In Situ Ferroptosis with Global Dynamics Visualization for Glioblastoma Theranostics PMID: 41267343

ADC Targets in Oncology

2026-04-10

In Situ Ferroptosis with Global Dynamics Visualization for Glioblastoma Theranostics

J Med Chem. 2025 Dec 11;68(23):25307-25323. doi: 10.1021/acs.jmedchem.5c02290.

Rajneesh Mungur ¹ , Ping Han ² , Jun Gu ¹ , Kaixin Zhang ³ , Xueyun Zhang ⁴ ⁵ ⁶ , Mahanand Chatoo ⁷ , Yuxia Liu ⁸ , Rui Shi ¹ , Haifeng He ¹ , Yindan Lin ⁴ ⁵ , Min Yan ¹ , Feng Xiao ¹ , Zebin Fang ¹ , Yuxiang Weng ¹ , Kaiyuan Huang ¹ , Ping Lan ¹ , Jiesheng Zheng ¹ , Ying Tong ¹ , Linchun Jin ¹ , Ben Wang ⁴ ⁹ ¹⁰ ¹¹ ¹² ¹³ , Guang Chen ⁸ , Renya Zhan ¹

Affiliations

1. Department of Neurosurgery, The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou 310003, China.
2. College of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.
3. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
4. Cancer Institute (key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
5. Department of Biochemistry, Zhejiang University School of Medicine, Hangzhou 310058, China.
6. School of Medicine, Taizhou University, Taizhou, Zhejiang 318000 China.
7. School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China.
8. College of Chemistry and Chemical Engineering, Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi'an 710021, China.
9. Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China.
10. Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310027, China.
11. Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, Hangzhou 310029, China.
12. Cancer Center, Zhejiang University, Hangzhou 310029, China.
13. State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China.

Abstract

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.