State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 211198, China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211100, China.
Nanoscale Horiz. 2024 Nov 19;9(12):2306-2319. doi: 10.1039/d4nh00189c.
Sonodynamic therapy (SDT) is gaining popularity in cancer treatment due to its superior controllability and high tissue permeability. Nonetheless, the efficacy of SDT is severely diminished by the transient generation of limited reactive oxygen species (ROS). Herein, we introduce an acid-activated nanosonosensitizer, CaO@PCN, by the controllable coating of porphyrinic metal-organic frameworks (PCN-224) on CaO to induce cascaded oxidative stress in tumors. The PCN-224 doping can generate ROS during SDT to induce intracellular oxidative stress and abnormal calcium channels. Meanwhile, the ultrasound also promotes extracellular calcium influx. In addition, CaO@PCN sequentially degrades in the tumor cell lysosomes, releasing Ca and HO to induce further abnormal calcium channels and elevate the levels of Ca. Insufficient catalase (CAT) in tumor cells promotes intracellular calcium overload, which can induce persistent ROS generation and mitochondrial dysfunction through ion interference therapy (IIT). More importantly, PCN-224 also protects CaO against significant degradation under neutral conditions. Hence, the well-designed CaO@PCN produces synergistic SDT/IIT effects and persistent ROS against cancer. More notably, the acidity-responsive biodegradability endows CaO@PCN with excellent biosafety and promising clinical potential.
声动力学疗法（SDT）因其优异的可控性和高组织通透性在癌症治疗中越来越受欢迎。然而，SDT 的疗效受到有限的活性氧（ROS）瞬时产生的严重限制。在此，我们通过在 CaO 上可控地包覆卟啉金属有机骨架（PCN-224），引入了一种酸激活的纳米声敏剂 CaO@PCN，以在肿瘤中诱导级联氧化应激。PCN-224 的掺杂可以在 SDT 期间产生 ROS，从而诱导细胞内氧化应激和异常钙通道。同时，超声也促进细胞外钙离子内流。此外，CaO@PCN 依次在肿瘤细胞溶酶体中降解，释放 Ca 和 HO，进一步诱导异常钙通道并提高 Ca 水平。肿瘤细胞中过氧化氢酶（CAT）不足会导致细胞内钙超载，通过离子干扰治疗（IIT）可通过离子干扰治疗（IIT）诱导持续的 ROS 生成和线粒体功能障碍。更重要的是，PCN-224 还能在中性条件下保护 CaO 免受明显降解。因此，精心设计的 CaO@PCN 产生协同的 SDT/IIT 效应和持续的 ROS 以对抗癌症。更值得注意的是，酸响应的生物降解性使 CaO@PCN 具有优异的生物安全性和有前途的临床潜力。
