Even after significant advances in polymerization and protein modification chemistries, the majority of polymeric biomaterials focus on poly(ethylene glycol) (PEG)-based monomers. Despite their widespread use, these polymers present concerns due to their non-biodegradable nature, the possibility of toxicity and immunogenicity, and their limited chemical functionality. Therefore, there is significant interest in the rational design of alternative polymers with specific chemical or biological properties. Specifically, approaches that allow for the rapid and divergent synthesis of a large number of biodegradable polymeric materials capable of functionalization would be broadly applicable. This dissertation focuses on novel degradable and modifiable polymers with applications in protein conjugation and stabilization.

In Chapter 1, the history of protein-polymer conjugates for therapeutic use is outlined, from PEGylation techniques to next-generation conjugation strategies. Alternative polymer technologies and future directions of the field are also presented. In Chapter 2, the synthesis and biological application of a degradable trehalose glycopolymer is described. The polymer is shown to stabilize the therapeutic protein granulocyte colony stimulating factor (G-CSF) against heat stress. While the polymer was noncytotoxic, its degradation products inhibited cell proliferation at high concentrations.

Chapter 3 details the development of poly(caprolactone)-based polyesters for protein stabilization. An alkene-substituted polyester was synthesized and modified using thiol-ene chemistry with thiols containing glucose, lactose, trehalose, PEG, and carboxybetaine units. The relative stabilizing ability of these side-chains toward G-CSF was assessed. Trehalose and carboxybetaine were found to maintain the most protein activity upon exposure to heat stress. We varied the size of these polymers and found a dependence on molecular weight, where longer polymers were more effective protein stabilizers. These materials and their degradation products were cytocompatible, yet exhibited minimal degradation in aqueous conditions. Chapter 4 describes the synthesis of trehalose- and carboxybetaine-funcitonalized polyesters and polycarbonates with tunable degradability, with half-lives from 10 hours to over 4 months. We expect these materials will be useful in the development of novel protein-polymer therapeutics.

We also describe the development of novel PEG analogs using ring-opening metathesis polymerization (ROMP). Chapter 5 describes the synthesis of these PEG analogs and subsequent conjugation to the model protein lysozyme. Exploration of post-polymerization modifications to install thiols onto the unsaturated polymer backbone are also described.