Blood-brain barrier-penetrative fluorescent anticancer agents triggering paraptosis and ferroptosis for glioblastoma therapy

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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 cytoplasmic vacuolation, accompanied by reactive oxygen species generation and intracellular Ca2+ overload, thereby disrupting metabolisms and inducing non-apoptotic 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 post-intravenous 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.

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