Bacterial infections are a continuing medical threat as they cost the healthcare system billions of dollars each year, in part due to myriad therapeutic resistance mechanisms. One of these mechanisms is the formation of biofilms: communal organizations of bacteria surrounded by a viscous extracellular polymeric substance (EPS). The EPS controls permeation of exogeneous materials through the biofilm, such as antimicrobial therapeutics, requiring exorbitant doses to ensure efficacy. Nanoparticles (NPs) represent a promising strategy to more efficiently permeate and distribute antimicrobials throughout the biofilm. Recent studies have determined that NPs must exhibit a positive, cationic charge for effective penetration. However, cationic NPs are toxic and rapidly cleared when administered systemically, thereby limiting their use. In order to mitigate these orthogonal requirements, we have synthesized an anionic polymer with hydrolysable amide side chains responsive to moderate acidic pHs (6.5), known to be present within biofilms. After hydrolysis, the resulting amine provides a net positive charge, enabling enhanced biofilm permeation. By modifying the polymer structure, we can tune the cleavage rates and surface charge reversal, ranging from hours to days. To prepare functionalized NPs, we utilize the layer-by-layer (LbL) particle assembly method, in which oppositely charge poly-ions are sequentially adsorbed onto a charged colloidal substrate. We then probe the biofilm penetration of NPs layered with these charge-converting polymers in vitro with Transwell penetration assays and confocal microscopy. Finally, we loaded the NPs with therapeutically relevant amounts of tobramycin and quantified reductions in bacterial CFUs both in vitro and, anticipated, in vivo in a chronic murine airway infection model. From these experiments, we identify structure-property relationships that can be used to maximize the delivery of nano-encapsulated antimicrobials throughout biofilms.

pH-Responsive Layer-by-Layer Nanoparticles Enhance Biofilm Permeation and Eradication

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.