Nanocarriers with conjugated antimicrobials to eradicate pathogenic biofilms evaluated in murine in vivo and human ex vivo infection models.
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| Abstract |
Conventional antimicrobials are becoming increasingly ineffective for treating bacterial infection due to the emergence of multi-drug resistant (MDR) pathogens. In addition, the biofilm-mode-of-growth of infecting bacteria impedes antimicrobial penetration in biofilms. Here, we report on poly(ethylene)glycol-poly(β-amino esters) (PEG-PAE) micelles with conjugated antimicrobials, that can uniquely penetrate biofilms, target themselves to bacterial cell surfaces once inside the low-pH environment of a biofilm and release conjugated antimicrobials through degradation of their ester-linkage with PAE by bacterial lipases. In vitro, PEG-PAE micelles with conjugated Triclosan (PEG-PAE-Triclosan) yielded no inadvertent leakage of their antimicrobial cargo and better killing of MDR Staphylococcus aureus, Escherichia coli and oral streptococcal biofilms than Triclosan in solution. In mice, PEG-PAE-Triclosan micelles with conjugated Triclosan yielded better eradication efficacy towards a MDR S. aureus-infection compared with Triclosan in solution and Triclosan-loaded micelles at equal Triclosan-equivalent concentrations. Ex vivo exposure of multi-species oral biofilms collected from orthodontic patients to PEG-PAE-Triclosan micelles, demonstrated effective bacterial killing at 30-40 fold lower Triclosan-equivalent concentrations than achieved by Triclosan in solution. Importantly, Streptococcus mutans, the main causative organism of dental caries, was preferentially killed by PEG-PAE-Triclosan micelles. Thus PEG-PAE-Triclosan micelles present a promising addendum to the decreasing armamentarium available to combat infection in diverse sites of the body. STATEMENT OF SIGNIFICANCE: pH-adaptive polymeric micelles with conjugated antimicrobials can efficiently eradicate infectious biofilms from diverse body sites in mice and men. An antimicrobial was conjugated through an ester-linkage to a poly(ethylene glycol) (PEG)/poly(β-amino ester) block copolymer to create micellar nanocarriers. Stable micelle structures were formed by the hydrophobic poly(β-amino ester) inner core and a hydrophilic PEG outer shell. Thus formed PEG-PAE-Triclosan micelles do not lose their antimicrobial cargo underway to an infection site through the blood circulation, but penetrate and accumulate in biofilms to release antimicrobials once inside a biofilm through degradation of its ester-linkage by bacterial lipases, to kill biofilm-embedded bacteria at lower antimicrobial concentrations than when applied in solution. PEG-PAE-Triclosan micelles effectively eradicate biofilms of multi-drug-resistant pathogens and oral bacteria, most notably highly cariogenic Streptococcus mutans, in mice and men respectively, and possess excellent clinical translation possibilities.
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| Authors | Yong Liu, Yijin Ren, Yuanfeng Li, Linzhu Su, Yumin Zhang, Fan Huang, Jinjian Liu, Jianfeng Liu, Theo G van Kooten, Yingli An, Linqi Shi, Henny C van der Mei, Henk J Busscher |
| Journal | Acta biomaterialia (Acta Biomater) Vol. 79 Pg. 331-343 (10 01 2018) ISSN: 1878-7568 [Electronic] England |
| PMID | 30172935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. |
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