A Photoactivated Sorafenib-Ruthenium(II) Prodrug for Resistant Hepatocellular Carcinoma Therapy through Ferroptosis and Purine Metabolism Disruption

The curative effect
of sorafenib in hepatocellular carcinoma
(HCC) is limited and sorafenib resistance remains a major obstacle
for HCC. To overcome this obstacle, a new photoactive sorafenib-Ru(II)
complex Ru-Sora has been designed. Upon irradiation (λ = 465
nm), Ru-Sora rapidly releases sorafenib and generates reactive oxygen
species, which can oxidize intracellular substances such as GSH. Cellular
experiments show that irradiated Ru-Sora is highly cytotoxic toward
Hep-G2 cells, including sorafenib-resistant Hep-G2-SR cells. Compared
to sorafenib, Ru-Sora has a significant photoactivated chemotherapeutic
effect against Hep-G2-SR cancer cells and 3D Hep-G2 multicellular
tumor spheroids. Furthermore, Ru-Sora inducing apoptosis and ferroptosis
is proved by GSH depletion, GPX4 downregulation, and lipid peroxide
accumulation. Metabolomics results suggest that Ru-Sora exerts photocytotoxicity
by disrupting the purine metabolism, which is expected to inhibit
tumor development. This study provides a promising strategy for enhancing
chemotherapy and combating drug-resistant HCC disease.

索拉非尼（sorafenib）在肝细胞癌（hepatocellular carcinoma, HCC）中的治疗效果有限，且索拉非尼耐药仍是肝细胞癌治疗的主要障碍。为克服这一难题，研究人员设计了一种新型光敏索拉非尼-钌(II)（Ru(II)）复合物Ru-Sora。在波长465 nm的辐照下，Ru-Sora可快速释放索拉非尼并产生活性氧物种，后者能够氧化谷胱甘肽（GSH）等胞内物质。细胞实验表明，经辐照的Ru-Sora对Hep-G2细胞（包括索拉非尼耐药的Hep-G2-SR细胞）具有极强的细胞毒性。与索拉非尼相比，Ru-Sora对Hep-G2-SR癌细胞及三维Hep-G2多细胞肿瘤球状体展现出显著的光活化化疗效果。通过谷胱甘肽耗竭、谷胱甘肽过氧化物酶4（GPX4）下调以及脂质过氧化物积累的实验结果，证实Ru-Sora可诱导细胞凋亡与铁死亡。代谢组学（metabolomics）结果显示，Ru-Sora通过干扰嘌呤代谢发挥光细胞毒性作用，有望抑制肿瘤进展。本研究为增强化疗效果、对抗耐药性肝细胞癌提供了一种极具前景的策略。