Ring-Strain-Driven One-Shot Synthesis of Glycosylated Cationic Block β-Peptides with Improved In Vivo Pharmacokinetics and Biodistribution

Abstract Cationic antimicrobial polymers exhibit potent antibacterial activity but frequently suffer from nonspecific interactions, systemic toxicity, and unfavorable in vivo disposition. Glycosylation offers a potential strategy to improve their biological compatibility; however, its effects on the in vivo pharmacokinetics and organ distribution of cationic antimicrobial polymers remain poorly understood. Here, we report a glycosylated cationic block poly(β-peptide) synthesized via a ring-strain-driven, one-pot anionic ring-opening polymerization (AROP) conducted at room temperature. The polymerization was rationally designed by exploiting the substantial difference in ring strain between the sugar-derived β-lactam monomers and the cationic β-lactam monomers. Compared with the non-glycosylated homopolymer, the glycosylated cationic block copolymer exhibited prolonged blood circulation, reduced systemic clearance, and increased systemic exposure. Glycosylation also altered organ distribution by reducing predominant hepatic accumulation and promoting kidney-associated distribution and urinary elimination. These results establish ring-strain differentiation as a simple principle for room-temperature block copolymerization and demonstrate that glycosylation can actively regulate the in vivo fate of cationic antimicrobial polymers.