Investigation and Development of Zwitterionic Biomaterials for Protein Therapeutics

Abstract

Proteins offer significant therapeutic potential over small-molecule drugs for many disease treatments, but they are more fragile and sensitive to environmental stress. The synthetic polymer poly(ethylene glycol) (PEG) has been used to increase protein size for prolonged circulation as well as act as a steric shield of immunogenic epitopes. However, it may interfere with substrate binding at the active site or elicit antibody responses toward itself, highlighting a need for an alternative strategy. This dissertation is a compilation of such efforts, specifically the development of zwitterionic materials for protein delivery. The champion zwitterionic polymer poly(carboxybetaine) (PCB) is a superhydrophilic macromolecule that is biomimetic, based on the naturally occurring amino-acid derivative trimethylglycine. We hypothesize that a polyzwitterion-protein conjugate will exhibit enhanced circulation without sacrificing enzyme activity or eliciting undesirable immune responses. This is tested in the context of immunogenic proteins and proteins with poor circulation residence times and examined in the following chapters: (1) introduction of zwitterionic materials, (2) synthesis of biocompatible zwitterionic polymers for bioconjugation, (3) direct comparison between same solution-size PEG and PCB in protecting an immunogenic therapeutic enzyme, (4) effect of varying polymer size and conjugation density on protein protection, and (5) preclinical investigations of a novel polymer-protein conjugate.