Stereoregular glycomacromolecules for selective carbohydrate-lectin recognition and targeted cell uptake

Glycopolymer research focuses on designing molecular scaffolds with specific architectures and the incorporation of functional sugar groups to create advanced materials for targeted drug or gene delivery. This PhD project aims to develop new glycopolymers that exploit the interaction between carbohydrates and saccharide-binding proteins, known as lectins, to selectively deliver therapeutic agents to specific cells. Certain sugars, such as glucose, mannose, and galactose, bind selectively to their corresponding lectin counterparts, enabling targeted cell interaction. A key objective is to investigate the structure-property relationships of glycopolymers in carbohydrate-lectin binding events, as the design of the polymer scaffold influences binding efficiency. By fine-tuning the topology of the glycopolymer, the lectin binding behaviour can be manipulated to achieve very specific recognition. This work is devoted to the investigation of the role of stereoconfiguration of the glycopolymer backbone on these binding processes. Surface plasmon resonance (SPR) spectroscopy is used to evaluate the lectin binding properties, providing insights into how stereochemistry affects avidity. Iterative exponential growth (IEG) is utilised in this thesis to synthesise glycooligomers with distinct stereoconfiguration and valency, which are subsequently glycosylated via thiol-ene chemistry and serve as targeting ligands for polymers and nanoparticles. Mannose, a carbohydrate linked to immune system functions, is employed for potential vaccine and cancer treatment development. Both R and S-configurated IEG-derived oligomers are prepared in each project, along with the racemic mixtures as controls. The resulting polytriazoles with pendant sugars are studied for their stereochemistry's effect on glycopolymer-lectin interactions. Additionally, the glycooligomers are conjugated onto nanoparticles, i.e. lipid nanoparticle formulations (LNPs) and polymersomes and tested for cellular uptake in collaboration with Imperial College London and the University of Basel, highlighting the significance of carbohydrate-mediated targeting in biomedical applications.