Xiao Kui, Hou Da-Yong, Zhang Ni-Yuan, Wang Wan, Leung Ming-Yi, Kwok Wing-Kei, Chen Ziyong, Jin Cong, Xu Wanhai, Wang Hao, Yam Vivian Wing-Wah, Zhao Liang
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing 100190, P. R. China.
J Am Chem Soc. 2025 Feb 5;147(5):4482-4492. doi: 10.1021/jacs.4c15820. Epub 2025 Jan 24.
Effective delivery and controlled release of metallo-prodrugs with sustained activation and rapid response feed the needs of precise medicine in metal chemotherapeutics. However, gold-based anticancer drugs often suffer from detoxification binding and extracellular transfer by sulfur-containing peptides. To address this challenge, we integrate a thiol-activated prodrug strategy of newly prepared hypercoordinated carbon-centered gold(I) clusters (HCGCs) with their photosensitization character to augment the mitochondrial release of Au(I) in tumors. In contrast to the distorted [CAu] kernel of a pentanuclear HCGC compound [], its dimeric congener [] exhibits a symmetrical [{CAu}-Au-{CAu}] structure with a remarkable hypercarbon-to-Au electron donation. This unique arrangement results in a microsecond long metal-metal-to-ligand charge transfer excited state relative to the nanosecond intraligand excited state of []. Upon light irradiation at 560 nm, [] generates active O to oxidize glutathione (GSH) into poorly coordinating GSSG in the cytoplasm and finally promotes subcellular delivery of HCGCs to mitochondria. Moreover, GSH further triggers consecutive release of active [AuPPh] ions to inhibit cytoplasmic glutathione peroxidase GPX4 and mitochondrial thioredoxin reductase TrxR2, which collectively result in accelerated ferroptosis of human bladder cancer EJ cells and show excellent antitumor performance in mouse bladder tumor models.
金属前药的有效递送和控释，以及持续激活和快速响应，满足了金属化疗中精准医学的需求。然而，基于金的抗癌药物常常会因含硫肽的解毒结合和细胞外转移而受到影响。为应对这一挑战，我们将新制备的超配位碳中心金（I）簇（HCGCs）的硫醇激活前药策略与其光敏特性相结合，以增强肿瘤中线粒体对Au（I）的释放。与五核HCGC化合物[]扭曲的[CAu]内核不同，其二聚体同系物[]呈现出对称的[{CAu}-Au-{CAu}]结构，具有显著的超碳到金的电子给予。这种独特的排列导致相对于[]的纳秒级配体内激发态，产生了微秒级的金属-金属到配体电荷转移激发态。在560 nm光照下，[]产生活性氧，将细胞质中的谷胱甘肽（GSH）氧化为配位性较差的GSSG，最终促进HCGCs向线粒体的亚细胞递送。此外，GSH进一步触发活性[AuPPh]离子的连续释放，以抑制细胞质中的谷胱甘肽过氧化物酶GPX4和线粒体中的硫氧还蛋白还原酶TrxR2，这共同导致人膀胱癌EJ细胞加速铁死亡，并在小鼠膀胱肿瘤模型中表现出优异的抗肿瘤性能。
