State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
Bosn J Basic Med Sci. 2022 Oct 23;22(6):934-948. doi: 10.17305/bjbms.2022.7194.
Camptothecin (CPT) has attracted much attention due to its potent antitumor activities. However, the undesirable physicochemical properties, including poor water-solubility, unstable lactone ring and severe adverse effects limit its further application. In this study, two water-soluble prodrugs, CPT-lysine (CPTK) and CPT-arginine (CPTR), were designed and synthesized by conjugating lysine or arginine with CPT, improving its solubility, pharmacokinetic properties and tumor penetration. Importantly, the introduction of arginine into CPTR contributed to the mitochondria-specific delivery, which increased mitochondrial reactive oxygen species (ROS) generation, induced mitochondria dysfunction and enhanced cell apoptosis and in vivo anti-cancer effect. This strategy is believed to hold great potential for organelle-specific synergistic anti-tumor therapy.
喜树碱（CPT）因其具有很强的抗肿瘤活性而备受关注。然而，其不理想的理化性质，包括较差的水溶性、不稳定的内酯环和严重的不良反应，限制了它的进一步应用。在本研究中，通过将赖氨酸或精氨酸与 CPT 缀合，设计并合成了两种水溶性前药，即 CPT-赖氨酸（CPTK）和 CPT-精氨酸（CPTR），以提高其溶解度、药代动力学性质和肿瘤穿透性。重要的是，将精氨酸引入 CPTR 有助于线粒体特异性递药，从而增加线粒体活性氧（ROS）的产生，诱导线粒体功能障碍，增强细胞凋亡，并增强体内抗癌作用。这种策略有望为细胞器特异性协同抗肿瘤治疗提供巨大潜力。
