Synthesis of Zwitterionic and Trehalose Polymers with Variable Degradation Rates and Stabilization of Insulin

Polymers that stabilize biomolecules are important as excipients in protein formulation. Herein, we describe a class of degradable polymers that have tunable degradation rates depending on the polymer backbone and are able to stabilize proteins to aggregation. Specifically, zwitterion- and trehalose-substituted polycaprolactone, polyvalerolactone, polycarbonate, and polylactide were prepared and characterized with regards to their hydrolytic degradation and ability to stabilize insulin to mechanical agitation during heat. Ring-opening polymerization (ROP) of allyl-substituted monomers was carried out using organocatalysis, resulting in well-defined alkene-substituted polymers with good control over molecular weight and dispersity. The polymers were then modified using photocatalyzed thiol-ene reactions to install protein-stabilizing carboxybetaine and trehalose side chains. The resulting polymers were water-soluble and exhibited a wide range of half-lives, from 12 hours to more than 4 months. The polymers maintained the ability to stabilize the therapeutic protein insulin from activity loss due to aggregation, demonstrating their potential as degradable excipients for protein formulation.