Disulfiram-loaded metal organic framework for precision cancer treatment via ultrasensitive tumor microenvironment-responsive copper chelation and radical generation.
J Colloid Interface Sci
; 615: 517-526, 2022 Jun.
Article
em En
| MEDLINE
| ID: mdl-35152072
ABSTRACT
Off-target toxicity remains a major limitation of current cancer therapy, necessitating an alternative precision approach to treat cancers. Herein, a tumor microenvironment (TME)-triggered anticancer strategy was developed by constructing an anti-alcoholism drug disulfiram (DSF)-loaded, Cu-doped zeolite imidazolate frameworks-8 (DSF-Cu/ZIF-8) nanoparticle followed by PEGylation (PEG-DSF-Cu/ZIF-8) to realize in situ generation of cytotoxic compounds specifically in TME. The PEG-DSF-Cu/ZIF-8 demonstrated excellent hydrolytic stability in normal physiological conditions, guaranteeing the minimized off-target release of disulfiram and Cu ions. Under the TME condition, the PEG-DSF-Cu/ZIF-8 exhibited acidity-triggered biodegradation and the associated payload release, through which low-toxic compounds (disulfiram and Cu2+ ions) were converted to highly cytotoxic Cu-chelate product to kill cells specifically in TME. Tumor-sensitive anti-cancer performance was further enhanced by hydroxyl radical generation via TME-responsive Fenton-like reactions catalyzed by Cu+ presenting in the PEG-DSF-Cu/ZIF-8 structure and Cu+ produced during formation of the chelate product. Anti-cancer therapeutic evaluation was performed in 2D 4T1 tumor cell culture and 3D 4T1 tumor spheroids, and demonstrated highly TME-responsive, low-dose induced anti-cancer effect. This proof-of-concept work provides a nanoparticle-based drug repurposing strategy by developing a tumor-sensitive anti-cancer agent for low-toxic and efficacious cancer therapy.
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MEDLINE
Assunto principal:
Estruturas Metalorgânicas
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Neoplasias
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En
Ano de publicação:
2022
Tipo de documento:
Article