18F-5-fluoro-aminosuberic acid PET/CT imaging of oxidative-stress features during the formation of DEN-induced rat hepatocellular carcinoma

Rationale: The role of oxidative stress metabolism during hepatocellular carcinoma (HCC) formation potentially allows for positron emission tomography (PET) imaging of oxidative stress activity for early and precise HCC detection. However, there is currently limited data available on oxidative-stress-related PET imaging for longitudinal monitoring of the pathophysiological changes during HCC formation. This work aimed to explore PET-based longitudinal monitoring of oxidative stress metabolism and determine the sensitivity of [18F]-5-fluoroaminosuberic acid ([18F]FASu) for assessing pathophysiological processes in diethylnitrosamine (DEN) induced rat HCC. Methods: Genomic and clinical data were obtained from the HCC dataset (n = 383) in The Cancer Genome Atlas (TCGA-LIHC) and Gene Expression Omnibus (GEO) datasets. Wistar rats were administered DEN weekly, either by gavage (i.g.) at doses of 10 mg/kg or 80 mg/kg or by intraperitoneal injection (i.p.) at 80 mg/kg, with continuous modeling over a 12-week period followed by 24 weeks of consecutive feeding. PET/CT imaging was conducted at weeks 8, 15, and 21 by tail vein injections of [18F]FASu and [18F]FDG (~3.7 MBq). Finally, contrast-enhanced CT imaging of the nodules was performed at the designed time point. The rats in each group were sacrificed at multiple time points to perform a correlation analysis between PET imaging findings and histological examinations. Results: Bioinformatics analysis revealed that upregulation expression of SLC7A11 in HCC indicates oxidative stress-altered cellular metabolism and allows early detection of HCC formation. By simulating different levels of oxidative stress in DEN-induced rat HCC, the SUVmax of [18F]FASu PET imaging positively correlated with the expression of CD44 and SLC7A11 (r = 0.7913, P < 0.0001; r = 0.7173, P < 0.0001, respectively), which maintain redox homeostasis in the cells. Compared with 18F-fluorodeoxyglucose ([18F]FDG), [18F]FASu PET imaging demonstrated higher sensitivity for HCC diagnosis and enabled the characterization of pathological changes in DEN-induced rat HCC at an early stage. Conclusions: Our findings regarding the oxidative stress characterization of HCC formation in DEN-induced rat models using [18F]FASu PET imaging demonstrated the exciting potential of oxidative-stress-related PET imaging for monitoring the pathophysiological changes during HCC formation.