National Glycoengineering Research Center and Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate-based Medicine, Shandong University, Qingdao, Shandong 266237, China.
Departments of Chemistry and Biomedical Engineering, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, USA.
Biomater Sci. 2023 Sep 12;11(18):6160-6166. doi: 10.1039/d3bm01072d.
Camptothecin (CPT) is an attractive natural drug for cancer chemotherapy. However, the poor water solubility, non-targeting feature, and adverse side effects of CPT are significant obstacles to developing an effective anticancer drug. Here, for the first time, 9-thiol-sialic acid (9-SH-Sia) is coupled to CPT by forming a disulfide releasable carbonate linkage, resulting in a novel CPT prodrug (CPT-ss-Sia) that self-assembles into nanostructures in an aqueous solution. Strikingly, CPT-ss-Sia exhibited excellent properties, including enhanced water solubility, glutathione (GSH)-triggered CPT release, and increased E-lactone ring stability. Furthermore, CPT-ss-Sia had good cancer cell-killing ability comparable to CPT. Intravenous administration of CPT-ss-Sia significantly inhibited the growth of multiple types of tumors. Histological analysis showed that CPT-ss-Sia treatment significantly reduced lesions in tumor-bearing mice compared to CPT treatment. Notably, CPT-ss-Sia treatment did not adversely affect the body weight of the mice. This is the first report of the 9-SH-Sia conjugate-based prodrug. Overall, CPT-ss-Sia has broad clinical application prospects.
喜树碱（CPT）是一种有吸引力的癌症化疗天然药物。然而，CPT 的水溶性差、非靶向性和不良反应等问题，是开发有效抗癌药物的重大障碍。在这里，首次通过形成可释放二硫键的碳酸酯键，将 9-巯基唾液酸（9-SH-Sia）偶联到 CPT 上，得到一种新型的 CPT 前药（CPT-ss-Sia），它在水溶液中自组装成纳米结构。引人注目的是，CPT-ss-Sia 表现出优异的性能，包括增强的水溶性、谷胱甘肽（GSH）触发的 CPT 释放和增加的 E-内酯环稳定性。此外，CPT-ss-Sia 具有与 CPT 相当的良好的癌细胞杀伤能力。CPT-ss-Sia 的静脉给药显著抑制了多种类型肿瘤的生长。组织学分析表明，与 CPT 治疗相比，CPT-ss-Sia 治疗显著减少了荷瘤小鼠的病变。值得注意的是，CPT-ss-Sia 治疗并未对小鼠的体重产生不利影响。这是首例基于 9-SH-Sia 缀合物的前药报告。总体而言，CPT-ss-Sia 具有广泛的临床应用前景。
