Zhang Xiaonong, Zhang Yingqi, Lv Xueli, Zhang Peng, Xiao Chunsheng, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.
College of Chemistry, Jilin University, Changchun 130012, P. R. China.
ACS Nano. 2024 Dec 10;18(49):33531-33544. doi: 10.1021/acsnano.4c11275. Epub 2024 Nov 28.
Concurrent induction of ferroptosis and apoptosis by enzyme catalysis represents a promising modality for cancer therapy. Inspired by the structures of DNA and G-quadruplex/hemin DNAzyme, a DNA-free guanosine-based polymer nanoreactor (HPG@hemin-GOx) is prepared as a ferroptosis-apoptosis inducer by a one-step assembly of phenylboronic acid-modified hyaluronic acid (HA-PBA), guanosine (G), hemin, and glucose oxidase (GOx). HPG@hemin-GOx shows GOx, peroxidase (POD)-like, catalase (CAT)-like, and glutathione peroxidase (GPX)-like activities. The GOx activity of the nanoreactor can increase intracellular hydrogen peroxide (HO) levels by oxidizing glucose in the presence of oxygen. The POD-like activity of HPG@hemin-GOx can then induce the generation of hydroxyl radicals utilizing generated HO. Meanwhile, the production of oxygen by the CAT-like activity can facilitate the oxygen-consuming glucose oxidation process of GOx, thus promoting the generation of intracellular reactive oxygen species (ROS). Moreover, the GPX-like activity of HPG@hemin-GOx can deplete intracellular glutathione and thus downregulate GPX4 expression. Consequently, HPG@hemin-GOx induces apoptosis and ferroptosis by ROS-mediated damages of nuclear DNA and mitochondria, and GPX4 depletion-induced lipid peroxidation accumulation, resulting in a strong anticancer effect as demonstrated both in vitro and in vivo. This work provides a method for the construction of polymeric nanoreactors with multienzyme activities for ferroptosis-apoptosis synergistic anticancer therapy.
通过酶催化同时诱导铁死亡和凋亡是一种很有前景的癌症治疗方式。受DNA和G-四链体/血红素DNAzyme结构的启发，通过一步组装苯基硼酸修饰的透明质酸（HA-PBA）、鸟苷（G）、血红素和葡萄糖氧化酶（GOx），制备了一种无DNA的基于鸟苷的聚合物纳米反应器（HPG@hemin-GOx）作为铁死亡-凋亡诱导剂。HPG@hemin-GOx表现出GOx、过氧化物酶（POD）样、过氧化氢酶（CAT）样和谷胱甘肽过氧化物酶（GPX）样活性。纳米反应器的GOx活性可以在有氧条件下通过氧化葡萄糖来提高细胞内过氧化氢（HO）水平。然后，HPG@hemin-GOx的POD样活性可以利用生成的HO诱导羟基自由基的产生。同时，CAT样活性产生的氧气可以促进GOx的耗氧葡萄糖氧化过程，从而促进细胞内活性氧（ROS）的产生。此外，HPG@hemin-GOx的GPX样活性可以消耗细胞内谷胱甘肽，从而下调GPX4的表达。因此，HPG@hemin-GOx通过ROS介导的核DNA和线粒体损伤以及GPX4缺失诱导的脂质过氧化积累来诱导凋亡和铁死亡，在体外和体内均显示出强大的抗癌效果。这项工作为构建具有多酶活性的聚合物纳米反应器用于铁死亡-凋亡协同抗癌治疗提供了一种方法。
