 nm LNCs的内吞速度比100 nm LNCs慢，两者对癌变的HepG2细胞的毒性高于分化的HepaRG细胞。LNCs主要通过洞蛋白介导的内吞作用被内吞。在慢性暴露条件下，LNCs对HepaRG细胞的毒性增强，尽管内吞途径未改变。细胞死亡研究表明，涉及铁死亡（ferroptosis），而非凋亡。在急性和反复暴露后，100 nm LNCs在HepaRG细胞中表现出良好的安全性。最终，LNCs在癌细胞模型中引发的毒性比在分化的HepaRG细胞中更明显，且内吞速度更快，为利用LNCs增强抗肿瘤药物的细胞毒性提供了有力证据。
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.