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 approximate to 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.

Automated summary

Cross-linked micelles made of amphiphilic poly(ethylene glycol)-polysulfide block copolymers act as effective anti-inflammatory agents by scavenging ROS and inhibiting the production of inflammatory cytokines. Compared to self-assembled micelles, cross-linked micelles exhibit better stability, lower toxicity, and less damage to cells.