College of Biotechnology, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science & Technology, No. 29 of 13th Street, TEDA, Tianjin 300457, China.
College of Biotechnology, Tianjin Key Laboratory of Industrial Microbiology, Tianjin University of Science & Technology, No. 29 of 13th Street, TEDA, Tianjin 300457, China.
Acta Biomater. 2023 Sep 1;167:374-386. doi: 10.1016/j.actbio.2023.06.016. Epub 2023 Jun 19.
The solid tumors are characterized with oxidative stress and metabolic reprogramming, which has been independently used for targeted tumor monotherapy. However, the potential of targeting metabolism-redox circuit in tumor therapy has long been neglected. Herein, we report a hybrid nanocarrier for concurrent targeting of glycolysis and redox balance in the current work. The nanocarriers are made of pH- and ATP-responsive zeolitic imidazolate framework (ZIF-8) as the porous core that was further coated with poloxamer 407 as the steric stabilizer. Two active cargos, glucose oxidase (GOx) and 3-bromopyruvate (3-BrPA) were co-loaded in the core of nanocarrier. GOx is well-known for its ability of producing hydrogen peroxide at the expense of glucose and oxygen. 3-BrPA can reduce oxygen and glucose consumption through glycolysis, which sensitized cancer cells to GOx-induced apoptosis. At the cellular level, the hybrid nanocarrier significantly impaired the redox balance in the liver hepatocellular carcinoma cell line (HepG2), as evidenced by the depletion of glutathione and boost of reactive oxygen species. The potency of hybrid nanocarrier in terms of suppressing HepG2 cell energy metabolism was proven by the exhaustion of ATP. As a consequence, cell viability was greatly reduced. The in vivo efficacy of hybrid nanocarriers was demonstrated in HepG2 tumor-bearing mice. The current work presents an approach of targeting metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies. STATEMENT OF SIGNIFICANCE: Metabolic alterations and elevated reactive oxygen species (ROS) are two characteristics of cancer. The metabolic patterns of cancer cells are elaborately reprogrammed to enable the rapid propagation of cancer cells. However, the potential of targeting the metabolism-redox circuit in anti-tumor therapy has long been neglected. As a proof-of-concept, we report an engineered stimuli-responsive nanomedicine that can eradicate cancer cells via cooperative glycolysis inhibition and redox impairment. The current work presents an approach of targeting the metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies.
实体瘤的特点是氧化应激和代谢重编程，这已被独立用于靶向肿瘤单药治疗。然而，靶向肿瘤治疗中代谢-氧化还原电路的潜力长期以来一直被忽视。在此，我们报告了一种用于协同靶向当前工作中糖酵解和氧化还原平衡的杂化纳米载体。纳米载体由 pH 和 ATP 响应的沸石咪唑酯骨架 (ZIF-8) 制成，作为多孔核，进一步用泊洛沙姆 407 作为空间稳定剂进行包覆。两种活性载药，葡萄糖氧化酶 (GOx) 和 3-溴丙酮酸 (3-BrPA) 被共负载在纳米载体的核内。GOx 以其消耗葡萄糖和氧气产生过氧化氢的能力而闻名。3-BrPA 通过糖酵解减少氧气和葡萄糖消耗，使癌细胞对 GOx 诱导的细胞凋亡敏感。在细胞水平上，杂化纳米载体显著破坏了肝癌细胞系 (HepG2) 的氧化还原平衡，表现为谷胱甘肽耗竭和活性氧增加。杂化纳米载体在抑制 HepG2 细胞能量代谢方面的功效通过耗尽 ATP 得到证明。结果，细胞活力大大降低。杂化纳米载体在 HepG2 荷瘤小鼠中的体内疗效得到了证明。本研究提出了一种靶向肿瘤治疗中代谢-氧化还原电路的方法，可能丰富现有的抗肿瘤策略。
代谢改变和活性氧 (ROS) 升高是癌症的两个特征。癌细胞的代谢模式被精心重编程，以促进癌细胞的快速增殖。然而，靶向抗肿瘤治疗中代谢-氧化还原电路的潜力长期以来一直被忽视。作为概念验证，我们报告了一种工程化的刺激响应纳米医学，可通过协同抑制糖酵解和氧化还原损伤来消灭癌细胞。本研究提出了一种靶向肿瘤治疗中代谢-氧化还原电路的方法，可能丰富现有的抗肿瘤策略。
