Blood–Brain Barrier-Penetrative Fluorescent Anticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma Therapy
Jiefei Wang, Mingyue Cao, Lulu Han, Ping Shangguan, Yi‐Sheng Liu, Yong Zhong, Chaoyue Chen, Gaoyang Wang, Xiaoyu Chen, Ming‐Wei Lin, Mengya Lu, Zhengqun Luo, Mu He, Herman H. Y. Sung, Guangle Niu, Jacky W. Y. Lam, Bingyang Shi, Ben Zhong Tang
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-ClO 4 and TriPEX-PF 6 ) 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 Ca 2+ overload, thereby disrupting metabolisms and inducing nonapoptotic cell death. In vivo imaging revealed that TriPEX-ClO 4 and TriPEX-PF 6 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.