Azide-Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy

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-N-3) of R848 is developed, which is selectively activated to R848 in hypoxic tumors. R848-N-3 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-N-3 by elevating the level of tumor hypoxia. R848-N-3+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-N-3, R848-N-3+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.