Fu Ji-Jun, Liu Cheng-Cheng, Feng Gui-Ning, Li Song-Pei, Yu Yuan-Yuan, Du Ling-Ran, Zhang Jian-Ye, Zhang Yu, Lei Xue-Ping, Dai Xiaoyan, Yu Xi-Yong
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou Medical University, Guangzhou 511436, China.
Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510630, PR China.
Biomater Adv. 2023 Apr;147:213323. doi: 10.1016/j.bioadv.2023.213323. Epub 2023 Feb 2.
The cancer chemodynamic therapy based on the Fenton reaction has been attracting more and more attention. However, the performance of the Fenton reaction is restricted by the unsuitable physiological pH value and inadequate HO content in the tumor microenvironment (TME). In this study, we proposed a novel method of inducing lipid peroxide (LPO) of the cancer cell membrane, whose performance is not limited by the pH value and HO in the TME. The activatable LPO-inducing liposomes were constructed by encapsulating Fe-containing compound ferric ammonium citrate (FC) in the unsaturated soybean phospholipids (SPC). It was found that the FC could be reduced by the overexpressed glutathione (GSH) in the TME and produce iron redox couple. The Fe/Fe mediated the peroxidation of the unsaturated SPC and induced the LPO in the cancer cells. Finally, LPO accumulation led to cancer cell death and tumor growth inhibition. Furthermore, the activatable liposomes did not damage healthy tissues because of the low GSH content in normal tissues and the GSH-triggered activation of the nanocarrier. Together, our findings revealed that FC-SPC-lipo displayed excellent anti-tumor performance and its therapeutic effects are less influenced by the TME, compared with the traditional ferroptosis.
基于芬顿反应的癌症化学动力疗法越来越受到关注。然而，芬顿反应的性能受到肿瘤微环境（TME）中不合适的生理pH值和不足的羟基自由基（·OH）含量的限制。在本研究中，我们提出了一种诱导癌细胞膜脂质过氧化物（LPO）的新方法，其性能不受TME中pH值和·OH的限制。通过将含铁化合物柠檬酸铁铵（FC）包裹在不饱和大豆磷脂（SPC）中构建可激活的LPO诱导脂质体。研究发现，FC可被TME中过表达的谷胱甘肽（GSH）还原并产生铁氧化还原对。Fe²⁺/Fe³⁺介导不饱和SPC的过氧化反应并诱导癌细胞中的LPO。最后，LPO积累导致癌细胞死亡和肿瘤生长抑制。此外，由于正常组织中GSH含量低以及纳米载体的GSH触发激活，可激活脂质体不会损害健康组织。总之，我们的研究结果表明，与传统铁死亡相比，FC-SPC-lipo表现出优异的抗肿瘤性能，其治疗效果受TME的影响较小。
