Core Cross‐Linking Enhances the Anti‐Inflammatory Performance of Oxidation‐Sensitive Polymeric Micelles

Abstract Nanomaterials able to scavenge biologically relevant oxidants (Reactive Oxygen Species, ROS) can directly act as anti‐inflammatory agents. Here, we focus on micelles made of amphiphilic poly(ethylene glycol)(PEG)‐polysulfide block copolymers; the polysulfide blocks are composed by propylene sulfide and ethylene sulfide units in ratios of 20:0, 15:5, 10:10, and are responsible of their ROS‐scavenging properties. Bearing terminal alkynes, these polymers can be intramicellarly cross‐linked by using a thermal thiol‐yne reaction (trithiol cross‐linker). Self‐assembled and cross‐linked micelles are virtually identical in size and scavenging kinetics, but greatly differ in stability against dilution (critical aggregation concentration (CAC) respectively of about 0.1 and <0.01 mg mL −1 ) and in the final state after oxidation (soluble polymers versus cross‐linked nanoparticles). Most importantly, normal (“self‐assembled”) micelles exhibit significant toxicity and membrane damaging behaviour at concentration of 0.5 mg mL −1 and above, which seriously hampers their anti‐inflammatory activity. On the contrary, cross‐linked micelles do not appreciably harm cells at least up to 1 mg mL −1 , and can effectively inhibit the production of the inflammatory cytokine TNF‐α in LPS‐activated macrophages. In this study, we provide a detailed interpretation of the morphological evolution of the two types of micelles during oxidation and prove that core cross‐linking significantly widen the therapeutic window. This article is protected by copyright. All rights reserved