Synthetic macromolecules inspired by host defence peptides are promising chemotherapeutic agents, capable of disrupting cancer cell membranes through electrostatic interactions with anionic membrane bound species. However, off-target toxicity remains a major barrier despite extensive macromolecular engineering to screen for cancer selective polymer complexes with optimal ratios of hydrophobic/philic components. Here we introduce a conceptually different approach where cells are engineered to capture chemotherapeutic polymers, and hence increase activity and selectivity.<br/><br/>Metabolic glycan labelling is first used to incorporate unnatural azido-glycans as reactive handles onto the cell surface for enhanced recruitment of strain-alkyne functionalised polycations. This approach reduces the effective concentration of chemotherapeutic macromolecule required to induce 50% cell death (EC<sub>50</sub>) by up to 10-fold towards azido-glycan labelled cancerous cells, dramatically enhancing selective chemotherapeutic activity. Remarkably, conditions where unlabelled cells retained &gt; 90% cell viability and metabolic glycan labelled cells dropped to &lt; 20% were identified. Multiple cell-death pathways (necrosis and apoptosis) were enhanced and monitored through activation of apoptosis markers (caspase-3/-7) and membrane integrity assays, including DNA binding dyes and cytosolic enzyme release. Against a 3-D tumour model, our chemotherapeutic polymer system revealed that a single dose allows enhanced penetration and comparable toxicity compared to doxorubicin in less time (from 24 h to 3 h). This conceptual approach of ‘engineering cells to capture polymers’ rather than ‘engineering polymers to target cells’ will bring new opportunities in non-traditional macromolecular therapeutics.

Enhancing chemotherapeutic polymer selectivity with metabolic glycan labelling

ACS Spring Meeting 2021

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