Glioblastoma (GBM) with TP53 mutations is a typical subtype of intracranial tumors that rapidly recurs. Herein, we demonstrated that PD0166285 (PD), a dual-targeted inhibitor of WEE1 and PKMYT1, specifically activated DNA damage of TP53-mutant GBM cells for inducing a robust apoptotic effect. Suiting the remedy to the case, the injectable double-network hydrogels (DNHs) encapsulating PD were constructed on the basis of acid-sensitive Fe³⁺/tannic acid (TA) metal-phenolic networks (MPNs). Particularly, the incorporation of MPNs not only endowed PD-loaded hydrogels (PDNHs) with on-demand drug delivery but also controllably generated reactive oxygen species (ROS). Furthermore, ROS could amplify DNA damage stress, which demonstrated the potential of PDNHs as an activatable initiator to in situ trigger high-level DNA damage of TP53-mutant GBM cells. Thus, PDNHs remarkably restricted the postsurgical relapse of orthotopic GBM carrying TP53 mutations and improved the survival time of mice. This study presents a valuable strategy for suiting the remedy to postsurgical TP53-mutant GBM.

中文翻译：

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对症下药：用于 TP53 突变胶质母细胞瘤术后治疗的可激活 DNA 损伤引发剂

TP53突变的胶质母细胞瘤（GBM）是一种典型的快速复发的颅内肿瘤亚型。在此，我们证明 PD0166285 (PD) 是一种 WEE1 和 PKMYT1 的双靶点抑制剂，可特异性激活 TP53 突变 GBM 细胞的 DNA 损伤，从而诱导强大的细胞凋亡效应。针对这种情况，在酸敏感的Fe ³⁺ /单宁酸（TA）金属酚网络（MPNs）的基础上构建了封装PD的可注射双网络水凝胶（DNHs） 。特别是，MPN的掺入不仅赋予PD负载水凝胶（PDNH）按需给药的能力，而且还可以可控地产生活性氧（ROS）。此外，ROS 可以放大 DNA 损伤应激，这证明了 PDNH 作为可激活引发剂原位触发TP53 突变 GBM 细胞高水平 DNA 损伤的潜力。因此，PDNHs显着限制了携带TP53突变的原位GBM的术后复发，并提高了小鼠的生存时间。这项研究为治疗术后 TP53 突变 GBM 提供了一个有价值的策略。