Figure 5.

ZVI-NP inhibited NRF2-regulated antioxidant transcription program in vivo and suppressed lung metastases. A-C, The tumor volume (A), the representative tumor images of the last time point (B), and the final tumor weight (C) of NOD/SCID mice bearing A549 xenografts treated with ZVI@Ag NPs or PBS by i.v. injection once a week (indicated by arrows) (n = 5 for each group). D, Immunohistochemistry revealed the expression of 4-HNE, NRF2, GPX4 and endothelial cells marker CD31 in tumor tissues from H460 xenografts (left) and A549 xenografts (right) with or without ZVI@Ag NPs treatment. E, Downregulation of NRF2 targeting genes in H460 xenografts treated with 50 mg/kg ZVI@Ag NPs was determined by RT-qPCR. F-H, The tumor volume (F), the representative tumor images at the endpoint of study (G), and the respective tumor weight (H) of NOD/SCID mice bearing H460 xenografts or NRF2-overexpressing H460 xenografts treated with ZVI@CMC NPs or PBS by 4 episodes of i.v. injection (indicated by arrows). Liproxstatin-1 (10 mg/kg) treatment was conducted by daily i.p. injection for 10 days. I-K, Histopathology of the lung tissues (I) dissected on day 21 from orthotopic mice that received tail vein injection of H460 cells then subjected to i.v. injection of ZVI-NPs or PBS every three days for five times. Quantification of the tumor nodule number (J) and nodule area (K). L-N, Histopathology of the lung tissues (L) dissected on day 54 from mice subcutaneously implanted with A549 cells then subjected to i.v. injection of ZVI@Ag NPs or PBS once a week for four weeks. Quantification of the tumor nodule number (M) and nodule area (N). Data were mean ± s.e.m. *, p < 0.05; **, p < 0.01; ***, p < 0.001.