2. Academic Validation
  3. Blood-Brain Barrier-Penetrative Fluorescent Anticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma Therapy

Blood-Brain Barrier-Penetrative Fluorescent Anticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma Therapy

  • J Am Chem Soc. 2024 Oct 23;146(42):28783-28794. doi: 10.1021/jacs.4c07785.
Jiefei Wang 1,  Mingyue Cao 2,  Lulu Han 1,  Ping Shangguan 1,  Yisheng Liu 1,  Yong Zhong 3,  Chaoyue Chen 4,  Gaoyang Wang 3,  Xiaoyu Chen 1,  Ming Lin 1,  Mengya Lu 1,  Zhengqun Luo 1,  Mu He 1,  Herman H Y Sung 4,  Guangle Niu 5,  Jacky W Y Lam 4,  Bingyang Shi 1,  Ben Zhong Tang 6 4
Affiliations

Affiliations

  • 1 Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan 475004, P. R. China.
  • 2 State Key Laboratory of Crystal Materials, Shandong University, Jinan 250100, P. R. China.
  • 3 Key Laboratory for Special Functional Materials of Ministry of Education, Henan University, Kaifeng 475004, P. R. China.
  • 4 Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, State Key Laboratory of Molecular Neuroscience, Division of Life Science, Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon 999077, Hong Kong, P. R. China.
  • 5 School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China.
  • 6 School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Shenzhen 518172, P. R. China.
PMID: 39394087 DOI: 10.1021/jacs.4c07785
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.

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