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Blood-Brain Barrier-Penetrative Fluorescent Anticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma
Jiefei Wang1, Mingyue Cao2, Lulu Han1
1Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, P. R. China.
Abstract:
Currently used drugs for glioblastoma (GBM) treatments are ineffective, primarily due to the significant challenges posed by strong drug resistance, poor blood-brain barrier (BBB) permeability, and the lack of tumor specificity. Here, we report two cationic fluorescent anticancer agents (TriPEX-ClO4 and TriPEX-PF6) capable of BBB penetration for efficient GBM therapy via paraptosis and ferroptosis induction. These aggregation-induced emission (AIE)-active agents specifically target mitochondria, effectively triggering ATF4/JNK/Alix-regulated paraptosis and GPX4-mediated ferroptosis. Specifically, they rapidly induce substantial mitochondria-derived vacuolation, accompanied by reactive oxygen species generation, decreased mitochondrial membrane potential, and intracellular Ca2+ overload, thereby disrupting metabolisms and inducing nonapoptotic cell death. In vivo imaging revealed that TriPEX-ClO4 and TriPEX-PF6 successfully traversed the BBB to target orthotopic glioma and initiated effective synergistic therapy postintravenous injection. Our AIE drugs emerged as the pioneering paraptosis inducers against drug-resistant GBM, significantly extending survival up to 40 days compared to Temozolomide (20 days) in drug-resistant GBM-bearing mice. These compelling results open up new venues for the development of fluorescent anticancer drugs and innovative treatments for brain diseases.
Insights
New fluorescent drugs effectively treat glioblastoma by inducing paraptosis and ferroptosis, overcoming drug resistance and blood-brain barrier challenges for improved survival in mice.
Area of Science:
- Oncology
- Nanotechnology
- Biomedical Engineering
Background:
- Current glioblastoma (GBM) treatments face limitations due to drug resistance, poor blood-brain barrier (BBB) penetration, and lack of tumor specificity.
- Novel therapeutic strategies are urgently needed to overcome these challenges and improve patient outcomes.
Purpose of the Study:
- To develop novel cationic fluorescent anticancer agents with BBB penetration capabilities for glioblastoma therapy.
- To investigate the efficacy of these agents in inducing paraptosis and ferroptosis, two distinct forms of non-apoptotic cell death.
Main Methods:
- Synthesis and characterization of two aggregation-induced emission (AIE)-active cationic fluorescent agents, TriPEX-ClO4 and TriPEX-PF6.
- Evaluation of BBB penetration and tumor targeting in vivo using imaging techniques.
- Assessment of cell death mechanisms, including paraptosis and ferroptosis induction, through molecular and cellular assays.
- In vivo efficacy studies in drug-resistant GBM mouse models.
Main Results:
- TriPEX-ClO4 and TriPEX-PF6 demonstrated efficient BBB penetration and targeted orthotopic glioma.
- These agents successfully induced paraptosis via ATF4/JNK/Alix pathway and ferroptosis via GPX4 inhibition.
- Induction of paraptosis and ferroptosis led to mitochondria-derived vacuolation, ROS generation, and metabolic disruption.
- In vivo studies showed significant survival extension (up to 40 days) in drug-resistant GBM mice compared to Temozolomide (20 days).
Conclusions:
- The developed AIE-active cationic agents represent a pioneering approach for inducing paraptosis and ferroptosis in drug-resistant glioblastoma.
- These agents show potential for effective synergistic therapy against GBM by overcoming BBB limitations and drug resistance.
- This study opens new avenues for developing fluorescent anticancer drugs for brain diseases.
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