The limited efficiency of the Fenton reaction within tumors restricts the therapeutic efficacy of chemodynamic therapy. Decreasing the glutathione (GSH) concentration in cancer cells is well established as an effective strategy to amplify the efficiency of the Fenton reaction. However, the rapid blood clearance of small molecule therapeutic agents and the inefficiency of conventional nanoparticle degradation have limited the development of this strategy. Herein, we report an amphiphilic self-immolative comb-block copolymer that cascades to degrade multiple- releases of azaquinone methide (AQM) derivatives and side-aminoferrocene after a single stimulus event. Both aminoferrocene (AFc) and its product Fe<sup>2+</sup> act as catalysts to convert high levels of intracellular hydrogen peroxide to more reactive hydroxyl radicals (<sup>.</sup>OH). AQM derivatives rapidly deplete the major antioxidant GSH in cancer cells, amplifying the efficiency of the Fenton reaction. We demonstrated the efficiency of this synergistic strategy and the low systemic toxicity of polymeric nanoparticles by establishing cell culture and mouse tumor models. This work establishes a robust CDT drug delivery platform with innate synergy based on amphiphilic self-immolative polymeric nanoparticles, which allows efficient delivery of target drugs with simple side-group substitution for tumor treatment in a synergistic manner.

Self-immolative comb-block copolymers with multiple-release of side-aminoferrocene and azaquinone methide to synergistically amplify chemodynamic therapy efficiency

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