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In Situ Ferroptosis with Global Dynamics Visualization for Glioblastoma Theranostics.
Rajneesh Mungur1, Ping Han2, Jun Gu1
1Department of Neurosurgery, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310003, China.
Journal of Medicinal Chemistry
|November 21, 2025
Summary
A novel theranostic probe, CDI, enables precise glioblastoma detection and treatment by activating in the tumor microenvironment to induce ferroptosis and monitor efficacy via fluorescence. This approach offers a new paradigm for GBM surgery.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Glioblastoma Multiforme (GBM) is a highly lethal brain cancer with limited therapeutic strategies.
- Current treatments face challenges due to GBM's invasive nature and the difficulty of precise tumor detection.
- There is a critical need for advanced theranostic tools for effective GBM management.
Purpose of the Study:
- To develop and evaluate a novel near-infrared (NIR) activatable theranostic probe (CDI) for glioblastoma.
- To integrate tumor detection, in situ ferroptosis induction, and treatment monitoring capabilities within a single agent.
- To establish a "see-treat-confirm" paradigm for GBM surgery.
Main Methods:
- Synthesis and characterization of the CDI theranostic probe.
- Evaluation of CDI's selective activation in the GBM tumor microenvironment (H2O2 >30 μM) via boronate ester cleavage.
- Assessment of CDI-induced ferroptosis through in situ Fe3+ chelation and Fenton reactions, confirmed by transcriptomic analysis.
- Monitoring treatment efficacy via ratiometric fluorescence shift (675 → 750 nm).
- In vitro and in vivo studies including blood-brain barrier penetration, tumor accumulation, and survival analysis in GBM models.
Main Results:
- CDI selectively activates in the GBM tumor microenvironment, enabling precise cancer discrimination.
- Activated CDI releases diacetic acid (MDA) to chelate Fe3+, inducing localized ferroptosis via Fenton reactions.
- Transcriptomic analysis confirmed ferroptosis as the primary cell death mechanism, impacting iron and lipid metabolism.
- CDI demonstrated blood-brain barrier penetration, tumor-specific accumulation, and inhibition of glioma cell migration/invasion.
- In vivo studies showed extended survival in GBM models with no significant adverse effects.
Conclusions:
- CDI is an effective theranostic probe for glioblastoma, integrating detection, treatment, and monitoring.
- The probe induces ferroptosis specifically within the tumor microenvironment, offering a targeted therapeutic approach.
- CDI facilitates a "see-treat-confirm" strategy, potentially revolutionizing GBM surgical management and improving patient outcomes.
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