TCEP-Enabled Click Modification of Glycidyl-Bearing Polymers with Biorelevant Sulfhydryl Molecules: Toward Chemoselective Bioconjugation Strategies.

Thiol-epoxy ring opening is a highly efficient and versatile click reaction for postpolymerization modification, ideal for the conjugation of sulfhydryl-containing biomolecules. This study investigated the reactivity of thiols, disulfides, and amines toward glycidyl-bearing polymers, aiming to optimize thiol conjugation using tris(2-carboxyethyl)phosphine (TCEP) as a disulfide-reducing agent. Epoxide groups were introduced via glycidyl methacrylate (GMA) polymerized by ATRP to yield PGMA homopolymers and poly(ε-caprolactone) (PCL)-based block copolymers. H NMR confirmed quantitative thiol functionalization, while amines showed poor reactivity. l-cysteine conjugation further demonstrated the reaction's chemoselectivity. Thioglycerol conjugation yielded poly(2-hydroxy-3-(thioglycerol)propyl methacrylate) (PTGMA), a highly hydroxylated PEG alternative. Functionalization was extended to PCL--PGMA and PEGMA-based copolymers, forming amphiphilic nanoparticles via nanoprecipitation. Sequential modification with thioglycerol and the cRGD peptide yielded bioactive, size-controlled nanocarriers. Overall, a robust strategy has emerged for synthesizing multifunctional polymeric nanomaterials. Its compatibility with equimolar reactants under ambient conditions makes it particularly suited for the efficient incorporation of sensitive, high-value biomolecules into targeted drug delivery systems.