Ring-opening Polymerization of Unprotected Hydroxyproline N-Carboxyanhydride for the Facile Synthesis of Linear and Branched Poly-L-hydroxyproline

Poly-L-hydroxyproline (PHyp) represents an important model for comprehending polyproline II helix and a key step toward mimicking collagen, the most abundant protein for animals, and holds immense potential for broad biomedical applications. The synthesis of PHyp, however, involves inefficient protection-deprotection steps and has been restricted to relatively low molecular weight (MW) and linear topology. Here, we report the first ring-opening polymerization (ROP) of unprotected hydroxyproline N-carboxyanhydrides (Hyp-NCA) for the facile one-step synthesis of PHyp with tunable linear or branching topologies. Employing an innovative water-assisted ultrafast polymerization technique, the research achieves the synthesis of linear PHyp with MW up to 11.0 kDa, featuring adjustable terminal groups and narrow dispersity. The study further introduces a tertiary amine-triggered one-pot polymerization method in DMSO, which leads to the facile preparation of branched PHyp (B-PHyp) within 2 h with MW up to 438 kDa, ~40 times higher than previous record of PHyp. Experimental and computational studies collectively uncovered novel details about the initiation, branching, and propagation steps of the reaction, providing fresh insights into the general mechanism regarding the ROP of NCA. Facile post-polymerization modification of B-PHyp affords injectable hydrogels with a critical gelization concentration as low as 1.0%. The polymers, characterized by their distinctive collagen-like polyproline type II (PPII) helices, offer significant prospects in drug delivery, wound healing, and other biomedical applications.