Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model

Invest Radiol. 2013 Jan;48(1):46-54. doi: 10.1097/RLI.0b013e3182749c0b.

Abstract

Objectives: Cyclic decapeptide CGLIIQKNEC (CLT1) has been demonstrated to target fibronectin-fibrin complexes in the extracellular matrix of different tumors and tissue lesions. Although liver fibrosis is characterized by an increased amount of extracellular matrix consisting of fibril-forming collagens and matrix glycoconjugates such as fibronectin, we aimed to investigate the feasibility of detecting and characterizing liver fibrosis using CLT1 peptide-targeted nanoglobular contrast agent (Gd-P) with dynamic contrast-enhanced magnetic resonance imaging in an experimental mouse model of liver fibrosis at 7 T.

Materials and methods: Gd-P, control peptide KAREC conjugated nanoglobular contrast agent (Gd-CP), and control nontargeting nanoglobular contrast agent (Gd-C) were synthesized. Male adult C57BL/6N mice (22-25 g; N = 54) were prepared and were divided into fibrosis (n = 36) and normal (n = 18) groups. Liver fibrosis was induced in the fibrosis group through subcutaneous injection of 1:3 mixture of carbon tetrachloride (CCl(4)) in olive oil at a dose of 4 μL/g of body weight twice a week for 8 weeks. Dynamic contrast-enhanced MRI was performed in all animals. Dynamic contrast-enhanced magnetic resonance imaging was analyzed to yield postinjection ΔR(1)(t) maps for quantitative measurements. Histological analysis was also performed.

Results: Differential enhancements were observed and characterized between the normal and fibrotic livers using Gd-P at 0.03 mmol/kg, when compared with nontargeted controls (Gd-CP and Gd-C). For Gd-P injection, both the peak and steady-state ΔR(1) of the normal livers were significantly lower than those after 4 and 8 weeks of CCl(4) dosing. Liver fibrogenesis with increased amount of fibronectin in the extracellular space in insulted livers were confirmed by histological observations.

Conclusions: These results indicated that dynamic contrast-enhanced magnetic resonance imaging with CLT1 peptide-targeted nanoglobular contrast agent can detect and stage liver fibrosis by probing the accumulation of fibronectin in fibrotic livers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Contrast Media*
  • Fibronectins / metabolism
  • Liver Cirrhosis / diagnosis*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Magnetic Resonance Imaging*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Diagnostic Techniques
  • Peptides, Cyclic* / metabolism

Substances

  • Contrast Media
  • Fibronectins
  • Peptides, Cyclic
  • cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl)