Effect of Nano-Gefitinib on Solid Ehrlich Carcinoma via Targeting EGFR, RIPK2 Pathways, and Macrophage Reprogramming

Background/Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a promising therapeutic avenue against mammary cancer. Thus, we investigated whether the EGFR inhibitor Nano-Gefitinib bilosome decreases Ehrlich tumor cells in a murine model, given that EGFR has been linked to carcinoma-macrophage crosstalk. Methods: Forty female mice were divided into control, Nano-Gefitinib, Ehrlich tumor and combination groups; the latter received Nano-Gefitinib treatment after tumor induction and lasted for 18 days. Results: Our results showed that Nano-Gefitinib ameliorated Ehrlich-induced hepatic injury, oxidative stress, and apoptosis in mice, as indicated by a significant reduction in serum level of hepatic enzymes, oxidative biomarkers (malondialdehyde and oxidized glutathione), total cholesterol, triglycerides, LDL, and BAX, along with an increase in antioxidant biomarkers, serum total protein, albumin, HDL, and hepatic antiapoptotic Bcl-2. A substantial reduction in tumor volume and size was noted in the combination group and was evidenced histopathologically by a reduction in tumor cell progression, mitotic activity, and giant cell formation. In addition, Nano-Gefitinib significantly inhibited EGFR/p-AKT/ERK1/2/RIPK2/NF-κB with subsequent suppression of TGF-triggered M2 macrophage reprogramming, evidenced by the lowered protein expression of the M2 surface markers CD163 and decreased M2 protein expression (Fizz1, MMPs, and VEGF). Additionally, Nano-Gefitinib significantly increased M1 macrophage phenotype, evidenced by the upregulation in the immunoexpression of the CD68, in addition to increasing CD8 and caspase-3 and decreasing CD4, with VEGF immunoreactivity in the combination group. Conclusions: Gefitinib biosomes encouraged macrophage polarization, apoptosis, and reduced inflammation, with a subsequent decrease in tumor volume.