Res@ZIF-90 suppress gastric cancer progression by disturbing mitochondrial homeostasis

Abstract

Background: Gastric cancer (GC) is still a serious threat to human health worldwide. As a natural compound, resveratrol has been proven to have anti-tumor activity, and the nano-delivery carrier has shown its excellent ability to retain and control drug release.

Methods: Res@ZIF-90 underwent synthesis via a one-pot method and subsequent characterization encompassing Dynamic Light Scattering, Scanning Electron Microscope, Transmission Electron Microscope, and UV-vis absorption spectroscope. The release of resveratrol from Res@ZIF-90 across varied pH environments were delineated employing High Performance Liquid Chromatography. The mitochondrial targeting of Res@ZIF-90 was scrutinized utilizing Fluorescent Inverted Microscopy. The cytotoxic impact of Res@ZIF-90 on HGC-27 cells was evaluated through CCK-8 assay, Live/Dead staining, scratch test, and JC-1 assay. Furthermore, the HGC-27 tumor-bearing mice model was established to explore the anti-tumor effect of Res@ZIF-90.

Results: ZIF-90 can effectively release resveratrol under acidic (pH = 5.5) conditions. In addition, Res@ZIF-90 could be taken up by cells and localized into mitochondria. ZIF-90 has no obvious cytotoxicity at the experimental concentration, while Res@ZIF-90 was more cytotoxic to HGC-27 cells than free resveratrol at the same concentration. Res@ZIF-90 significantly reduced the expressions of PGCS 1α, TFAM, PINK1, and COX IV, which together induced mitochondrial homeostasis disorders and inhibited the tumor growth of HGC-27 tumor-bearing mice in vivo.

Conclusions: Res@ZIF-90 can inhibit the progression of gastric cancer by targeting the mitochondria of gastric cancer cells and disrupting mitochondrial homeostasis to produce cytotoxic effects. Res@ZIF-90 may be a promising antitumor drug with potential application value.

Keywords: Gastric cancer; Mitochondria; Mitophagy; Res@ZIF-90; Resveratrol.

Scheme

Synthesis of Res@ZIF-90 and its mechanism of anti-tumor. Using one-pot method, Res@ZIF-90 was successfully synthesized, enabling targeted delivery of resveratrol to the mitochondria of gastric cancer cells and demonstrating an anti-tumor effect by disrupting mitochondrial homeostasis.

Fig. 1

(A) Hydrodynamic size distribution and zeta potential of Res@ZIF-90. (B) SEM image of Res@ZIF-90. Scale bar: 500 nm. (C) TEM image of Res@ZIF-90. Scale bar: 100 nm. (D) The UV–Vis absorption of different Res concentration. (E) The UV–Vis absorption of ZIF-90 and Res@ZIF-90. (F) The release of Res from Res@ZIF-90 at different pH condition. Data were presented as the Mean ± SD (n = 3). *p < 0.05, **p < 0.01, and ***p < 0.001, Student's t-test.

Fig. 2

(A) Endocytosis ability of Res@ZIF-90 by HGC-27 cells and corresponding quantitative data. scale bars: 20 μm. Data were presented as the Mean ± SD (n = 3). (B) The mitochondrial targeting ability of Res@ZIF-90, scale bars: 20 μm. ***p < 0.001. One-way ANOVA.

Fig. 3

(A) Cytotoxicity of ZIF-90, Res and Res@ZIF-90 against HGC-27 cells. Data were presented as the Mean ± SD (n = 3). (B) Live/dead cell staining images of HGC-27 cells treated with PBS, ZIF-90, Res and Res@ZIF-90. Scale bar: 200 μm. (C) Statistical analyses of Live/dead cell staining of HGC-27 cells. Data were presented as the Mean ± SD (n = 3). One-way ANOVA. (D) JC-I staining images of HGC-27 cells treated with PBS, ZIF-90, Res and Res@ZIF-90. Scale bar: 50 μm. (E) Scratch assay of HGC-27 cells treated with PBS, ZIF-90, Res and Res@ZIF-90. Scale bar: 200 μm. **p < 0.01.

Fig. 4

(A) ROS assay and corresponding statistical analysis in HGC-27 cell line after treated with PBS, ZIF-90, Res, and Res@ZIF-90. scale bars: 50 μm. Data were presented as the Mean ± SD (n = 3). One-way ANOVA. (B) and (C) Expression of mitochondrial homeostasis related protein in HGC-27 cell line after treated with PBS, ZIF-90, Res, and Res@ZIF-90. Data were presented as the Mean ± SD (n = 3). **P < 0.01. One-way ANOVA.

Fig. 5

(A) Relative body weight of mice treated with PBS, ZIF-90, Res, and Res@ZIF-90. Data were presented as the Mean ± SD (n = 6). (B) Relative tumor volume of mice treated with PBS, ZIF-90, Res, and Res@ZIF-90. Data were presented as the Mean ± SD (n = 6). (C) Tumor weight and (D) tumor tissue pictures of mice after PBS, ZIF-90, Res, and Res@ZIF-90 treatment for 14 days. Data were presented as the Mean ± SD (n = 6). (E) H&E staining of tumors and major organs (heart, liver, spleen, lung, kidney) in different groups, scale bars: 200 μm.***p < 0.001, One-way ANOVA.