improved biological impacts of anti-egfr monoclonal antibody in kras-mutant colorectal cancer cells by silica-coated magnetic nanoparticle conjugation

Background: the therapeutic potential of epidermal growth factor receptor (egfr) targeting in colorectal cancer (crc) is hindered by the presence of kras codon 12 activating mutations, prevalent in approximately 25% of advanced crc cases. this study investigates the role of reactive oxygen species (ros) in conferring resistance to anti-egfr monoclonal antibodies in kras mutant crc cells, focusing on ros-mediated apoptosis induction using cetuximab-pegylated silica-coated magnetic nanoparticles (mnps). methods: mnps were synthesized and surface-coated with silica, followed by functionalization and stabilization with polyethylene glycol (peg). cetuximab (cet) was covalently conjugated to generate emnp-peg-cet. structural and compositional analyses were performed using scanning electron microscopy (sem), dynamic light scattering (dls), uv-vis spectroscopy, and fourier transform infrared (ftir) analysis. apoptosis induction, chromatin condensation, and ros production were evaluated in kras mutant sw-480 crc cells. results: successful synthesis of emnp-peg-cet was confirmed, revealing a particle size of 67 nm and a surface charge of -8.3 mv. the conjugate exhibited significant cytotoxicity against crc cells, with notable apoptosis induction and ros generation in egfr-positive/kras mutant sw-480 cells, surpassing the effects observed with bare cet and emnp-peg controls. the nuclear factor erythroid 2-related factor 2/kelch-like ech-related protein 1 (nrf2-kaep1) gene expression analysis by real-time pcr showed that cells treated with emnp-peg-cet exhibited a noteworthy decrease in nrf2 expression and a simultaneous increase in keap1 expression compared to those treated with free cet. conclusion: these findings highlight the potential of ros-mediated apoptosis induction to enhance the cytotoxicity of cet in egfr-positive/kras mutant crc cells, offering new avenues for overcoming drug resistance mechanisms in metastatic crc.