Azide‐Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy

Abstract Resiquimod (R848) is an immunomodulator that causes a severe systemic inflammatory reaction due to low tumor selectivity, thus hindering its use in cancer therapy. Therefore, an azide‐masked prodrug (R848‐N₃) of R848 is developed, which is selectively activated to R848 in hypoxic tumors. R848‐N₃ significantly reduces pro‐inflammatory cytokines in treated mice to 1/12 compared to R848 at the same dose. In addition, combretastatin A4 nanoparticles (CA4‐NPs) are used to enhance the tumor selectivity of R848‐N₃ by elevating the level of tumor hypoxia. R848‐N₃+CA4‐NPs has higher tumor selectivity than the intratumoral injection of R848 at 1 h after administration. The concentration of the active R848 in the tumor is 21.45‐fold that in the heart. Benefiting from the high tumor selectivity of R848‐N₃, R848‐N₃+CA4‐NPs+anti‐PD1 exerted 94.1% tumor suppression and 40.0% tumor cure. Therefore, this work highlights the potential of azide‐masking strategy in the development of tumor‐selective prodrugs with reduced toxicity.