Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria.

Infections caused by multidrug-resistant bacteria are on the rise and, therefore, new antimicrobial agents are required to prevent the onset of a postantibiotic era. In this study, we develop new antimicrobial compounds in the form of single-chain polymeric nanoparticles (SCPNs) that exhibit excellent antimicrobial activity against Gram-negative bacteria (e.g., Pseudomonas aeruginosa) at micromolar concentrations (e.g., 1.4 µM) and remarkably kill ≥99.99% of both planktonic cells and biofilm within an hour. Linear random copolymers, which comprise oligoethylene glycol (OEG), hydrophobic, and amine groups, undergo self-folding in aqueous systems due to intramolecular hydrophobic interactions to yield these SCPNs. By systematically varying the hydrophobicity of the polymer, we can tune the extent of cell membrane wall disruption, which in turn governs the antimicrobial activity and rate of resistance acquisition in bacteria. We also show that the incorporation of OEG groups into the polymer design is essential in preventing complexation with proteins in biological medium, thereby maintaining the antimicrobial efficacy of the compound even in in vivo mimicking conditions. In comparison to the last-resort antibiotic colistin, our lead agents have a higher therapeutic index (by ca. 2-3 times) and hence better biocompatibility. We believe that the SCPNs developed here have potential for clinical applications and the information pertaining to their structure-activity relationship will be valuable toward the general design of synthetic antimicrobial (macro)molecules.

Biocompatible Single-Chain Polymeric Nanoparticles via Organo-Catalyzed Ring-Opening Polymerization.

This study presents a novel approach to synthesize biocompatible single-chain polymeric nanoparticles (SCPN) under mild reaction conditions via organo-catalyzed ring-opening polymerization (ROP). Linear polymeric precursors containing pendent polymerizable caprolactone groups, made by reversible addition-fragmentation chain transfer (RAFT) polymerization, were intramolecularly cross-linked via ROP in the presence of benzyl alcohol (nucleophilic initiator) and methanesulfonic acid (organo catalyst) to form discrete, well-defined SCPN, as confirmed by GPC, DLS, 1H NMR, and AFM analysis. The formed SCPN are tunable in size (2-5 nm), depending on the molecular weight of the parent linear macromolecule. Furthermore, cytotoxicity studies revealed that the SCPN, which were covalently cross-linked by biodegradable polyester linkages, were nontoxic toward human embryonic kidney (HEK293T) cells. This study demonstrates the efficiency and versatility of this approach to generate uniformly sized soft nanoparticles with tunable dimensions that are potentially useful for a range of targeted applications, including drug delivery systems and membranes for gas separation technologies.