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Metabolic oligosaccharide engineering for glycocalyx remodelling with synthetic polymers
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Tomás, Ruben M. F. (2021) Metabolic oligosaccharide engineering for glycocalyx remodelling with synthetic polymers. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3736718~S15
Abstract
Re-engineering cellular interfaces with natural and synthetic polymers to endogenous membrane components can alter cell fate by regulating cellular signalling pathways, masking surface antigens, controlling cell-substrate and cell-cell interactions, and/or installing non-native functionality. However, current polymer grafting-to and grafting-from cell surface strategies suffer from several caveats limiting potential use in the study of fundamental biological processes and applications in cell-based therapies, including non-specific targetting, lack of cytocompatibility, short surface retention times, non-native conjugation conditions and heterogeneous and inefficient labelling.
Metabolic oligosaccharide engineering allows the installation of exogenous glycans into the cellular glycocalyx through chemically modified versions of native sugars, providing a potential new strategy for cell surface recruitment of polymeric materials. These unnatural sugars ‘hijack’ the promiscuous biosynthetic or salvage pathways of endogenous glycans allowing the installation of biorthogonal functional groups onto the cell surface. Although metabolic oligosaccharide engineering has been studied for the capture and internalisation of nanoparticles, in vitro and in vivo, limited research is present on the ability to recruit synthetic polymers.
Herein, this thesis reports on a series of studies, intended to demonstrate that metabolic oligosaccharide engineering can expand cell surface polymer grafting strategies for the development of cell-polymer hybrids and to enhance the recruitment, and activity, of polycationic chemotherapeutic polymers. Chapter 1 provides a comprehensive literature study of the pre-existing field covering current applications of conventional polymer grafting-to and grafting-from cell surface strategies, along with their limitations, and current uses of metabolic oligosaccharide engineering for the recruitment of polymeric materials. Chapter 2 follows with the first reported instance where metabolic oligosaccharide engineering is used to recruit reversible addition-fragmentation transfer synthesised polymers, to generate cell-polymer hybrids with fluorescent coatings and simple biomolecule capture functionality. Chapter 3 expands on this work, providing quantitative insight into the newly engineered cell-polymer hybrids. Various parameters that govern the successfulness of this ‘grafting to’ process were assessed, to compare against conventional strategies and provide a guide for controllable polymer re-engineering of cell surfaces with metabolic oligosaccharide engineering. Finally, Chapter 4 reports the first use of metabolic oligosaccharide engineering to improve the activity of chemotherapeutic polycationic macromolecules towards target cells, through the enhancement of multi-mechanistic cell death pathways, also demonstrating improvements against 3-D tumour models.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QD Chemistry Q Science > QH Natural history Q Science > QP Physiology T Technology > TA Engineering (General). Civil engineering (General) T Technology > TP Chemical technology |
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Library of Congress Subject Headings (LCSH): | Oligosaccharides -- Metabolism, Oligosaccharides -- Physiological effect, Glycocalyces, Polymers, Polymeric composites | ||||
Official Date: | May 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Molecular Analytical Science Centre for Doctoral Training | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Gibson, Matthew I. | ||||
Sponsors: | Engineering and Physical Sciences Research Council | ||||
Extent: | xlix, 457 leaves | ||||
Language: | eng |
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