Polymer-mediated protein/peptide therapeutic stabilization: Current progress and future directions

Abstract

Proteins and peptides have played a pivotal role in revolutionizing disease treatment over the last century. Despite their commercial success, protein therapeutics can be eliminated or inactivated in the body via excretion or other metabolic pathways. Polymeric materials have been used to stabilize these biomolecules in the presence of external stressors as excipients, conjugates, and in nanomaterial formulations. Numerous advantages arise from the combination of therapeutic agents with polymeric carriers, including improved stability, solubility, prolonged blood circulation, and reduced immunogenicity. PEGylation, the covalent conjugation of poly(ethylene glycol) to a biomolecule of interest, is a common technique that has been employed in 31 FDA-approved therapeutic protein formulations to date. Although PEGylation has been widely adopted, there have been numerous advancements in the protein stabilization field using a variety of polymers including, but not limited to, poly(oxazolines), polypeptides, zwitterionic polymers, and polysaccharides with additional beneficial properties such as biocompatibility and biodegradability. Polymeric carriers can also protect lyophilized protein-peptide products from the stresses of supercooling, ice crystallization, sublimation, and desorption. This review discusses recent progress on the design principles of polymeric tools for biomolecule stabilization and delivery, with a focus on conjugates and nanomaterials. The clinical status of these materials and current challenges impeding the clinical translation are presented. In addition, various future possibilities for polymeric-protein therapies are also highlighted. Finally, the current computational landscape that harnesses the tools of machine learning combined with experimental validation to design polymeric systems tailored for biomolecule stability are discussed.