Polymer nanomedicine: understanding activity at the cellular and molecular level using metabolomicsTools Al-Natour, Mohammad (2019) Polymer nanomedicine: understanding activity at the cellular and molecular level using metabolomics. PhD thesis, University of Nottingham.
AbstractNanomedicine can be defined as the science and application of therapeutic entities which have dimensions in the 10-1000 nm range. Polymer nanomedicine involves using polymers to aid drug delivery at the nanoscale, the research underlying this discipline employs nanotechnology methods to prevent, diagnose and treat diseases. In attempt to understand the biological effects of polymer nanomedicine on living tissues, a global metabolic profiling approach was utilised to study the impact of different polymeric nanoparticles on various cell lines. In this project, Poly (lactic-co-glycolic acid) (PLGA) was adopted to fabricate Nanoparticles (NPs). This choice was made because PLGA is a versatile synthetic co-polymer that is already widely used in pharmaceutical applications. Cell-based metabolomics were applied to investigate the metabolic changes in human-like macrophages and lung carcinoma cell lines after the exposure to different types of PLGA NPs. The studies revealed that the plain PLGA NPs perturbed metabolism of some important amino acids, including arginine and proline and altered membrane lipids levels in different degrees. The next phase in the study was to evaluate the metabolic effects of drug loaded NPs. Methotrexate (MTX) was selected as the model drug, as it is a folate analogue antimetabolite, and has been widely used for the treatment of rheumatoid arthritis and cancer. MTX loaded NPs were thus prepared and tested in metabolomics assays in comparison with free MTX. The data showed that MTX loaded NPs had less impact on the macrophages than free MTX, and the effects of the NPs containing MTX were limited to changes of nucleotide metabolism and suppressing the tricarboxylic acid cycle (TCA). In comparison, MTX loaded NPs showed a higher impact on A549 cells, compared to the free drug, which was again in accord similar to other cell lines in literature. Finally, DNA loaded NPs in the form of polyplexes made of cationic polymers and plasmid DNA were studied. The study revealed that the polyplexes downregulated metabolites associated with glycolysis and the TCA cycle and induced oxidative stress in both cell lines. The fold changes of the metabolites indicated that the polyplexes of polyethyleneimine and hyperbranched polylysine affected the metabolism much more than the polyplexes of hyperbranched polylysine-co-histidine. This was in line with transfection results, suggesting a correlation between the toxicity and transfection efficiency of these polyplexes. These results highlight the importance of the metabolomics approach not just to assess the potential toxicity of polyplexes but also to understand the molecular mechanisms underlying their actions, which could help in designing more efficient drug delivery systems.
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