Geng Lujing, Lu Tong, Jing Huaqing, Zhou Yue, Liang Xiaoyang, Li Jiao, Li Nan
Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
School of Precision Instruments and Optoelectronics Engineering, Tianjin University, Tianjin 300072, China.
Acta Pharm Sin B. 2023 Feb;13(2):863-878. doi: 10.1016/j.apsb.2022.05.011. Epub 2022 May 15.
Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD)-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe/Fe) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both and studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.
铁死亡（FPT）是一种新型的程序性细胞死亡形式，其特征是铁/活性氧（ROS）依赖性脂质过氧化（LPO）的过度积累。然而，内源性铁和ROS水平的不足在很大程度上限制了FPT的治疗效果。为了克服这一障碍，将含溴结构域蛋白4（BRD）抑制剂（+）-JQ1（JQ1）和补铁剂柠檬酸铁铵（FAC）负载的金纳米棒（GNRs）封装到沸石咪唑酯骨架-8（ZIF-8）中，形成火柴盒状的GNRs@JF/ZIF-8用于增强FPT治疗。火柴盒（ZIF-8）在生理中性条件下稳定，但在酸性环境中可降解，这可以防止负载的药物过早反应。此外，GNRs作为药物载体，由于局域表面等离子体共振（LSPR）吸收，在近红外II（NIR-II）光照射下诱导光热疗法（PTT）效应，而热疗也促进了JQ1和FAC在肿瘤微环境（TME）中的释放。一方面，FAC在TME中诱导的芬顿/类芬顿反应可同时生成铁（Fe/Fe）和ROS，通过升高LPO启动FPT治疗。另一方面，JQ1作为BRD蛋白的小分子抑制剂，可通过下调谷胱甘肽过氧化物酶4（GPX4）的表达来放大FPT，从而抑制ROS消除并导致LPO积累。体内和体外研究均表明，这种pH敏感的纳米火柴盒在具有良好生物安全性和生物相容性的情况下，实现了对肿瘤生长的明显抑制。因此，我们的研究指出了一种PTT联合铁基/BRD下调策略用于增强铁疗法，这也为铁疗法系统的未来开发打开了大门。
