上海交通大学姜大朋团队报道了酶介导的生物正交级联催化反应对神经母细胞瘤代谢干预和增强的铁下垂。相关研究成果发表在2024年3月12日出版的《美国化学会杂志》。

神经母细胞瘤是一种致命的癌症，预后不良，治疗结果令人失望，探索有效的治疗方法仍然是一个巨大的挑战。

考虑到传统治疗方式的局限性和神经母细胞瘤的内在脆弱性，研究人员开发了一种开创性的顺序催化治疗系统，该系统利用乳酸氧化酶（LOx）/辣根过氧化物酶（HRP）负载的无定形锌金属-有机框架，命名为LOx/HRP-aZIF，并结合3-吲哚乙酸（IAA）前药。

在肿瘤微环境中发生的异常乳酸盐积累的基础上，LOx和HRP的级联反应消耗内源性谷胱甘肽和还原形式的烟酰胺腺嘌呤二核苷酸，以实现通过抗氧化失能和电子传递链干扰杀死癌症细胞的第一阶段。

此外，HRP和IAA通过生物正交催化诱导的活性氧的产生促进了铁蛋白的降解和脂质过氧化，最终通过启动内源性Fenton反应引发具有正反馈的自增强脱铁症。

该项工作强调了天然酶依赖级联和生物正交催化反应的优越性，为基于酶的代谢协同治疗脱铁性贫血提供了一种范例。

附：英文原文

Title: Enzyme-Mediated Bioorthogonal Cascade Catalytic Reaction for Metabolism Intervention and Enhanced Ferroptosis on Neuroblastoma

Author: Qi Wang, Xiangze Li, Zhiyao Cao, Wei Feng, Yu Chen, Dapeng Jiang

Issue&Volume: March 12, 2024

Abstract: It remains a tremendous challenge to explore effective therapeutic modalities against neuroblastoma, a lethal cancer of the sympathetic nervous system with poor prognosis and disappointing treatment outcomes. Considering the limitations of conventional treatment modalities and the intrinsic vulnerability of neuroblastoma, we herein develop a pioneering sequential catalytic therapeutic system that utilizes lactate oxidase (LOx)/horseradish peroxidase (HRP)-loaded amorphous zinc metal–organic framework, named LOx/HRP-aZIF, in combination with a 3-indole-acetic acid (IAA) prodrug. On the basis of abnormal lactate accumulation that occurs in the tumor microenvironment, the cascade reaction of LOx and HRP consumes endogenous glutathione and a reduced form of nicotinamide adenine dinucleotide to achieve the first stage of killing cancer cells via antioxidative incapacitation and electron transport chain interference. Furthermore, the generation of reactive oxygen species induced by HRP and IAA through bioorthogonal catalysis promotes ferritin degradation and lipid peroxidation, ultimately provoking self-enhanced ferroptosis with positive feedback by initiating an endogenous Fenton reaction. This work highlights the superiority of the natural enzyme-dependent cascade and bioorthogonal catalytic reaction, offering a paradigm for synergistically enzyme-based metabolism-ferroptosis anticancer therapy.

DOI: 10.1021/jacs.3c13165

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.3c13165