MOLECULAR SIEVING ON DENDRITIC POLYMER-PROTEIN CONJUGATES

Abstract

Polymer-protein conjugates are hybrid biomaterials that combine the unique biological functions of proteins with the tunable properties of synthetic polymers. Conjugates often exhibit unique properties that set them apart from their native counterparts, including higher stability towards environmental stressors, altered interactions with their substrates, and lowered immunogenicity in therapeutic applications. Such qualities have made them excellent candidates for therapeutics, and the development of polymer-protein is an intense area of ongoing research. In recent years, increasing attention is being paid to controlling conjugate interaction with their substrates solely based on size – an effect known as molecular sieving. The grafting polymer forms a porous layer which blocks macromolecules above a certain size threshold from approaching the protein surface, while smaller substrates can diffuse through and interact with the protein. The objective of this work is to present approaches to regulating protein-ligand binding stoichiometry and specificity without making genetic modification to the protein itself. We first describe the development of a series of dendrimers with a highly stable backbone and modular click functionalities. The chemistry of which is then incorporated to dendritic architectures in the second portion of our work, where we explore dendritic-linear architectures as grafting polymers for introducing molecular sieving to chymotrypsin conjugates. Lastly, we systematically investigate how size-dependent sieving on avidin is controlled by dendron generation on both the protein surface and on its biotin ligands. We demonstrate throughout this thesis that dendrimers are a viable platform for tuning binding in protein hybrids.