Monitoring Sorafenib Resistance and Efficacy in Hepatocellular Carcinoma Using [18F]Alfatide II and [18F]Fluorodeoxyglucose Positron Emission Tomography.

Abstract

Integrin αvβ3 expression is associated with sorafenib resistance in hepatocellular carcinoma (HCC). Therefore, monitoring its expression in HCC may serve as a valuable indicator of the efficacy of sorafenib treatment. In this study, longitudinal positron emission tomography (PET) was performed to assess [¹⁸F]Alfatide II and [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) as suitable probes for evaluating the treatment efficacy of sorafenib in a Huh-7 human (HCC) xenograft model. Huh-7 tumor cells were used to establish both normal and sorafenib-resistant cell lines, and xenograft models were developed. The mice were categorized into four groups based on the cell type and treatment: normal nontreatment, normal treatment, sorafenib-resistant nontreatment, and sorafenib-resistant treatment. Huh-7 tumor mice received intragastric injections of sorafenib (30 mg/kg/day) or vehicle for 15 consecutive days. Tumor size and weight were assessed throughout the study. Longitudinal microPET/computed tomography (CT) scans with [¹⁸F]Alfatide II and [¹⁸F]FDG were acquired to quantitatively measure angiogenesis on days -2, 3, 7, and 14 and metabolism on days -1, 4, 8, and 15 following therapy initiation. The tumor uptake (ID%/g_mean) of each probe was calculated. No significant difference in [¹⁸F]FDG uptake was observed between the normal and sorafenib-resistant groups (P = 0.452); however, [¹⁸F]Alfatide II uptake differed significantly between the two groups (P < 0.001). Sorafenib successfully inhibited normal Huh-7 tumor growth, inducing significant differences in tumor size 9 days after sorafenib treatment (P < 0.05). The uptake of [¹⁸F]Alfatide II in the tumor lesions changed significantly on day 14 (P = 0.001). However, no change was observed in the uptake of [¹⁸F]FDG (P > 0.05). The PET imaging data of [¹⁸F]Alfatide II and [¹⁸F]FDG were validated through ex vivo immunohistochemistry analysis targeting integrin αvβ3, VEGF, and GULT-1. [¹⁸F]Alfatide II PET was more effective in monitoring sorafenib resistance and therapeutic efficacy in the Huh-7 human HCC xenograft model than [¹⁸F]FDG.