Bleomycin has a long-studied mechanism of action through the formation of a complex with metals, such as iron. The bleomycin–iron complex was recently shown to induce membrane damage by free radical reactivity. Because the use of Fe nanoparticles is spreading for drug delivery strategies, molecular mechanisms of cell damage must include different compartments in order to observe the progression of the cell reactivity. In this study, human embryonic kidney (HEK-293) cells were exposed for 24 h to bleomycin and polymeric iron oxide nanoparticles (Fe-NPs), alone or in combination. The fatty acid–based membrane lipidomic analysis evidenced the fatty acid remodeling in response to the treatments. Bleomycin alone caused the increase of saturated fatty acid (SFA) moieties in cell membrane glycerophospholipids with concomitant diminution of monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acid levels. Under Fe-NPs treatment, omega-6 PUFA decreased and trans fatty acid isomers increased. Under coadministration bleomycin and Fe-NPs, all membrane remodeling changes disappeared compared to those of the controls, with only an increase of omega-6 PUFA that elevates peroxidation index remaining. Our results highlight the important role of fatty-acid-based membrane lipidome monitoring to follow up the fatty acid reorganization induced by the drug, to be considered as a side effect of the pharmacological activity, suggesting the need of an integrated approach for the investigation of drug and carrier molecular mechanisms.

中文翻译：

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博来霉素和氧化铁纳米颗粒在人胚胎肾细胞中诱导膜甘油磷脂的脂肪酸重塑。

博来霉素通过与金属（如铁）形成络合物而具有长期研究的作用机制。最近显示博来霉素-铁复合物通过自由基反应诱导膜损伤。由于 Fe 纳米颗粒的使用正在广泛用于药物递送策略，细胞损伤的分子机制必须包括不同的隔室，以便观察细胞反应性的进展。在这项研究中，人类胚胎肾 (HEK-293) 细胞单独或组合暴露于博莱霉素和聚合氧化铁纳米颗粒 (Fe-NPs) 24 小时。基于脂肪酸的膜脂质组学分析证明了脂肪酸对治疗的反应。单独的博来霉素导致细胞膜甘油磷脂中饱和脂肪酸 (SFA) 部分的增加，同时单不饱和 (MUFA) 和多不饱和 (PUFA) 脂肪酸水平降低。在 Fe-NPs 处理下，omega-6 PUFA 减少，反式脂肪酸异构体增加。在博来霉素和 Fe-NPs 的共同给药下，与对照组相比，所有膜重塑变化都消失了，只有 omega-6 PUFA 的增加会提高过氧化指数。我们的结果强调了基于脂肪酸的膜脂质组监测在跟踪药物诱导的脂肪酸重组方​​面的重要作用，被认为是药理活性的副作用，表明需要一种综合方法来研究药物和载体分子机制。