Re-engineering cell surfaces with synthetic materials allows modulation of cell function and fate through masking of cell surface antigens and by introducing glycan epitopes that stimulate receptors or recruit growth factors. The most widely explored strategies to recruit synthetic materials to the cell surface include conjugation to surface amino acid residues, hydrophobic insertion into the lipid bilayer and electrostatic layer-by-layer deposition. Several limitations arise from the lack of specificity and poor surface retention times of conventional recruitment strategies, which hinder potential applications in both the discovery of cellular interactions/signalling pathways and cell therapies.<br/><br/>Metabolic oligosaccharide engineering (MOE) offers an alternative platform to selectively recruit synthetic materials through the installation of exogenous glycan chemical receptor sites. Cells are treated with an azido-modified mannosamine analogue, to hijack the sialic acid biosynthetic pathway and decorate the glycocalyx with azido groups. Highly controllable grafting of fluorescent telechelic polymers, bearing a strained alkyne, to the cell surface can be achieved. Using this method, over 95% of cell populations were labelled and polymer coatings persisted through several mitotic divisions. This strategy was further deployed to install ligands onto cell surfaces to capture proteins, providing a simple demonstration that recruitment of synthetic materials with MOE allows introduction of non-native functionality, without resorting to gene-editing techniques.<br/><br/>Guided by this, we also demonstrate that host defence peptide inspired cationic chemotherapeutic polymers, modified with a strained alkyne, can achieve enhanced selectivity towards target azido-labelled cells and 3-D tumour models. Careful selection of polymer concentration and length enabled unlabelled cells to retain &gt; 90% cell viability, whilst azido-labelled cells dropped to &lt; 20%, thus combating the longstanding selectivity issues of chemotherapeutic. Engineering target cells to recruit synthetic chemotherapeutic polymers, rather than extensive macromolecular engineering to screen for cancer selective polymer complexes, offers a conceptually new approach to improve therapeutic efficacy and will help advance the discovery and application of polymeric therapeutics as active agents.

Engineering cell surfaces by grafting polymers to metabolically engineered glycans: From labelling to chemotherapeutics

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.