Abstract
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Introduction: Reversibility and curability of mild to moderate liver fibrosis arouse realistic expectations for early diagnosis and precise staging. However, current diagnostic methods still fail to paint a complete picture of the disease. Negligible expressed levels in normal liver but highly in areas of active fibrosis, making fibroblast activation protein (FAP) an excellent theranostic target. Galium-68 labeled FAP inhibitor (68Ga-FAPI) targeting FAP may provide a non-invasive approach to visualize liver fibrosis. The study induced preclinical PET imaging to explore the value of 68Ga-DOTA-FAPI-04 PET for monitoring and diagnosing liver fibrosis.
Methods: Mice liver fibrosis models were induced twice weekly with carbon tetrachloride (CCl4). After giving CCl4 for 6, 8, 10 and 12 weeks, 68Ga-DOTA-FAPI-04 micro-PET/CT was administered. After acquiring the images, three non-overlapping uptake-specific regions of interest on each liver were outlined and the mean %ID/cc values were measured. In vitro radioactivity counts and autoradiography were used to validate in vivo imaging. The extensive evaluation was performed using a combination of non-alcoholic steatohepatitis activity score (NAS), Sirius red collagen staining, serum indicators (hydroxyproline, ALT and AST) and immunofluorescence staining quantification to confirm the existence and progression of liver fibrosis, the expression and distribution of FAP and α-SMA, and the relationship between FAP and liver fibrosis.
Results: Continued administration of CCl4 resulted in an increased inflammatory response in the liver (a 2-fold increase in NAS from 3.40±1.06 at week 6 to 6.56±1.24 at week 12) and an increasingly severe degree of fibrosis (all p<0.001, Fig.1 A-B). Sirius red collagen staining revealed non-significant progression in liver fibrosis between two weeks but significant progression between four weeks (p<0.001, Fig.1 C). Hydroxyproline and AST levels increased correlating with the extent of fibrosis (Fig.1 D-E). Hepatic 68Ga-DOTA-FAPI-04 uptake generally paralleled the severity of the disease (Fig.2 A). The accumulation of 68Ga-DOTA-FAPI-04 in fibrotic liver at 10-12 weeks was significantly higher than that in healthy liver and early fibrotic liver at 6-8 weeks (Fig.2 B). Quantitative analysis indicated a 1.5-fold and 4.8-fold increase in liver uptake and radioactivity counts of 68Ga-DOTA-FAPI-04 during the 6-week to 10-week modelling (%ID/cc 0.494 to 0.759, %ID/g 0.267 to 1.283), which decreased slightly in advanced 12-week models (%ID/cc 0.681, %ID/g 0.612; Fig.3 A-B). Immunohistochemistry showed a significant increase of FAP and a-SMA expression in liver fibrotic tissue (all p<0.001), and hepatic FAP expression paralleled a-SMA expression (Fig.4 A-D) and disease duration (Fig.4 E).
Conclusions: 68Ga-DOTA-FAPI-04 has the potential to display activated fibroblasts involved in the fibrotic process and to assess different stages of liver fibrosis. It is a new PET imaging agent with promising applications in the accurate assessment and potential prediction of the prognosis of liver fibrosis, which should be evaluated in further clinical studies.
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