title: Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms.
abstract: 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(β-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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University , Tianjin 300071, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: University of Groningen and University Medical Center Groningen , Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Busscher
authors.affiliation: University of Groningen and University Medical Center of Groningen , Department of Orthodontics, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
authors.forename: Bingran
authors.initials: B
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University , Tianjin 300071, China.
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University , Tianjin 300071, China.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: University of Groningen and University Medical Center Groningen , Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Henny C
authors.initials: HC
authors.lastname: van der Mei
authors.affiliation: University of Groningen and University Medical Center of Groningen , Department of Orthodontics, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University , Tianjin 300071, China.
authors.forename: Linqi
authors.initials: L
authors.lastname: Shi
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D065546:Drug Liberation; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D040141:Staphylococcaceae / Q000187:drug effects*; D055672:Static Electricity; D013499:Surface Properties; D014260:Triclosan / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D005456:Fluorescent Dyes; D008823:Micelles; D011092:Polyethylene Glycols; D014260:Triclosan
keywords: Triclosan; antimicrobials; biofilm; electrostatic interactions; micelles; pH-responsiveness; staphylococci