Karolina Kasza

Antimicrobial resistance is a threat to public health for which new treatments are urgently required. The capability of bacteria to form biofilms is of particular concern as it enables high bacterial tolerance to conventional therapies by reducing drug diffusion through the dense, exopolymeric biofilm matrix and the upregulation of antimicrobial resistance machinery. Quorum sensing (QS), a process where bacteria use diffusible chemical signals to coordinate group behaviour, has been shown to be closely interconnected with biofilm formation and bacterial virulence in many top priority pathogens including Pseudomonas aeruginosa. Inhibition of QS pathways therefore pose an attractive target for new therapeutics. We have recently reported a new series of pqs quorum sensing inhibitors (QSIs) that serve as potentiators for antibiotics in P. aeruginosa infections. The impact on biofilms of some reported QSIs was however hindered by their poor penetration through the bacterial biofilm, limiting the potential for clinical translation. In this study we developed a series of poly(β-amino ester) (PBAE) triblock copolymers and evaluated their ability to form micelles, encapsulate a QSI and enhance subsequent delivery to P. aeruginosa biofilms. We observed that the QSI could be released from polymer micelles, perturbing the pqs pathway in planktonic P. aeruginosa. In addition, one of the prepared polymer variants increased the QSIs efficacy, leading to an enhanced potentiation of ciprofloxacin (CIP) action and therefore improved reduction in biofilm viability, compared to the non-encapsulated QSI. Thus, we demonstrate QSI encapsulation in polymeric particles can enhance its efficacy through improved biofilm penetration.

The biocompatibility, biodegradability, and responsiveness of poly( β ‐amino esters) (PBAEs) has led to their widespread use as biomaterials for drug and gene delivery. Nonetheless, the step‐growth polymerization mechanism that yields PBAEs limits the scope for their structural optimization toward specific applications because of limited monomer choice and end‐group modifications. Moreover, to date the post‐synthetic functionalization of PBAEs has relied on grafting‐to approaches, challenged by the need for efficient polymer–polymer coupling and potentially difficult post‐conjugation purification. Here a novel grafting‐from approach to grow reversible addition–fragmentation chain transfer (RAFT) polymers from a PBAE scaffold is described. This is achieved through PBAE conversion into a macromolecular chain transfer agent through a multistep capping procedure, followed by RAFT polymerization with a range of monomers to produce PBAE–RAFT hybrid triblock copolymers. Following successful synthesis, the potential biological applications of these ABA triblock copolymers are illustrated through assembly into polymeric micelles and encapsulation of a model hydrophobic drug, followed by successful nanoparticle (NP) uptake in breast cancer cells. The findings demonstrate this novel synthetic methodology can expand the scope of PBAEs as biomaterials.