Co-Delivery of an Amyloid-Disassembling Polyphenol Cross-Linked in a Micellar Shell with Core-Loaded Antibiotics for Balanced Biofilm Dispersal and Killing

Amyloid-fibers help to maintain the structure of infectious biofilms. Disassembly of amyloid-fibers contributes to biofilm-dispersal in the blood-circulation, from which bacteria should be cleared by the host immune system. However, often the immune system is insufficiently prepared for increasing bacterial concentrations in blood, causing septic symptoms. Here, poly(ethylene glycol)/poly(beta-amino ester), pH-responsive micelles are prepared for co-delivery of (-)-epigallocatechin-3-O-gallate (EGCG) as a dispersant. Hydrophilic EGCG can not be loaded in the micellar core, but is cross-linked in the micellar shell through pH-reversible, boronic-ester binding. Disassembly of micelles under acidic biofilm conditions facilitates release of EGCG and dispersal of biofilm-bacteria. When core-loaded with ciprofloxacin, in-shell EGCG prevents ciprofloxacin-leakage at physiological pH. Bacterial killing by core-loaded ciprofloxacin in Staphylococcus aureus biofilms is enhanced when released in combination with EGCG in vitro and in vivo. In mice, micelles with in-shell EGCG self-target after tail-vein injection to an infection site, yielding dispersal of pathogens with mild septic symptoms and bacterial killing by the immune system. Septic symptoms disappear slightly faster when micelles are additionally core-loaded with ciprofloxacin. Thus, micelles with in-shell EGCG yield balanced biofilm dispersal inducing only mild septic symptoms, which is good news in an era of increasing antibiotic-resistance.