Carrier-Free Self-Assembly Nano-Sonosensitizers for Sonodynamic-Amplified Cuproptosis-Ferroptosis in Glioblastoma Therapy.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Ferroptosis*/drug effects ; Glioblastoma*/metabolism ; Glioblastoma*/therapy ; Copper*/chemistry ; Chlorophyllides* ; Porphyrins*/chemistry ; Porphyrins*/pharmacology; Animals ; Mice ; Humans ; Cell Line, Tumor ; Nanoparticles/chemistry ; Disease Models, Animal ; Brain Neoplasms/therapy ; Brain Neoplasms/metabolism

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half-life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier-free nanoparticles (Ce6@Cu NPs), which self-assembled by the coordination of Cu ²⁺ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic-triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu ⁺ concentration in tumor cells significantly increases as Cu ²⁺ reacts with reductive GSH, resulting in the downregulation of ferredoxin-1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood-brain barrier, resulting in significant accumulation in orthotopic U87MG-Luc glioblastoma. The sonodynamic-triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

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YJRC4112 Fujian Medical University; 2023Y9090 Joint Funds for the innovation of science and Technology; 2021Y2001 Technology Platform Construction Project of Fujian Province; NUHSRO/2020/133/Startup/08 National University of Singapore; NUHSRO/2023/008/NUSMed/TCE/LOA National University of Singapore; NUHSRO/2021/034/TRP/09/Nanomedicine National University of Singapore; NUHSRO/2021/044/Kickstart/09/LOA National University of Singapore; MOH-001388-00 National Medical Research Council; CG21APR1005 National Medical Research Council; MOE-000387-00 Singapore Ministry of Education; NRF-000352-00 National Research Foundation; IACUC FJMU2022-0608 Ethical Committee of Fujian Medical University

Keywords: carrier‐free nanoparticles; cuproptosis; ferroptosis; lipid peroxidation; sonodynamic therapy

789U1901C5 (Copper)
0 (Chlorophyllides)
5S2CCF3T1Z (phytochlorin)
0 (Porphyrins)

Date Created: 20240406 Date Completed: 20240619 Latest Revision: 20240622

20240622

PMC11187904

10.1002/advs.202402516

38582500