Tumor Targeted Cuprous-Based Nanocomposite as Responsive Cascade Nanocatalyst for Efficient Tumor Synergistic Therapy

The single-functionality of traditional chemodynamic therapy (CDT) reagents usually limits the therapeutic efficacy of cancer treatment. Synergistic nanocomposites that involve cascade reaction provide a promising strategy to achieve satisfactory anticancer effects. Herein, a cuprous-based nanocomposite (CCS@GOx@HA) is fabricated, which owns the tumor targeting ability and can undergo tumor microenvironment responsive cascade reaction to enhance the tumor therapeutic efficiency significantly. Surface modification of nanocomposite with hyaluronic acid enables the targeted delivery of the nanocomposite to cancer cells. Acid-triggered decomposition of nanocomposite in cancer cell results in the release of Cu+, Se2- and GOx. The Cu+ improves the Fenton-like reaction with endogenous H2O2 to generate highly toxic center dot OH for CDT. While GOx can not only catalyze the in situ generation of endogenous H2O2, but also accelerate the consumption of intratumoral glucose to reduce nutrient supply in tumor site. In addition, Se2- further improves the therapeutic effects of CDT by upregulating the reactive oxygen species (ROS) in tumor cells. Meanwhile, the surface modification endows the nanocomposite the good water dispersibility and biocompatibility. Moreover, in vitro and in vivo experiments demonstrate satisfactory anti-cancer therapeutic performance by the synergistic cascade function of CCS@GOx@HA than CDT alone. A cascade nanocatalytic reaction system is fabricated. The reasonable combination of the high catalytic efficiency derived from Cu+, in situ generation of endogenous H2O2 and consumption of intratumoral glucose induced by GOx, and the upregulation of ROS level evoked by selenocompounds has resulted in the excellent synergistic therapeutic effect in cancer treatment.image