Enhanced radiation effect on SMCC7721 cells through endoplasmic reticulum stress induced by C225-GNPs in vitro and in vivo

The high atomic number of gold nanoparticles (GNPs) enables them to offer potential as practical and efficient radiosensitizing agents for cancer radiotherapy applications. In the present study, it was demonstrated that GNPs can significantly modulate the irradiation response of hepatocellular carcinoma (HCC) cells in vitro and in vivo, of which the underlying mechanisms were investigated. Cetuximab (C225) is a targeting agent, which binds to the extracellular domain of epidermal growth factor receptor (EGFR). Hepatocyte-targeting, EGFR-specific C225 was synthesized onto GNP surfaces (C225-GNPs) to increase the GNP targeting specificity. C225-GNPs was synthesized successfully and characterized. The cytotoxicity was tested using a Cell Counting Kit-8 assay and 50% inhibition concentration of SMCC7721 cells was calculated. Cell uptake assay was detected using transmission electron microscopy. Radiosensitization was tested using a cell colony formation assay and cell cycle was detected using flow cytometry. The expression of a number of apoptotic proteins were tested by western blot analysis. Orthotropic SMCC7721 xenografts were used in order to verify its radiosensitizing effect. The results revealed that a higher number of C225-GNPs were effectively uptaken by SMCC7721 cells and markedly enhanced cancer cell death. The sensitization mechanism of C225-GNPs was associated with the apoptotic gene signalling process activated by endoplasmic reticulum stress and the unfolded protein response in cancer cells. In orthotopic SMCC7721 xenografts, the C225-GNPs significantly enhanced the radiation-induced suppression of tumour growth. The results of the present study provided evidence that C225-GNPs are potent radiosensitizers with radiotherapeutic value for HCC with the overexpression of EGFR.