[ 18 F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis

J Hepatol. 2020 Jul;73(1):161-169. doi: 10.1016/j.jhep.2020.02.018. Epub 2020 Mar 5.

Abstract

Background & aims: The vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [18F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis.

Methods: PET with [18F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl4] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.

Results: Fibrotic mouse livers showed enhanced [18F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvβ3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvβ3 and its signaling complex were higher in CCl4 and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings.

Conclusions: Imaging hepatic integrin αvβ3 with PET and [18F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis.

Lay summary: Integrin αvβ3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [18F]-Alfatide, binds to integrin αvβ3 with high affinity and specificity. [18F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.

Keywords: Integrin αvβ3; Liver fibrosis; PET imaging; [(18)F]-Alfatide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Progression
  • Fluorescent Antibody Technique / methods
  • Fluorine Radioisotopes / pharmacology
  • Gene Expression Profiling / methods
  • Hepatic Stellate Cells / metabolism*
  • Integrin alphaVbeta3 / metabolism*
  • Liver Cirrhosis* / diagnostic imaging
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / pathology
  • Mice
  • Molecular Imaging / methods
  • Peptides, Cyclic / pharmacology*
  • Positron-Emission Tomography / methods*
  • Reproducibility of Results
  • Sensitivity and Specificity

Substances

  • Fluorine Radioisotopes
  • Integrin alphaVbeta3
  • Peptides, Cyclic
  • alfatide II