上海交通大学谭蔚泓团队报道了多价适体纳米药物缀合物，通过铜超载和谷胱甘肽耗竭实现有效的肿瘤铜增生治疗。相关研究成果发表在2024年10月28日出版的《美国化学会杂志》。

铜增生是一种最近发现的铜依赖性细胞死亡形式，显示出有希望的肿瘤抑制作用，且耐药性很小。然而，其治疗效果因其对铜离子和肿瘤中富含谷胱甘肽（GSH）的微环境的依赖而受到阻碍。

该文中，研究人员开发了具有核小体样结构的多价适配体纳米药物偶联物（称为CuPEs@PApt)，通过利用线粒体铜超载和GSH耗竭来改善肿瘤铜中毒治疗。

多价适配体（PApt）包括用于肿瘤靶向的多价上皮细胞粘附分子适配体，和用于铜螯合的重复PolyT序列，有助于高效装载和靶向递送过氧化铜-埃氏藻纳米点（CuPE）。

在肿瘤细胞内化后，从CuPEs@PApt中释放的Elesclomon在线粒体中积累铜离子以启动铜沉积，而CuP纳米点的溶酶体降解产生外源性Cu²⁺和H₂O₂，引发Fenton样反应以消耗GSH，从而增强铜沉积。

体外和体内实验证实了该策略，在诱导肿瘤细胞铜沉积和免疫原性细胞死亡方面的有效性，后者有助于激活抗肿瘤免疫反应，以协同抑制肿瘤生长。

附：英文原文

Title: Polyvalent Aptamer Nanodrug Conjugates Enable Efficient Tumor Cuproptosis Therapy Through Copper Overload and Glutathione Depletion

Author: Shuang Wang, Xueliang Liu, Dali Wei, Huayuan Zhou, Jiawei Zhu, Qing Yu, Lei Luo, Xinfeng Dai, Yiting Jiang, Lu Yu, Yu Yang, Weihong Tan

Issue&Volume: October 28, 2024

Abstract: Cuproptosis, a recently identified form of copper-dependent cell death, shows promising tumor suppressive effects with minimal drug resistance. However, its therapeutic efficacy is hampered by its dependence on copper ions and the glutathione (GSH)-rich microenvironment in tumors. Here, we have developed polyvalent aptamer nanodrug conjugates (termed CuPEs@PApt) with a nucleosome-like structure to improve tumor cuproptosis therapy by exploiting mitochondrial copper overload and GSH depletion. Polyvalent aptamer (PApt), comprising polyvalent epithelial cell adhesion molecule aptamers for tumor targeting and repetitive PolyT sequences for copper chelation, facilitates efficient loading and targeted delivery of copper peroxide-Elesclomol nanodots (CuPEs). Upon internalization by tumor cells, Elesclomol released from CuPEs@PApt accumulates copper ions in mitochondria to initiate cuproptosis, while lysosomal degradation of CuP nanodots generates exogenous Cu2+ and H2O2, triggering a Fenton-like reaction for GSH depletion to enhance cuproptosis. In vitro and in vivo experiments confirm the efficacy of this strategy in inducing tumor cell cuproptosis and immunogenic cell death, the latter contributing to the activation of the antitumor immune response for synergistic tumor growth inhibition.

DOI: 10.1021/jacs.4c06338

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c06338