Hypoxia-triggered photothermal/drug combination therapy of tumors using a perylene diimide molecular capsule

Hypoxia is a common characteristic of tumors and associated with poor outcome in most cancer types, thus hypoxia-triggered combined therapeutic systems with well-defined structure hold significant promise for achieving specific and effective tumor destruction. Herein, a water-soluble perylene diimide (PDI) cyclophane "Gemini Box" (GBox-14+) is demonstrated as both a hypoxia-responsive photothermal agent and a drug capsule for tumor-specific combination therapy. First, owing to the covalent enclosure of PDI chromophore by double-sided molecular straps, GBox-14+ can significantly stabilize labile PDI radical anions generated through bioreduction at the lesion site of hypoxic tumors, leading to high-efficiency near-infrared photothermal ablation of tumors. Meanwhile, GBox-14+ can act as a molecular capsule to bind water-insoluble antitumor drugs camptothecin and hydroxycamptothecin in 1:1 host-guest stoichiometry with high affinities, greatly enhancing the water solubility of drugs. Eventually, such drug-loading cyclophane system as a hypoxia-activated photothermal/drug combined therapeutic platform exhibits more effective inhibition of tumor growth than the single treatment under identical conditions. This study significantly extends the application range of host-guest cyclophane systems and opens a promising avenue to structurally uniform combined therapeutic agents against hypoxic tumors with improved specificity.