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Azide-Masked Resiquimod Activated by Hypoxia for Selective Tumor Therapy
Advanced Materials ( IF 27.4 ) Pub Date : 2023-04-22 , DOI: 10.1002/adma.202207733
Jiali Sun 1, 2 , Zhilin Liu 1 , Haochen Yao 3 , Honglei Zhang 1, 4 , Mengfei Zheng 1, 2 , Na Shen 1 , Jianjun Cheng 5 , Zhaohui Tang 1, 2 , Xuesi Chen 1, 2
Advanced Materials ( IF 27.4 ) Pub Date : 2023-04-22 , DOI: 10.1002/adma.202207733
Jiali Sun 1, 2 , Zhilin Liu 1 , Haochen Yao 3 , Honglei Zhang 1, 4 , Mengfei Zheng 1, 2 , Na Shen 1 , Jianjun Cheng 5 , Zhaohui Tang 1, 2 , Xuesi Chen 1, 2
Affiliation
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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.
中文翻译：
缺氧激活叠氮掩蔽的瑞西莫德用于选择性肿瘤治疗
Resiquimod (R848)是一种免疫调节剂，由于肿瘤选择性低而引起严重的全身炎症反应，从而阻碍了其在癌症治疗中的应用。因此，开发了R848的叠氮化物掩蔽前药(R848-N 3 )，其在缺氧肿瘤中选择性地激活R848。与相同剂量的 R848 相比，R848-N 3显着将治疗小鼠的促炎细胞因子降低至 1/12。此外，考布他汀A4纳米颗粒（CA4-NPs）用于通过提高肿瘤缺氧水平来增强R848-N 3的肿瘤选择性。R848-N 3 +CA4-NPs比给药后1小时瘤内注射R848具有更高的肿瘤选择性。肿瘤中活性R848的浓度是心脏中的21.45倍。受益于R848-N 3的高肿瘤选择性，R848-N 3 +CA4-NPs+抗PD1发挥了94.1%的肿瘤抑制率和40.0%的肿瘤治愈率。因此，这项工作强调了叠氮掩蔽策略在开发具有降低毒性的肿瘤选择性前药方面的潜力。
更新日期：2023-04-22
中文翻译：
缺氧激活叠氮掩蔽的瑞西莫德用于选择性肿瘤治疗
Resiquimod (R848)是一种免疫调节剂，由于肿瘤选择性低而引起严重的全身炎症反应，从而阻碍了其在癌症治疗中的应用。因此，开发了R848的叠氮化物掩蔽前药(R848-N 3 )，其在缺氧肿瘤中选择性地激活R848。与相同剂量的 R848 相比，R848-N 3显着将治疗小鼠的促炎细胞因子降低至 1/12。此外，考布他汀A4纳米颗粒（CA4-NPs）用于通过提高肿瘤缺氧水平来增强R848-N 3的肿瘤选择性。R848-N 3 +CA4-NPs比给药后1小时瘤内注射R848具有更高的肿瘤选择性。肿瘤中活性R848的浓度是心脏中的21.45倍。受益于R848-N 3的高肿瘤选择性，R848-N 3 +CA4-NPs+抗PD1发挥了94.1%的肿瘤抑制率和40.0%的肿瘤治愈率。因此，这项工作强调了叠氮掩蔽策略在开发具有降低毒性的肿瘤选择性前药方面的潜力。
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