PET-RAFT polymerization of redox-responsive lipoic acid-derived cationic polymers: influence of hydrophobicity and degree of polymerization on antimicrobial activity.

Antimicrobial polymers are increasingly recognized as effective agents against a broad spectrum of microorganisms, including bacteria, fungi, and viruses. Their performance is largely determined by macromolecular topology, molecular weight, and the strategic arrangement of cationic and hydrophobic groups. However, the persistence and accumulation of non-degradable polymers raise environmental and health concerns. In this work, we systematically evaluate photoinduced electron/energy transfer reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization against traditional thermal RAFT polymerization for the copolymerization of acrylate and acrylamide monomers with benzyl lipoate. The PET-RAFT technique offers distinct advantages, such as accelerated reaction kinetics and enhanced incorporation of benzyl lipoate diads, resulting in copolymers with superior redox-responsive degradability. Leveraging this optimized strategy, a library of antimicrobial copolymers was synthesized. To tailor antimicrobial performance, four hydrophobic monomers derived from modified lipoic acid, including benzyl lipoate, ethyl lipoate, menthyl lipoate and heptyl lipoate, were incorporated. These copolymers exhibited rapid degradation under reducing conditions, addressing concerns regarding long-term toxicity and accumulation. The library was screened against a panel of clinically relevant pathogens, including the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and the fungal pathogen Candida albicans. Furthermore, therapeutic selectivity and biocompatibility were assessed via hemolysis assays and 3T3 fibroblast viability studies. This work provides a robust framework for the design of biocompatible and degradable antimicrobial polymers.