一种新型的四面体框架核酸衍生的化学动力学治疗剂，用于有效胶质母细胞瘤治疗
A novel tetrahedral framework nucleic acid-derived chemodynamic therapy agent for effective glioblastoma treatment
影响因子:5.60000
分区:生物学1区 Top / 细胞生物学1区
发表日期:2025 Jan
作者:
Xiaodie Li, Lei Li, Xin Fu, Shiqian Huang, Yuhao Wang, Yuepeng Yang, Shuqin Zhou, Zhaowei Zou, Qing Peng, Chao Zhang
摘要
化学动力疗法（CDT）由于其微创性质，减少对健康组织的损害以及潜在的减轻副作用而引起了对多种恶性肿瘤的治疗，引起了极大的关注。然而，它在胶质母细胞瘤（GBM）中的应用受到CDT剂横穿血脑屏障（BBB）的能力降低，肿瘤靶向效率不足以及肿瘤微环境（TME）内H2O2的限制。为了应对这些挑战，我们设计了一种基于四面体框架核酸（TFNA）的新型CDT剂（Fe@TFNAS-ANG-3AT）。 Fe@TFNAS-ANG-3AT是通过将铁离子（Fe3+）固定在双附件修饰的TFNA上来构建的。具体而言，一个附属物是AngiOpep-2（ANG，A渗透肽），促进Fe@TFNAS-ANG-3AT穿透BBB渗透，并选择性靶向肿瘤细胞。同时，第二个附属物为3-氨基-1,2,4-三唑（3AT，H2O2酶抑制剂），增加了有效CDT治疗所需的H2O2水平。肿瘤细胞内在化后，Fe@tfnas-ang-3AT中的Fe3+被TME中的过表达的谷胱甘肽（GSH）降低至Fe2+，从而催化了细胞毒性羟基自由基（以·OH）的产生，并通过肿瘤镇定的氧化应激水平引起肿瘤细胞死亡。预计FE@TFNAS-ANG-3AT将有望成为GBM的变革性治疗策略。
Abstract
Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood-brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H2O2 within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs-ANG-3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs-ANG-3AT was constructed by anchoring iron ions (Fe3+) onto the dual appendages-modified tFNAs. Specifically, one appendage, Angiopep-2 (ANG, a penetrating peptide), facilitates Fe@tFNAs-ANG-3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3-Amino-1,2,4-triazole (3AT, a H2O2 enzyme inhibitor), augments the H2O2 levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe3+ in Fe@tFNAs-ANG-3AT is reduced to Fe2+ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (·OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs-ANG-3AT holds promise as a transformative treatment strategy for GBM.