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. 2024 Mar 24:26:101040.
doi: 10.1016/j.mtbio.2024.101040. eCollection 2024 Jun.

Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis

Min Wang  1 , Aoling Yu  1 , Wen Han  1 , Jingyi Chen  2 , Chunhua Lu  1 , Xiankun Tu  2
Affiliations

Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis

Min Wang et al. Mater Today Bio. .

Abstract

Ferroptosis, a newly discovered form of regulated cell death, has garnered significant attention in the field of tumor therapy. However, the presence of overexpressed glutathione (GSH) and insufficient levels of H2O2 in the tumor microenvironment (TME) hinders the occurrence of ferroptosis. In response to these challenges, here we have constructed the self-assembled nanocomplexes (FeE NPs) utilizing epigallocatechin-3-gallate (EGCG) from green tea polyphenols and metal ions (Fe3+) as components. After grafting PEG, the nanocomplexes (FeE@PEG NPs) exhibit good biocompatibility and synergistically enhanced tumor-inhibitory properties. FeE@PEG NPs can be disassembled by H2O2 in the TME, leading to the rapid release of Fe3+ and EGCG. The released Fe3+ produces large amounts of toxic •OH by the Fenton reactions while having minimal impact on normal cells. The generated •OH effectively induces lipid peroxidation, which leads to ferroptosis in tumor cells. Meanwhile, the released EGCG can autoxidize to produce H2O2, which further promotes the production of •OH radicals and increases lipid peroxide levels. Moreover, EGCG also depletes the high levels of intracellular GSH, leading to an intracellular redox imbalance and triggering ferroptosis. This study provides new insights into advancing anticancer ferroptosis through rational material design, offering promising avenues for future research.

Keywords: Epigallocatechin-3-gallate; Ferroptosis; GSH depletion; H2O2 self-supplementation; Self-assembly.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
Preparation of FeE@PEG NPs and schematic illustration of FeE@PEG NPs induced ferroptosis therapy.
Fig. 1
Fig. 1
(a) TEM image of FeE NPs. (b) SEM image of FeE NPs; (c) TEM image of FeE@PEG NPs. (d) High-angle annular dark-field-scanning TEM (HAADF-STEM) EDS elemental mapping images (for C, O and Fe) of FeE@PEG NPs. (e) XPS spectrum of FeE@PEG NPs. (f) FTIR spectra of EGCG, DSPE-PEG, FeN NPs and FeE@PEG NPs. (g) Hydrodynamic diameters of FeE@PEG NPs incubated with PBS or 10% FBS for different times.
Fig. 2
Fig. 2
(a) TEM image of FeE@PEG NPs after incubation with H2O2 for 1 h. (b) Hydrodynamic diameters of FeE@PEG NPs before and after incubation with H2O2 for 1 h. (c) The UV–vis absorption spectra of TMB aqueous solution with different treatments. (d) ESR spectroscopy of different reaction systems. (e) The ability to product H2O2 of FeE@PEG NPs and EGCG at different concentrations (f) Decrease of UV–Vis absorption at 410 nm showing the GSH depletion with different treatments.
Fig. 3
Fig. 3
(a) Intracellular internalization of FeE@PEG NPs after incubating with SKOV3 cells for 0, 3, 6, 12 and 24 h, respectively. (b) Intracellular GSH depletion of SKOV3 cells after incubation with EGCG and FeE@PEG NPs for 12 h. (c) Western blot image of the expression of GPX4 with different treatments. (d) CLSM of SKOV3 cells stained with DCFH-DA after different treatments for 4 h. (e) CLSM of SKOV3 cells stained with Liperfluo after different treatment for 4 h. Data represent mean values ± s.d., n = 3.
Fig. 4
Fig. 4
Relative cell viabilities of (a) L02 and (b) SKOV3 cells after incubation with EGCG and FeE@PEG NPs for 24 h. (c) Live/dead staining of L02 and SKOV3 cells after incubation with different treatments for 24 h. (d) JC-1 determining the mitochondrial membrane potential changes after treatment of SKOV3 cells with EGCG, and FeE@PEG NPs for 24 h. (e) TUNEL assay of SKOV3 cells after different treatments for 24 h. (f) Flow cytometry of SKOV3 cells after different treatments for 24 h. Data represent mean values ± s.d., n = 3.
Fig. 5
Fig. 5
(a) Time-dependent bodyweight curves for nude mice bearing SKOV3 cells after intravenous injection of EGCG, and FeE@PEG NPs. (b) Time-dependent tumor growth curves for nude mice bearing SKOV3 cells under different treatments. (c) Visual image of excised tumor after different treatments on the 14th day. (d) H&E and (e) TUNEL staining of tumor tissues of nude mice bearing SKOV3 cells after different treatments. Data represent mean values ± s.d., n = 5.
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