Wang Sizhen, Zhang Hanzhe, Chen Tianheng, Jiang Weiwei, Wang Feng, Yu Yuhao, Guo Beibei, Xu Jia, Yang Feng, Kang Qinglin, Ma Zhiqiang
Department of Inorganic Chemistry, Pharmacy School, Naval Medical University, 325 Guohe Road, Shanghai, 200433, People's Republic of China.
Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, People's Republic of China.
Mater Today Bio. 2024 Nov 23;29:101368. doi: 10.1016/j.mtbio.2024.101368. eCollection 2024 Dec.
The prognosis for osteosarcoma patients, a devastating malignancy affecting young individuals, remains grim despite multimodal therapeutic advances. Recently, the advent of cuproptosis, a novel programmed cell death, offers hope in fighting osteosarcoma. In this study, we introduce SAHA@{[Cu(HA-Cys)]Cl}, an injectable hyaluronate-L-cysteine hydrogel that integrates both copper ions (Cu) and vorinostat (SAHA) for the possible therapeutic effect. The Cu targets the TCA cycle, inducing cuproptosis in osteosarcoma cells. While SAHA acts as both a histone deacetylase inhibitor and an ROS generator for eliminating tumor cells. The mechanism involves amplifying FDX-1 expression via SAHA modulation of the TCA cycle, which was an original discovery. Critically, the combined mechanisms and localized injection enables the hydrogel partially eradicating osteosarcoma without metastasis in rats. Therefore, this study advances cuproptosis induced photothermal therapy for promising clinical translations, shedding light on favorable prognosis for osteosarcoma.
骨肉瘤是一种影响年轻人的毁灭性恶性肿瘤，尽管多模式治疗取得了进展，但其患者的预后仍然严峻。最近，一种新型程序性细胞死亡——铜死亡的出现，为对抗骨肉瘤带来了希望。在本研究中，我们引入了SAHA@{[Cu(HA-Cys)]Cl}，一种可注射的透明质酸-L-半胱氨酸水凝胶，它整合了铜离子（Cu）和伏立诺他（SAHA）以发挥可能的治疗作用。铜靶向三羧酸循环，诱导骨肉瘤细胞发生铜死亡。而SAHA既作为组蛋白去乙酰化酶抑制剂，又作为活性氧生成剂来消除肿瘤细胞。其机制包括通过SAHA对三羧酸循环的调节来放大FDX-1的表达，这是一项原创性发现。至关重要的是，联合机制和局部注射使水凝胶能够在大鼠体内部分根除骨肉瘤且无转移。因此，本研究推进了铜死亡诱导的光热疗法，有望实现临床转化，为骨肉瘤的良好预后带来曙光。
