Protection of DNase in the shell of a pH-responsive, antibiotic-loaded micelle for biofilm targeting, dispersal and eradication

作者：Shuang Tian, Linzhu Su, Yingli An, Henny C. van der Mei, Yijin Ren, Henk J. Busscher, Linqi Shi · 发表于：Chemical Engineering Journal · 年份：2022 · DOI：10.1016/j.cej.2022.139619 · 被引用次数：26 · 研究领域：Bacterial biofilms and quorum sensing、Bacteriophages and microbial interactions、Advanced biosensing and bioanalysis techniques

DNase can break down the extracellular matrix that keeps infectious bacterial biofilm together through cleavage of eDNA. Herewith, biofilm bacteria can become dispersed to assist antibiotic eradication but this has hitherto remained an in vitro possibility. In vivo DNase is rapidly broken down in blood, impeding blood-injection of DNase combined with antibiotics to cure bacterial infections. Herein, we report the synthesis of pH-responsive, self-targeting micelles self-assembled from a solution of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and poly(ε-caprolactone)-block-poly(amino ester) (PCL-b-PAE) with DNase conjugated to PAE-blocks. At physiological pH, this conjugation protected DNase inside the micellar shell, while PEG prevented adsorption of blood-borne proteins to the micelles. PAE became positively-charged below pH 6.4 facilitating self-targeting to an infectious biofilm. Simultaneously, PAE became hydrophilic and stretched to expose DNase upon accumulation in an infectious S. aureus biofilm where it degraded the biofilm matrix. PEG/PAE-DNase micelles internally core-loaded with ciprofloxacin significantly better eradicated murine pneumonia after blood-injection than ciprofloxacin-loaded PEG/PAE micelles without conjugated DNase or ciprofloxacin free in solution. Considering that DNase is clinically approved for use in cystic fibrosis patients, this paves the way for clinical translation of ciprofloxacin-loaded, PEG/PAE-DNase micelles for the treatm...