Nanocarriers with conjugated antimicrobials
to eradicate pathogenic biofilms evaluated in murine in vivo and human ex vivo
infection models
Liu, Y (Liu, Yong)[ 1,2,3 ] ; Ren, YJ (Ren, Yijin)[ 4,5 ] ; Li, YF (Li, Yuanfeng)[ 1,2,3 ] ; Su, LZ (Su, Linzhu)[ 1,2,3 ] ; Zhang, YM (Zhang, Yumin)[ 6,7 ] ; Huang, F(Huang, Fan)[ 6,7 ] ; Liu, JJ (Liu, Jinjian)[ 6,7 ] ; Liu, JF (Liu, Jianfeng)[ 6,7 ] ; van Kooten, TG (van Kooten, Theo G.)[ 2,3 ] ; An, YL (An, Yingli)[ 1 ] ; Shi, LQ (Shi, Linqi)[1 ] ; van der Mei, HC (van der Mei, Henny C.)[ 2,3 ] ; Busscher, HJ (Busscher, Henk J.)[ 2,3 ]
ACTA BIOMATERIALIA, 2018, 79: 331-343
DOI: 10.1016/j.actbio.2018.08.038
WOS:000447477600025
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)gly col-poly((beta-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(beta-amino ester) block copolymer to create micellar
nanocarriers. Stable micelle structures were formed by the hydrophobic
poly((beta-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. (C) 2018 Acta Materialia Inc.
Published by Elsevier Ltd. All rights reserved.
