High‐Fidelity End‐Functionalization of Poly(ethylene glycol) Using Stable and Potent Carbamate Linkages

Abstract Commercial PEG‐amine is of unreliable quality, and conventional PEG functionalization relies on esterification and etherification steps, suffering from incomplete conversion, harsh reaction conditions, and functional‐group incompatibility. To solve these challenges, we propose an efficient strategy for PEG functionalization with carbamate linkages. By fine‐tuning terminal amine basicity, stable and high‐fidelity PEG‐amine with carbamate linkage was obtained, as seen from the clean MALDI‐TOF MS pattern. The carbamate strategy was further applied to the synthesis of high‐fidelity multi‐functionalized PEG with varying reactive groups. Compared to with an ester linkage, amphiphilic PEG‐PS block copolymers bearing carbamate junction linkage exhibits preferential self‐assembly tendency into vesicles. Moreover, nanoparticles of the latter demonstrate higher drug loading efficiency, encapsulation stability against enzymatic hydrolysis, and improved in vivo retention at the tumor region.