Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms
Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms
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表面适应性、负载抗菌剂的胶束纳米载体，对葡萄球菌生物膜具有增强的渗透和杀灭效率
DOI：
10.1021/acsnano.6b01370
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发表时间：
2016-04-01
期刊：
影响因子：
17.1
通讯作者：
Shi, Linqi
中科院分区：
文献类型：
--
作者：
Liu, Yong;Busscher, Henk J.;Shi, Linqi
生物膜引起持续的细菌感染，并且对抗微生物剂极其排斥，部分原因是抗微生物剂向生物膜中的渗透减少，这使得驻留在生物膜深处的细菌能够在抗微生物剂处理中存活。在这里，我们描述了表面适应性的、负载三氯生的胶束纳米载体的制备，其显示（1）增强的生物膜渗透和积累，（2）在酸性pH下静电靶向生物膜中带负电荷的细菌细胞表面，以及（3）由于细菌脂肪酶降解胶束核心而导致的抗菌剂释放。首先，它是建立的混合壳聚合物胶束（MSPM）组成的亲水性聚（乙二醇）（PEG）-壳和pH-响应性聚（β-氨基酯）在pH 5.0时带正电荷，而在生理pH值带负电荷。这是相反的单壳聚合物胶束（SSPM）只有一个PEG-壳，并保持在pH 5.0时带负电荷。的PEG壳结合其表面自适应电荷的隐身性能允许MSPM渗透和积累在葡萄球菌生物膜中，如使用共聚焦激光扫描显微镜的荧光尼罗红加载胶束所示。SSPM在pH 5.0下不适应正电荷，不能被证明渗透和积累在生物膜中。一旦胶束纳米载体结合到葡萄球菌细胞表面，细菌酶降解MSPM核心以释放其抗微生物内容物并杀死生物膜深度上的细菌。这构成了使用抗微生物剂控制血液可及的葡萄球菌生物膜的高度有效的途径，绕过生物膜渗透到抗微生物剂渗透。
Biofilms cause persistent bacterial infections and are extremely recalcitrant to antimicrobials, due in part to reduced penetration of antimicrobials into biofilms that allows bacteria residing in the depth of a biofilm to survive antimicrobial treatment. Here, we describe the preparation of surface-adaptive, Triclosan-loaded micellar nanocarriers showing (1) enhanced biofilm penetration and accumulation, (2) electrostatic targeting at acidic pH toward negatively charged bacterial cell surfaces in a biofilm, and (3) antimicrobial release due to degradation of the micelle core by bacterial lipases. First, it was established that mixed-shell-polymeric-micelles (MSPM) consisting of a hydrophilic poly(ethylene glycol) (PEG)-shell and pH-responsive poly(beta-amino ester) become positively charged at pH 5.0, while being negatively charged at physiological pH. This is opposite to single-shell-polymeric-micelles (SSPM) possessing only a PEG-shell and remaining negatively charged at pH 5.0. The stealth properties of the PEG-shell combined with its surface adaptive charge allow MSPMs to penetrate and accumulate in staphylococcal biofilms, as demonstrated for fluorescent Nile red loaded micelles using confocal-laser-scanning-microscopy. SSPMs, not adapting a positive charge at pH 5.0, could not be demonstrated to penetrate and accumulate in a biofilm. Once micellar nanocarriers are bound to a staphylococcal cell surface, bacterial enzymes degrade the MSPM core to release its antimicrobial content and kill bacteria over the depth of a biofilm. This constitutes a highly effective pathway to control blood-accessible staphylococcal biofilms using antimicrobials, bypassing biofilm recalcitrance to antimicrobial penetration.