Diselenide-Containing Polymer Based on New Antitumor Mechanism as Efficient GSH Depletion Agent for Ferroptosis Therapy.
Adv Healthc Mater
; 13(17): e2303896, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38551494
ABSTRACT
Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 µg mL-1, CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ferroptose
/
Glutationa
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Adv Healthc Mater
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China