Chen Haoyu, Wang Minjuan, Yang Qiquan, Liu Jing, Liu Feng, Zhu Xiaohua, Huang Shu, Yin Peng, Wang Xingfeng, Li Haitao, Zhang Youyu, Liu Meiling, Wei Mingjie, Yao Shouzhuo, Liu Yang
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education, China), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, China; Department of Chemistry, Kay Lab of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, Beijing Key Laboratory for Analytical Methods and Instrumentation, Tsinghua University, 100084 Beijing, China.
School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, China.
J Colloid Interface Sci. 2025 Apr 15;684(Pt 1):423-438. doi: 10.1016/j.jcis.2025.01.041. Epub 2025 Jan 8.
The integration of reactive oxygen species (ROS) related photodynamic therapy (PDT) with the strategy of reshaping the tumor microenvironment (TME) has emerged as a potential approach for nanodiagnostic and therapeutic interventions. However, the therapeutic efficacy based on ROS treatments may be hindered by intracellular antioxidants such as glutathione (GSH) and tumor hypoxia. To address these challenges, a nanoplatform based on GSH-responsive multifunctional porphyrinic metal-organic framework (PCN-224@Au@MnO@HA, PAMH) was proposed. It was developed through a layer-by-layer in-situ growth method. This method avoids the need for high-temperature calcination and complex modification processes while improving the stability of PCN-224 in a phosphate-rich environment. GSH depletion leads to oxidation-reduction imbalance in TME. With the inactivation of GSH peroxidase 4 (GPX4), the content of hydrogen peroxide (HO) increases, ultimately triggering lipid peroxidation (LPO) and promoting ferroptosis. The catalase-like activity of Au nanozymes facilitates the generation of oxygen (O), thereby mitigating tumor hypoxia and downregulating hypoxia-inducing factors (HIF-1α). Due to the presence of porphyrin ligands in PCN-224, the generated O can be further converted to toxic singlet oxygen (O) under laser irradiation. Additionally, the platform allows near-infrared (NIR) fluorescence imaging, providing real-time information on intracellular GSH changes during PDT and ferroptosis. The PAMH nanoplatform has shown effective inhibition of tumor growth in subcutaneous models via both intravenous and intratumoral injection, indicating its potential in modulating reactive oxygen/sulfur species and reshaping TME, thereby facilitating imaging-guided cascaded nanocatalytic therapy.
将活性氧（ROS）相关的光动力疗法（PDT）与重塑肿瘤微环境（TME）的策略相结合，已成为一种用于纳米诊断和治疗干预的潜在方法。然而，基于ROS治疗的疗效可能会受到细胞内抗氧化剂如谷胱甘肽（GSH）和肿瘤缺氧的阻碍。为了解决这些挑战，提出了一种基于GSH响应的多功能卟啉金属有机框架（PCN-224@Au@MnO@HA，PAMH）的纳米平台。它是通过逐层原位生长方法开发的。该方法避免了高温煅烧和复杂的修饰过程，同时提高了PCN-224在富磷环境中的稳定性。GSH耗竭导致TME中的氧化还原失衡。随着谷胱甘肽过氧化物酶4（GPX4）的失活，过氧化氢（HO）的含量增加，最终引发脂质过氧化（LPO）并促进铁死亡。金纳米酶的过氧化氢酶样活性促进氧气（O）的产生，从而减轻肿瘤缺氧并下调缺氧诱导因子（HIF-1α）。由于PCN-224中存在卟啉配体，在激光照射下，产生的O可以进一步转化为有毒的单线态氧（O）。此外，该平台允许近红外（NIR）荧光成像，提供PDT和铁死亡过程中细胞内GSH变化的实时信息。PAMH纳米平台通过静脉内和瘤内注射在皮下模型中均显示出对肿瘤生长的有效抑制，表明其在调节活性氧/硫物种和重塑TME方面的潜力，从而促进成像引导的级联纳米催化治疗。
