Synergy between pH- and hypoxia-responsiveness in antibiotic-loaded micelles for eradicating mature, infectious biofilms
作者:
Su, LZ (Su, Linzhu) [1] , [2] , [3] , [4] , [5] ;
Li, YF (Li, Yuanfeng) [3] , [4] ;
Tian, S (Tian, Shuang) [3] , [4] ;
Huang, F (Huang, Fan) [5] ;
Ren, YJ (Ren, Yijin) [6] , [7] ;
Yang, CH (Yang, Cuihong) [5] ;
van der Mei, HC (van der Mei, Henny C.) [3] , [4] ;
Busscher, HJ (Busscher, Henk J.) [3] , [4] ;
Shi, LQ (Shi, Linqi) [1] , [2]
ACTA BIOMATERIALIA
DOI
10.1016/j.actbio.2022.10.020
出版时间
DEC 2022
已索引
2023-01-25
文献类型
Article
摘要
Antibiotic-loaded PEG/PAE-based micelles are frequently considered for eradicating infectious biofilms. At physiological pH, PEG facilitates transport through blood. Near an acidic infection-site, PAE becomes protonated causing micellar targeting to a biofilm. However, micellar penetration and accumulation is confined to the surface region of a biofilm. Especially matured biofilms also possess hypoxic regions. We here designed dual-responsive PEG/PAE-b-P(Lys-NBCF) micelles, responding to both acidity and low oxygen-saturation level in matured biofilms. Dual, pH-and hypoxia-responsive micelles targeted and accumulated evenly over the depth of 7-to 14-days old biofilms. Delineation demonstrated that pH -responsiveness was responsible for targeting of the infection-site and accumulation of micelles in the surface region of the biofilm. Hypoxia-responsiveness caused deep penetration in the biofilm. Dual, pH -and hypoxia-responsive micelles loaded with ciprofloxacin yielded more effective, synergistic eradication of 10-days old, matured Staphylococcus aureus biofilms underneath an abdominal imaging-window in liv-ing mice than achieved by ciprofloxacin in solution or single, pH-or hypoxia responsive micelles loaded with ciprofloxacin. Also, wound-healing after removal of window and its frame proceeded fastest after tail-vein injection of ciprofloxacin-loaded, dual, pH-and hypoxia-responsive micelles. Concluding, pH -and hypoxia-responsiveness are both required for eradicating mature biofilms and advancing responsive antibiotic nanocarriers to clinical application.Statement of significance pH-responsive antibiotic nanocarriers have emerged as a possible new strategy to prevent antimicrobial -resistant bacterial infections from becoming the leading cause of death. In this paper, we show that com-monly studied, pH-responsive micellar nanocarriers merely allow self-targeting to an infectious biofilm, but do not penetrate deeply into the biofilm. The dual-responsive (acidic pH-and hypoxia) antibiotic -loaded micelles designed here not only self-target to an infectious biofilm, but also penetrate deeply. The in vitro and in vivo advantages of dual-responsive nanocarriers are most obvious when studied in infec-tious biofilms grown for 10 viz a viz the 2 days, usually applied in the literature. Significantly, clinical treatment of bacterial infection usually starts more than 2 days after appearance of the first symptoms.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )