Al-Natour Mohammad A, Abdelrazig Salah, Ghaemmaghami Amir M, Alexander Cameron, Kim Dong-Hyun
Molecular Therapeutics and Formulation Division, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, U.K.
Division of Pharmaceutics and Pharmaceutical Sciences, Faculty of Pharmacy, University of Petra, Amman 11196, Jordan.
ACS Omega. 2022 Aug 12;7(33):28806-28819. doi: 10.1021/acsomega.2c01660. eCollection 2022 Aug 23.
Polymeric nanoparticles (NPs) are widely used in preclinical drug delivery investigations, and some formulations are now in the clinic. However, the detailed effects of many NPs at the subcellular level have not been fully investigated. In this study, we used differentiated THP-1 macrophage cells, as a model, to investigate the metabolic changes associated with the use of poly (lactic--glycolic acid) (PLGA) NPs with different surface coating or conjugation chemistries. Liquid chromatography-mass spectrometry-based metabolic profiling was performed on the extracts ( = 6) of the differentiated THP-1 cells treated with plain, Pluronic (F-127, F-68, and P-85)-coated and PEG-PLGA NPs and control (no treatment). Principal component analysis and orthogonal partial least squares-discriminant analysis (OPLS-DA) in conjunction with univariate and pathway analyses were performed to identify significantly changed metabolites and pathways related to exposure of the cells to NPs. OPLS-DA of each class in the study compared to the control showed clear separation and clustering with cross-validation values of and > 0.5. A total of 105 metabolites and lipids were found to be significantly altered in the differentiated THP-1 cell profiles due to the NP exposure, whereas more than 20 metabolic pathways were found to be affected. These pathways included glycerophospholipid, sphingolipid, linoleic acid, arginine and proline, and alpha-linolenic acid metabolisms. PLGA NPs were found to perturb some amino acid metabolic pathways and altered membrane lipids to a different degree. The metabolic effect of the PLGA NPs on the cells were comparable to those caused by silver oxide NPs and other inorganic nanomaterials. However, PEG-PLGA NPs demonstrated a reduced impact on the cellular metabolism compared to Pluronic copolymer-coated PLGA and plain PLGA NPs.
聚合物纳米颗粒（NPs）广泛应用于临床前药物递送研究，目前一些制剂已进入临床阶段。然而，许多纳米颗粒在亚细胞水平上的详细作用尚未得到充分研究。在本研究中，我们以分化的THP-1巨噬细胞为模型，研究了使用具有不同表面涂层或共轭化学性质的聚（乳酸-乙醇酸）（PLGA）纳米颗粒相关的代谢变化。对用普通、普朗尼克（F-127、F-68和P-85）涂层及聚乙二醇-聚乳酸-乙醇酸纳米颗粒处理的分化THP-1细胞提取物（n = 6）和对照（未处理）进行基于液相色谱-质谱的代谢谱分析。进行主成分分析和正交偏最小二乘判别分析（OPLS-DA），并结合单变量和通路分析，以识别与细胞暴露于纳米颗粒相关的显著变化的代谢物和通路。与对照相比，本研究中各类别的OPLS-DA显示出清晰的分离和聚类，交叉验证值Q2和R2 > 0.5。由于纳米颗粒暴露，在分化的THP-1细胞谱中总共发现105种代谢物和脂质有显著变化，而发现超过20条代谢通路受到影响。这些通路包括甘油磷脂、鞘脂、亚油酸、精氨酸和脯氨酸以及α-亚麻酸代谢。发现PLGA纳米颗粒扰乱了一些氨基酸代谢通路，并不同程度地改变了膜脂。PLGA纳米颗粒对细胞的代谢作用与氧化银纳米颗粒和其他无机纳米材料引起的作用相当。然而，与普朗尼克共聚物涂层的PLGA和普通PLGA纳米颗粒相比，聚乙二醇-聚乳酸-乙醇酸纳米颗粒对细胞代谢的影响较小。
