Synthesis of Heterotelechelic Poly(N-ethylglycine) Polymers: from Polypeptoid Lipid Conjugates to Protein-Polymer...

The need for alternative hydrophilic polymers to polyethylene glycol (PEG) has intensified due to increasing concerns about immunogenicity and hypersensitivity reactions. In this work, we report the synthesis of well-defined heterotelechelic poly-N-ethylglycine (pNEtGly) via acid-catalyzed ring-opening polymerization of N-substituted N-carboxyanhydrides with a degree of polymerization from 25 to 400. The Leuchs synthesis was modified and optimized for the preparation of high-purity N-ethylglycine NCA monomers, enabling controlled polymerization with the use of organic acid catalysts. The resulting pNEtGly have low polydispersity values (Ð < 1.05) and quantitative end-group fidelity, enabling the synthesis of well-defined polymer-lipid and polymer-protein conjugates. A palmitamide-functionalized pNEtGly demonstrated near-quantitative conversion to polymer-lipid conjugates. Furthermore, maleimide-functionalized pNEtGly was conjugated to human serum albumin (HSA) via thiol-maleimide coupling, forming a protein-polymer conjugate with high purity. These results establish pNEtGly as another interesting hydrophilic polymer for biomedical applications, particularly in lipid-based drug delivery and bioconjugation strategies.