Department of Chemistry, Virginia Tech Center for Drug Discovery, and Macromolecules, Innovation Institute, Virginia Tech, 24061, Blacksburg, VA, USA.
Engineering Research Center of Cell & Therapeutic Antibody, School of Pharmacy, Shanghai Jiao Tong University, 200240, Shanghai, China.
Angew Chem Int Ed Engl. 2023 May 22;62(22):e202302303. doi: 10.1002/anie.202302303. Epub 2023 Apr 20.
Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H S donor conjugate, complexed with Fe , termed AAN-PTC-Fe . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H S, an inhibitor of catalase, an enzyme that detoxifies H O . Fe and H S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe , the AAN sequence, or the ability to generate H S. AAN-PTC-Fe performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H S-amplified, enzyme-responsive platform for synergistic cancer treatment.
诱导肿瘤细胞内产生大量活性氧（ROS）是一种被称为化学动力学治疗（CDT）的癌症治疗方法。CDT 依赖于递呈芬顿反应促进剂（如 Fe），利用肿瘤微环境中过量产生的 ROS。我们开发了一种肽-H2S 供体偶联物，与 Fe 络合，称为 AAN-PTC-Fe。AAN 三肽被组织蛋白酶 L 特异性切割，组织蛋白酶 L 在神经胶质瘤细胞中过度表达，释放羰基硫（COS）。碳酸酐酶水解 COS 形成 H2S，H2S 是过氧化氢酶的抑制剂，过氧化氢酶可以解毒 H2O2。与缺乏 Fe、AAN 序列或生成 H2S 能力的对照组相比，Fe 和 H2S 共同增加了 C6 神经胶质瘤细胞内的 ROS 水平并降低了细胞活力。AAN-PTC-Fe 的性能优于替莫唑胺，同时对 H9C2 心肌细胞没有细胞毒性。本研究提供了一个 H2S 放大、酶响应的平台，用于协同癌症治疗。
