Postpolymerization Modifications of Poly(ethylene oxide) through C–H Functionalization: Embracing Functionality, Degradability, and Molecular Delivery

This study presents a novel organocatalytic approach for direct modification of poly(ethylene oxide) (PEO) by attaching functional groups using C-H bond functionalization, yielding functionalized PEO with degradability and molecular delivery capabilities. Direct functionalization of PEO has been a challenging task due to the difficulty in finding versatile polymerization conditions that can accommodate various functional epoxides. The presented method overcomes these limitations and allows for a broad substrate scope including biologically active carboxylic acids such as ibuprofen and glycyrrhetinic acid. The modification process preserves the parent PEO structure throughout the highly reactive radical and oxocarbenium intermediate. The resulting functional PEO contains a degradable acetal unit, making it desirable for molecular delivery applications. Hydrolysis studies confirm the steady release of fragmented PEO and carboxylic acid. The drug-loaded PEO demonstrates cytoprotective activity in RAW264.7 cells stimulated with lipopolysaccharide (LPS). The hydrophobic drug moieties taken up by cells and released via the acid-triggered cleavage of acetal linkages in the acidic environment of endosomes. Crosslinked PEO is also demonstrated with a dicarboxylic acid, which loses its gel architecture upon contact with water. The presented method offers a versatile and efficient way to modify PEO, with potential applications in drug delivery and tissue engineering.