Gefitinib-Loaded Starch/Chitosan Polymeric Nanoparticles for Enhanced Colorectal Cancer Therapy: Network Pharmacology, Molecular Docking, Physicochemical Characterization, and Evaluation in HCT-116 Cells and DMH-Induced Wistar Rats

The Gefitinib-loaded potato starch-chitosan nanoparticles (GEF-PS-CS-NPs) designed for the treatment of colorectal cancer had a size range of 190 ± 18.7 to 210 ± 20.45 nm, a zeta potential range of +2.26 ± 0.56 to +10.5 ± 2.67 mV, and an entrapment efficiency range of 66.5 ± 6.45 to 76.6 ± 8.45%. The application of 4–8% w/v potato starch increased the size ( p < 0.7154) and zeta potential of the nanoparticles owing to the swelling effect and electrostatic interaction. In silico network pharmacology study (STRING/Cytoscape) identified EGFR/SRC/MAPK hubs in CRC PPI networks, which were further corroborated by molecular docking and experimental validation in HCT116 cells and DMH-induced rats. Schrödinger docking research indicated high-affinity gefitinib binding to EGFR (Glide scores of −8.2 to −9.1 kcal/mol), corroborating the hypothesized EGFR-mediated mechanism. In vitro, GEF-PS-CS-NPs exhibited higher cytotoxicity against HCT116 CRC cells. GEF-PS-CS-NPs decreased BCL2 levels and triggered apoptotic DNA fragmentation in HCT116 CRC cells, confirming downstream reduction of survival signaling predicted by network pharmacology. The induction of 1,2-dimethylhydrazine (DMH) resulted in tumor formation, aberrant crypt foci, and biochemical changes in colorectal cancer-induced Wistar rats. GEF-PS-CS-NPs had 20-fold greater AUC (3690 ng·h/mL), increased t1/2 (29 h vs 14 h), increased C max (6.9 ng/mL), and increased Vd (2361 mL) compared with free GEF. GEF-PS-CS-NPs showed hemolysis below 5% and minimal platelet aggregation. Histopathology showed reduced colon damage and significantly improved inflammatory/oxidative markers, validating the pharmacological relevance of the expected EGFR/PI3K-AKT-associated anticancer effect. GEF-PS-CS-NPs confirmed as a promising nanocarrier for the treatment of colorectal cancer.