Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China; The Second Clinical Medical School, Lanzhou University, Lanzhou, China.
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
Colloids Surf B Biointerfaces. 2024 Dec;244:114162. doi: 10.1016/j.colsurfb.2024.114162. Epub 2024 Aug 13.
Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.
癌症对人类健康和生命构成重大威胁。化疗、免疫疗法和化学动力学疗法（CDT）是治疗癌症的有效方法。然而，肿瘤细胞中通过谷氨酰胺进行的代谢重编程限制了它们的治疗效果。在此，我们提出了一种有效的组装策略，用于合成一种新型的基于金属-多酚的多功能纳米药物（Fe-DBEF），该纳米药物包含 Pluronic F127 稳定的铁离子交联表没食子儿茶素没食子酸酯（EGCG）纳米颗粒，负载有谷氨酰胺合成酶 1（GLS1）抑制剂双-2-（5-苯乙酰氨基-1,3,4-噻二唑-2-基）乙基二硫化物（BPTES）和化疗药物多柔比星（DOX）。我们的研究表明，通过体外细胞实验、人类类器官实验和 KPC 动物实验，Fe-DBEF 纳米药物在胰腺癌中表现出高效的抗增殖特性。值得注意的是，Fe-DBEF 纳米药物可以减少肿瘤细胞中谷胱甘肽（GSH）的产生，从而降低其对 ROS 治疗的抵抗力。此外，过量的 ROS 产生也会加重 DOX 引起的 DNA 损伤，协同增强化疗敏感性并促进细胞凋亡，从而有效治疗胰腺癌。总的来说，我们的研究结果表明，通过使用基于金属-多酚的多功能纳米药物抑制谷氨酰胺代谢来提高化疗/CDT 的敏感性，为治疗胰腺癌提供了一种有前途的多种治疗手段的联合方案。
