In Situ Ferroptosis with Global Dynamics Visualization for Glioblastoma Theranostics

Glioblastoma Multiforme (GBM) remains a lethal cancer due to its invasive nature and limited treatment options. We present 1-ethyl-2-((E)-2-((E)-3-(2-((E)-1-ethyl-3,3-dimethylindolin-2-ylidene)ethylidene)-2-(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenoxy)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-3H-indol-1-ium (CDI), a near-infrared (NIR) activatable theranostic probe that integrates tumor detection, in situ ferroptosis induction, and treatment monitoring. CDI selectively activates in the GBM tumor microenvironment (H2O2 >30 μM) via boronate ester cleavage, enabling precise cancer discrimination. Upon activation, CDI releases diacetic acid (MDA) that chelates endogenous Fe3+ in situ, driving localized Fenton reactions to induce ferroptosis without systemic iron supplementation. A concurrent ratiometric fluorescence shift (675 → 750 nm) provides potential real-time feedback on treatment efficacy. Transcriptomic analysis verified ferroptosis as the primary cell death mechanism, with significant dysregulation of iron/lipid metabolism pathways. In vitro and in vivo studies demonstrated blood–brain barrier (BBB) penetration, tumor-specific accumulation, inhibition of glioma cell migration/invasion, and extended survival in GBM models with no major adverse effects. CDI establishes a transformative “see–treat–confirm” paradigm for GBM surgery.多形性胶质母细胞瘤（Glioblastoma Multiforme, GBM）因其侵袭性特性与有限的治疗选择，仍是一种致死性癌症。本研究报道了1-乙基-2-((E)-2-((E)-3-(2-((E)-1-乙基-3,3-二甲基吲哚啉-2-亚基)亚乙基)-2-(4-(6-甲基-4,8-二氧代-1,3,6,2-二氧杂硼杂环庚烷-2-基)苯氧基)环己-1-烯-1-基)乙烯基)-3,3-二甲基-3H-吲哚鎓（CDI）——一种可被近红外（near-infrared, NIR）激活的诊疗探针，其集成了肿瘤检测、原位铁死亡（ferroptosis）诱导与治疗监测三大功能。CDI可在GBM肿瘤微环境（过氧化氢浓度>30 μM）中通过硼酸酯裂解实现选择性激活，从而实现精准的癌症鉴别。激活后，CDI可释放二乙酸（MDA），后者可原位螯合内源性Fe³+，驱动局部芬顿反应以诱导铁死亡，无需全身性铁补充。同时伴随的比率荧光位移（675 nm → 750 nm）可提供潜在的治疗效果实时反馈。转录组学分析证实铁死亡为主要的细胞死亡机制，且铁/脂代谢通路存在显著失调。体外与体内实验均证实，该探针可穿透血脑屏障（blood–brain barrier, BBB）、特异性富集于肿瘤组织，抑制胶质瘤细胞的迁移与侵袭，并可延长GBM模型小鼠的生存期，且未观察到明显不良反应。CDI为GBM手术建立了一种革命性的“显像-治疗-验证”范式。