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Iron-based and BRD_(4)-downregulated strategy for amplified ferroptosis based on pH-sensitive/nir-Ⅱ-boosted nano-matchbox

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Acta Pharmaceutica Sinica B 2023年第2期13卷 863-878页

作者： Lujing Geng Tong Lu Huaqing Jing Yue Zhou Xiaoyang Liang Jiao Li Nan Li Tianjin Key Laboratory of Drug Delivery&High-Efficiency School of Pharmaceutical Science and TechnologyTianjin UniversityTianjin 300072China School of Precision Instruments and Optoelectronics Engineering Tianjin UniversityTianjin 300072China

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 *** overcome this obstacle,the bromodomain-containing protein 4(BRD_(4))-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 *** existence of matchbox(ZIF-8)is stable in physiologically neutral conditions but degradable in acidic environment,which could prevent the loaded agents from prematurely ***,GNRs as the drug-carriers induce the photothermal therapy(PTT)effect under the irradiation of near-infraredⅡ(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^(3+)/Fe^(2+))and ROS to initiate the FPT treatment by LPO *** the other hand,JQ1 as a small molecule inhibitor of BRD_(4)protein can amplify FPT through downregulating the expression of glutathione peroxidase 4(GPX4),thus inhibiting the ROS elimination and leading to the LPO *** in vitro and in vivo studies reveal that this p H-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and *** a result,our study points out a PTT combined iron-based/BRD_(4)-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

关键词： BDR_(4)protein Ferroptosis Photothermal therapy pH-Sensitive nir-ⅱlight ZIF-8 Fenton reactions Nano-matchbox

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