Dual end-functionalisation of poly(beta-amino ester) gene delivery vectors using multicomponent chemistry

Abstract

The use of RNA therapeutics provides a potent tool to enhance patient outcomes, but successful RNA delivery requires efficient and safe vectors. Cationic polymers provide one technology platform for this delivery and among these materials, poly(beta-amino esters) (PBAEs) have emerged as efficient and well tolerated vectors. Changing the end group of these materials can have a profound impact on their physical and biological properties, and the development of new pathways for end-group functionalisation can provide access to untapped material libraries for further development. We therefore developed a synthetic pathway that exploits the Passerini 3-component reaction as a means to incorporate aldehyde and isocyanide materials into the end-groups of an acid terminated PBAE. Polyplexes were then prepared and studied for encapsulation efficiencies, formulation properties and gene transfectability in vitro. Select polymers demonstrated high mRNA transfection efficiency in HEK293T cells. Our findings indicate that this synthetic pathway provides a versatile and adaptable pathway for the further modification of PBAEs and that this modification serves to provide new materials with enhanced nucleic acid delivery properties.