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

Nanomaterials able to scavenge biologically relevant oxidants (reactive oxygen species, ROS) can directly act as anti‐inflammatory agents. Here, micelles made of amphiphilic poly(ethylene glycol)(PEG)‐polysulfide block copolymers are focused on; the polysulfide blocks are responsible of ROS‐scavenging and are composed of propylene sulfide and ethylene sulfide units in ratios of 20:0, 15:5, 10:10. These polymers can be intramicellarly cross‐linked through thermal thiol‐yne reaction of terminal alkynes (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 ≈0.1 and <0.01 mg mL−1) and in the final state after oxidation (soluble polymers vs cross‐linked nanoparticles). Most importantly, self‐assembled micelles have significant toxicity and damage cell membranes already at 0.5 mg mL−1, 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 effectively inhibit the production of inflammatory cytokines in activated macrophages. In this study, a detailed interpretation of the morphological evolution of the two types of micelles during oxidation is provided and it is proved that core cross‐linking significantly widens the therapeutic window. [ABSTRACT FROM AUTHOR]