Resiquimod（R848）是一种免疫调节剂，由于肿瘤选择性低而导致严重的全身性炎症反应，因此阻碍了它在癌症治疗中的使用。因此，开发了一种R848的偶氮酰蒙蔽前药（R848-N3），它在缺氧肿瘤中被选择性激活为R848。与相同剂量的R848相比，R848-N3显着降低了治疗小鼠的促炎细胞因子到1/12。此外，利用丛枝藤毒素A4纳米粒子（CA4-NPs）提高了R848-N3的肿瘤选择性，通过升高肿瘤缺氧水平。与给药后1小时的R848肿瘤内注射相比，R848-N3 + CA4-NPs具有更高的肿瘤选择性。肿瘤中活性的R848浓度是心脏的21.45倍。由于R848-N3的高肿瘤选择性，R848-N3 + CA4-NPs + 抗PD1表现出94.1％的肿瘤抑制和40.0％的肿瘤治愈作用。因此，本研究强调了偶氮酰蒙蔽策略在开发具有减少毒性的肿瘤选择性前药方面的潜力。本文受版权保护。版权所有。

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-N3 ) of R848 was developed, which was 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) were used to enhance the tumor selectivity of R848-N3 by elevating the level of tumor hypoxia. R848-N3 +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-N3 , R848-N3 +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.This article is protected by copyright. All rights reserved.