Disulfide Cross-Linked Polyurethane Micelles as a Reduction-Triggered Drug Delivery System for Cancer Therapy

Nanoscale carriers that stably load drugs in blood circulation and release the payloads in desirable sites in response to a specific trigger are of great interest for smart drug delivery systems. For this purpose, a novel type of disulfide core cross‐linked micelles, which are facilely fabricated by cross‐linking of poly(ethylene glycol)/polyurethane block copolymers containing cyclic disulfide moieties via a thiol‐disulfide exchange reaction, are developed. A broad‐spectrum anti‐cancer drug, doxorubicin (DOX), is loaded into the micelles as a model drug. The drug release from the core cross‐linked polyurethane micelles (CCL‐PUMs) loaded with DOX is suppressed in normal phosphate buffer saline (PBS), whereas it is markedly accelerated with addition of an intracellular reducing agent, glutathione (GSH). Notably, although DOX‐loaded CCL‐PUMs display lower cytotoxicity in vitro compared to either free DOX or DOX‐loaded uncross‐linked polyurethane micelles, the drug‐loaded CCL‐PUMs show the highest anti‐tumor efficacy with reduced toxicity in vivo. Since enhanced anti‐tumor efficacy and reduced toxic side effects are key aspects of efficient cancer therapy, the novel reduction‐responsive CCL‐PUMs may hold great potential as a bio‐triggered drug delivery system for cancer therapy. A novel type of disulfide core cross‐linked polyurethane micelles (CCL‐PUMs) is reported. Although the CCL‐PUMs loaded with doxorubicin (DOX) display lower cytotoxicity in vitro compared to free DOX or DOX‐loaded uncross‐linked polyurethane micelles, the drug‐loaded CCL‐PUMs exhibit the highest anti‐tumor efficacy in vivo.