Chemodynamic therapy (CDT) based on the intracellular Fenton reaction has become increasingly explored in cancer treatment. However, the mildly acidic tumor microenvironment and the limited amount of intracellular hydrogen peroxide (H2O2) will create issues for CDT to perform a sustained and high-efficiency treatment. Therefore, how to selectively reduce the pH value and augment the amount of H2O2 in tumor tissues has become the key factor for realizing excellent CDT. Besides, the majority of the reported CDT systems have been constructed from iron-based inorganic or metal-organic framework nanomaterials due to the decisive role of metals in CDT, which restricts the development of CDT. In this study, inspired by the host-guest interactions between pillar[6]arene and ferrocene, a ternary pillar[6]arene-based supramolecular nanocatalyst (GOx@T-NPs) for CDT is reported for the first time. GOx@T-NPs not only exhibited a high-efficiency catalytic ability to convert glucose into hydroxyl radicals (•OH) and to reduce the pH value inside cancer cells for significant enhancement of the CDT effect, but they also showed sensitive glutathione-induced camptothecin (CPT) prodrug release capacity for further improving the efficiency of CDT. Hence, GOx@NPs possessed excellent ability to synergistically enhance the CDT. Additionally, an antitumor mechanism study showed that the prominent tumor inhibition capacity of GOx@T-NPs was derived from trimodal synergistic interactions of CDT, starvation therapy, and chemotherapy. Moreover, GOx@T-NPs manifested good biocompatibility and tumor selectivity with few side effects in major organs. This work broadens the range of materials available for CDT and demonstrates new developments in pillar[n]arene-based multimodal synergistic treatment systems.
Keywords: chemodynamic therapy; host−guest interaction; pillar[n]arenes; supramolecular drug delivery systems; synergistic therapy.