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.