Ring-opening polymerization of Amino Acid N‑Carboxyanhydrides with Unprotected/Reactive Side Groups. II. L‑Hydroxyproline N‑Carboxyanhydride

Poly-L-hydroxyproline (PHyp) is a synthetic analogue of 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 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 7.5 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 preparation of branched PHyp (B-PHyp) with MW up to 438 kDa, ~40 times higher than previous record of PHyp. 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.