Light-Catalyzed Synthesis of Carbohydrate Polymers for In Situ Cell Surface Engineering

Glycans are a class of carbohydrate oligomers that densely coat many cell surface proteins and lipids, acting as the first point of contact between a cell and its microenvironment. A network of over 700 glycan-processing enzymes, 10 monosaccharides, and architectural complexity give rise to diverse glycan structures with specific biological functions. Cell-surface proteins can act as receptors for glycans, initiating binding events which influence myriad biological processes within the cell. Receptor-glycan binding interactions occur with weak affinity (mM); therefore, high copy numbers of glycans are essential to realize meaningful biological outcomes. In order to study these complex pathways, access to structurally defined glycan material is required. However, glycans are not encoded in DNA and cannot be produced using genetic strategies. As such,there is a need for chemical approaches to access analogous macromolecules with a multivalent display of glycans for biological research. Polymers designed with pendant glycans (glycopolymers) are ideal analogs as the length and side-chain density can be tailored to ensure high valency, thus mimicking natural displays of these structures. Notably, emerging advances in polymer chemistry offer opportunities to synthesize and covalently install molecules on the cell surface. Pioneering work on grafting-from cell-surface polymerizations using PEG-based acrylamide monomers achieved excellent control over polymer chain distribution and density, as well as cell viability. Such a strategy has not been applied to access glycan analogs despite its potential impact on understanding glycan structure-function relationships in biology. This work aims to extend in situ cell-surface polymerization approaches to glycopolymers and profile biological outcomes. We developed a synthesis to modify glycans and obtain appropriate vinyl monomers. Subsequent aqueous photo-induced electron-transfer reversible-addition fragmentation chain transfer (PET-RAFT) yielded glycopolymers of varying molecular weight and side chain density. Future work will apply this technology to grow glycopolymers on the surface of primary immune cells and advance our understanding of the fundamental roles of glycans in health and disease.

Green chemistry component: Through my project I have assessed the efficacy of my carbohydrate-based monomers in aqueous light-catalyzed polymerizations, evaluating the level of control over polymer molecular weights. The synthesis of carbohydrate-based polymers is of great interest for a variety of materials and biomedical applications as these polymers are biomass-derived and nontoxic. The isolation of carbohydrate-based polymers (polysaccharides) from nature is difficult – purification is an exhaustive process and the polymers obtained have a wide range of molecular weights inferring different properties and they are not structurally defined. Various polymerization systems are currently being explored on carbohydrate-based monomers – allowing for control over the polymer structure and composition – however none to date have focused on using photocatalysis in mild aqueous conditions. Though my project is ultimately designated towards a biological application, the synthetic challenges accompanied allow me to explore the use of bio-based monomers – derived from glucosamine, galactosamine etc. in a scalable polymerization approach that exemplifies green chemistry principles. The findings from this work will be broadly valuable for researchers working in the carbohydrate-based polymer sphere. One aspect of my work that requires more integration of green chemistry metrics is the synthesis of the monomer from bio-based glucosamine. I hope to learn from other researchers at the ACS green chemistry school to develop a mild and safe synthetic route towards my monomer.