Azide‐Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy

Abstract

AbstractResiquimod (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.