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

Wang, J; Cao, M; Han, L; Shangguan, P; Liu, Y; Zhong, Y; Chen, C; Wang, G; Chen, X; Lin, M; Lu, M; Luo, Z; He, M; Sung, HHY; Niu, G; Lam, JWY; Shi, B; Tang, BZ

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

Wang, J Cao, M Han, L Shangguan, P Liu, Y Zhong, Y Chen, C Wang, G Chen, X Lin, M Lu, M Luo, Z He, M Sung, HHY Niu, G Lam, JWY Shi, B

Tang, BZ

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Publisher:: American Chemical Society (ACS)
Publication Type:: Journal Article
Citation:: J Am Chem Soc, 2024, 146, (42), pp. 28783-28794
Issue Date:: 2024-10-23

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Field	Value	Language
dc.contributor.author	Wang, J
dc.contributor.author	Cao, M
dc.contributor.author	Han, L
dc.contributor.author	Shangguan, P
dc.contributor.author	Liu, Y
dc.contributor.author	Zhong, Y
dc.contributor.author	Chen, C
dc.contributor.author	Wang, G
dc.contributor.author	Chen, X
dc.contributor.author	Lin, M
dc.contributor.author	Lu, M
dc.contributor.author	Luo, Z
dc.contributor.author	He, M
dc.contributor.author	Sung, HHY
dc.contributor.author	Niu, G
dc.contributor.author	Lam, JWY
dc.contributor.author	Shi, B https://orcid.org/0000-0002-1043-3163
dc.contributor.author	Tang, BZ
dc.date.accessioned	2025-03-13T04:05:31Z
dc.date.available	2025-03-13T04:05:31Z
dc.date.issued	2024-10-23
dc.identifier.citation	J Am Chem Soc, 2024, 146, (42), pp. 28783-28794
dc.identifier.issn	0002-7863
dc.identifier.issn	1520-5126
dc.identifier.uri	http://hdl.handle.net/10453/185773
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Chemical Society (ACS)
dc.relation.ispartof	J Am Chem Soc
dc.relation.isbasedon	10.1021/jacs.4c07785
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	03 Chemical Sciences
dc.subject.classification	General Chemistry
dc.subject.classification	34 Chemical sciences
dc.subject.classification	40 Engineering
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Ferroptosis
dc.subject.mesh	Humans
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Animals
dc.subject.mesh	Fluorescent Dyes
dc.subject.mesh	Mice
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Paraptosis
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Fluorescent Dyes
dc.subject.mesh	Ferroptosis
dc.subject.mesh	Paraptosis
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Glioblastoma
dc.subject.mesh	Ferroptosis
dc.subject.mesh	Humans
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Animals
dc.subject.mesh	Fluorescent Dyes
dc.subject.mesh	Mice
dc.subject.mesh	Brain Neoplasms
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Paraptosis
dc.title	Blood-Brain Barrier-Penetrative Fluorescent Anticancer Agents Triggering Paraptosis and Ferroptosis for Glioblastoma Therapy.
dc.type	Journal Article
utslib.citation.volume	146
utslib.location.activity	United States
utslib.for	03 Chemical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	closed_access	*
dc.date.updated	2025-03-13T04:05:29Z
pubs.issue	42
pubs.publication-status	Published
pubs.volume	146
utslib.citation.issue	42

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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http://hdl.handle.net/10453/185773