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-((<i>E</i>)-2-((<i>E</i>)-3-(2-((<i>E</i>)-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-3<i>H</i>-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 (H<sub>2</sub>O<sub>2</sub> >30 μM) via boronate ester cleavage, enabling precise cancer discrimination. Upon activation, CDI releases diacetic acid (MDA) that chelates endogenous Fe<sup>3+</sup> 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. <i>In vitro</i> and <i>in vivo</i> 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.
Authors
- Yuxiang Weng (ORCID: https://orcid.org/0009-0002-1589-0280)
- Min Yan (ORCID: https://orcid.org/0000-0002-1355-1261)
- Xueyun Zhang (ORCID: https://orcid.org/0000-0002-7849-8609)
- Ping Lan (ORCID: https://orcid.org/0000-0002-8901-8498)
- Rajneesh Mungur
- Zebin Fang
- Ying Tong (ORCID: https://orcid.org/0000-0003-2356-8398)
- Mahanand Chatoo
- Rui Shi (ORCID: https://orcid.org/0000-0002-5927-7763)
- Renya Zhan (ORCID: https://orcid.org/0000-0002-0619-6257)
- Yindan Lin
- Haifeng He (ORCID: https://orcid.org/0000-0001-8669-9948)
- Ping Penny Han (ORCID: https://orcid.org/0000-0001-6025-1651)
- Jun Gu (ORCID: https://orcid.org/0000-0002-8225-9651)
- Yuxia Liu (ORCID: https://orcid.org/0000-0003-1139-8563)
- Kaiyuan Huang (ORCID: https://orcid.org/0000-0002-4301-7676)
- Guang Chen (ORCID: https://orcid.org/0000-0002-0454-1686)
- Ben Wang (ORCID: https://orcid.org/0000-0002-4134-1835)
- Kaixin Zhang (ORCID: https://orcid.org/0000-0002-9786-546X)
- Jie-Sheng Zheng (ORCID: https://orcid.org/0000-0002-9027-4018)
- Feng Xiao (ORCID: https://orcid.org/0000-0003-2770-7578)
- Linchun Jin (ORCID: https://orcid.org/0000-0002-9867-2037)
Institutions
- Allen Institute for Brain Science (US)
- Qufu Normal University (CN)
- Shaanxi Coal Chemical Industry Technology Research Institute (CN)
- First Affiliated Hospital of Chinese PLA General Hospital (CN)
- Ministry of Education (ET)
- Hangzhou Cancer Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Indiana University School of Medicine
- Shaanxi University of Science and Technology (CN)
- Zhejiang University (CN)
- Taizhou University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-21
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02290
- Citations
- 1
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 1.52