功能高分子材料教育部重点实验室

近期发表论文

史林启课题组 | ACTA BIOMATERIALIA

发布人:功能高分子材料教育部重点实验室    发布时间:2018/11/01   浏览次数: 151 次

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.