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.