Azide-Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy.

Resiquimod (R848) is an immunomodulator causing 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 was developed, which was 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) were used to enhance the tumor selectivity of R848-N 3 by elevating the level of tumor hypoxia. R848-N 3 +CA4-NPs had higher tumor selectivity than the intratumoral injection of R848 at 1 h after administration. The concentration of the active R848 in the tumor was 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 highlighted the potential of azide-masking strategy in the development of tumor-selective prodrugs with reduced toxicity. This article is protected by copyright. All rights reserved.