Synergy between pH- and hypoxia-responsiveness in antibiotic-loaded micelles for eradicating mature, infectious biofilms

作者：Linzhu Su, Yuanfeng Li, Shuang Tian, Fan Huang, Yijin Ren, Cuihong Yang, Henny C. van der Mei, Henk J. Busscher, Linqi Shi · 发表于：Acta Biomaterialia · 年份：2022 · DOI：10.1016/j.actbio.2022.10.020 · 被引用次数：31 · 研究领域：Nanoplatforms for cancer theranostics、Orthopedic Infections and Treatments、Inhalation and Respiratory Drug Delivery

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 living 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 mat...