Metabolic Signatures of Surface-Modified Poly(lactic-co-glycolic acid) Nanoparticles in Differentiated THP-1 Cells Derived with Liquid Chromatography-Mass Spectrometry-based Metabolomics

Abstract

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- co -glycolic acid) (PLGA) NPs with different surface coating or conjugation chemistries. Liquid chromatography-mass spectrometry-based metabolic profiling was performed on the extracts ( n = 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 R 2 and Q 2 > 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.

Effects of multi‐walled carbon nanotubes and halloysite nanotubes on plasma lipid profiles and autophagic lipolysis pathways in mouse aortas and hearts

“…49 Similarly, polymeric nanoparticles (NPs) altered metabolic pathways related with glycerophospholipid, sphingolipid, linoleic acid, arginine and proline, and alpha-linolenic acid metabolisms in macrophages. 50 We reported that MWCNTs and graphene oxide upregulated Cer in endothelial cells 29 and human brain organoids, 51 which could be related with the cytotoxicity of the materials to these models. As such, the upregulation of sphingolipids especially by MWCNTs could be related with cardiovascular disease development.…”

Metabolomics-directed nanotechnology in viral diseases management: COVID-19 a case study

“…Furthermore, they affected cell membrane integrity by reducing levels of PC and phosphatidylethanolamines, which are essential membrane components. On the contrary, PEGylated PLGA NPs showed less disturbance in amino acid metabolism and cell membrane’s glycerophospholipids composition [ 193 ]. A summary of the effect of versatile NPs on various metabolites and metabolic pathways is provided in Table 1 .…”