Functional epoxide monomers were copolymerized with ethylene oxide (EO) via anionic epoxy ring-opening polymerization to overcome the limitations of poly(ethylene glycol) (PEG), such as lack of functionality and non-biodegradability. First, in order to introduce multi-functionality along the polymer backbone, allyl glycidyl ether (AGE) and ethylene glycol vinyl glycidyl ether (EGVGE) were statistically copolymerized with EO. Besides the general effectiveness of the anionic mechanism on copolymerizing epoxide monomers, some issues regarding geometric and structural isomerism in the resultant copolymers was unambiguously characterized and controlled. Isomerization of pendent allyl groups on AGE during the anionic polymerization process was found to be dependent on the reaction temperature.

The isomerization was therefore controlled by lowering the temperature during polymerization resulting in robust preparative strategies for poly[(ethylene oxide)-co-(allyl glycidyl ether)] (P(EO- co-AGE)) with defined structure and functionality. Unknown comonomer sequence distributions of P(EO-co-AGE) and P(EO- co-EGVGE) were able to be characterized through the development of a novel methodology to estimate reactivity ratios. The measured relative reactivity remarkably contradicted the prevailing understanding of substituted epoxide reactivity in copolymerization. Our findings were supported by both independent kinetic observations and theoretical calculations. Next, for introducing biodegradability along PEG backbone, hydrolytically degradable methylene ethylene oxide (MEO) units were incorporated via activated monomer polymerization of EO and epichlorohydrin (ECH) followed by a simple elimination reaction.

The synthesized P(EO-co-MEO)s underwent hydrolytic degradation under physiological conditions at different rates dependent on temperature and pH. The only products of degradation were small fragments having defined molar masses and end-group structures. Finally, using many of our new strategies for addressing PEGs deficiencies, a PEG-based copolymer platform was developed for a targeted therapy application in order to demonstrate the potential capability of our PEG modification strategies. As a polymeric drug carrier, poly[(ethylene oxide)-b-(ethylene glycol vinyl glycidyl ether)] (P(EO-b-EGVGE)) was functionalized to carry multiple drug molecules via enzymatically cleavable ester linkages, and then efficiently conjugated with a targeting nucleoline aptamer. The synthesized aptamer-polymer hybrids successfully performed all of their designed functions: The long EO block provided enough water-solubility for the hybrid molecules to maintain their small size in aqueous medium.

The EGVGE repeat units securely carried the payload while the aptamer recognized and promoted internalization into the target cells, and selectively released the drug cargo by enzymatic cleavage of the pendent ester bonds.