Tumor-targeted supramolecular catalytic nanoreactor for synergistic chemo/chemodynamic therapy via oxidative stress amplification and cascaded Fenton reaction

Utilizing intratumoral iron mediated Fenton reaction to induce cancer cells destruction, chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the CDT efficacy is severely restrained by insufficient endogenous H2O2 and catalytic ferrous ions in tumor site. Herein, based on innovative small molecule prodrug design concept, an acid-labile ferrocene-modified cinnamaldehyde prodrug (Fc-CA) was first synthesized. Skillfully combining ROS-generator CA with Fenton catalyst Fc in its molecular structure, Fc-CA could synchronously elevate H2O2 level and catalytic iron amount for enhanced CDT efficacy. Then, hydrophobic Fc-CA was efficiently encapsulated into hydrophilic cyclodextrin-modified hyaluronic acid conjugate (HA-CD) via host-guest interactions, to spontaneously form pH/redox dual-responsive supramolecular catalytic nanoreactor (HA-CD/Fc-CA NPs). The nanoreactor with high drug loading and stability, excellent catalytic activity and tumor specificity could preferentially accumulate in tumor tissues via EPR effect and CD44 receptor-mediated internalization. Through the cleavage of acid-labile hydrazone bond under acidic lysosome environments, the nanoreactor would be dissociated and release pre-protected CA for reinforced oxidation therapy and amplified H2O2 level, which would in turn react with Fc through cascaded Fenton reaction, to generate highly cytotoxic center dot OH for enhanced cancer killing in a positive feedback process. Both in vitro and in vivo results verified excellent cascade-amplifying therapeutic performance and favorable biocompatibility of this nanoreactor. This study provides an innovative strategy for exploiting versatile organic therapeutic nanoplatforms, simultaneously activating tumor-specific oxidative stress amplification and cascaded enhanced Fenton reaction for superior cancer therapy with excellent biosafety.