pH-Responsive, Charge-Reversing Layer-by-Layer Nanoparticle Surfaces Enhance Biofilm Penetration and Eradication
Name
nihms-1992200.pdf
Description
Submitted version
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1.33 MB
Format
Adobe PDF
Checksum (MD5)
5e752d12626cf50f6b36ed26d3adc609
Author(s)
Deiss-Yehiely, Elad
Cárcamo-Oyarce, Gerardo
Berger, Adam G
Ribbeck, Katharina
Hammond, Paula T
Date Issued
June 30, 2023
Journal
ACS Biomaterials Science & Engineering
Publisher
American Chemical Society
Citation
Elad Deiss-Yehiely, Gerardo Cárcamo-Oyarce, Adam G. Berger, Katharina Ribbeck, and Paula T. Hammond. ACS Biomaterials Science & Engineering 2023 9 (8), 4794-4804.
Version
Author's final manuscript
Abstract
Microbes entrenched within biofilms can withstand 1000-fold higher concentrations of antibiotics, in part due to the viscous extracellular matrix that sequesters and attenuates antimicrobial activity. Nanoparticle (NP)-based therapeutics can aid in delivering higher local concentrations throughout biofilms as compared to free drugs alone, thereby enhancing the efficacy. Canonical design criteria dictate that positively charged nanoparticles can multivalently bind to anionic biofilm components and increase biofilm penetration. However, cationic particles are toxic and are rapidly cleared from circulation in vivo, limiting their use. Therefore, we sought to design pH-responsive NPs that change their surface charge from negative to positive in response to the reduced biofilm pH microenvironment. We synthesized a family of pH-dependent, hydrolyzable polymers and employed the layer-by-layer (LbL) electrostatic assembly method to fabricate biocompatible NPs with these polymers as the outermost surface. The NP charge conversion rate, dictated by polymer hydrophilicity and the side-chain structure, ranged from hours to undetectable within the experimental timeframe. LbL NPs with an increasingly fast charge conversion rate more effectively penetrated through, and accumulated throughout, wildtype (PAO1) and mutant overexpressing biomass (ΔwspF) Pseudomonas aeruginosa biofilms. Finally, tobramycin, an antibiotic known to be trapped by anionic biofilm components, was loaded into the final layer of the LbL NP. There was a 3.2-fold reduction in ΔwspF colony forming units for the fastest charge-converting NP as compared to both the slowest charge converter and free tobramycin. These studies provide a framework for the design of biofilm-penetrating NPs that respond to matrix interactions, ultimately increasing the efficacious delivery of antimicrobials.
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DOI of Published Version
https://doi.org/10.1021/acsbiomaterials.3c00481
