Synthesis of Heterotelechelic Poly( <i>N</i> ‐ethylglycine) Polymers: from Polypeptoid Lipid Conjugates to Protein‐Polymer Conjugates

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.