Al-Natour Mohammad Ahmad, Alazzo Ali, Ghaemmaghami Amir M, Kim Dong-Hyun, Alexander Cameron
School of Pharmacy, University of Nottingham, University Park, Nottingham NG72RD, UK.
Department of Pharmacy, Faculty of Pharmacy & Medical Sciences, University of Petra, Amman, Jordan.
Int J Pharm X. 2019 Nov 12;1:100036. doi: 10.1016/j.ijpx.2019.100036. eCollection 2019 Dec.
Methotrexate (MTX) is a folate analogue antimetabolite widely used for the treatment of rheumatoid arthritis and cancer. A number of studies have shown that MTX delivered via nanoparticle carriers is more potent against cancer cells than free MTX, a phenomenon attributed to higher cellular uptake of the particles compared to the saturable folate receptor pathway. In this study, a cell-based global metabolic profiling approach was applied to study the effects of MTX in both free drug form and when encapsulated in -poly(lactide-co-glycolide) (PLGA) nanoparticles on a cancer cell line, A549, and also on human-like THP-1 macrophages. The results showed that MTX loaded nanoparticles had less impact on the macrophages than free MTX, and the effects on macrophages were limited to changes in nucleotide metabolism and suppression of the tricarboxylic acid cycle, whereas free MTX also led to a drop in glycolytic activity and impairment in redox homeostasis. In contrast, MTX loaded nanoparticles showed a greater impact on A549 cells than the free drug, which was in accord with studies in other cell lines in prior literature with MTX-carrier nanoparticles.
甲氨蝶呤（MTX）是一种叶酸类似物抗代谢物，广泛用于治疗类风湿性关节炎和癌症。多项研究表明，通过纳米颗粒载体递送的MTX对癌细胞的效力比游离MTX更强，这种现象归因于与饱和叶酸受体途径相比，颗粒的细胞摄取量更高。在本研究中，采用基于细胞的全局代谢谱分析方法，研究游离药物形式的MTX以及包裹在聚乳酸-羟基乙酸共聚物（PLGA）纳米颗粒中的MTX对癌细胞系A549以及类人THP-1巨噬细胞的影响。结果表明，负载MTX的纳米颗粒对巨噬细胞的影响小于游离MTX，对巨噬细胞的影响仅限于核苷酸代谢的变化和三羧酸循环的抑制，而游离MTX还导致糖酵解活性下降和氧化还原稳态受损。相比之下，负载MTX的纳米颗粒对A549细胞的影响比游离药物更大，这与先前文献中其他细胞系使用MTX-载体纳米颗粒的研究结果一致。
