title: Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Laboratory of Biomedical Imaging and Signal Processing The University of Hong Kong Pokfulam, Hong Kong SAR, China.|Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: April M
authors.initials: AM
authors.lastname: Chow
authors.affiliation: Department of Biomedical Engineering Case Western Reserve University Cleveland, Ohio, United States.
authors.forename: Mingqian
authors.initials: M
authors.lastname: Tan
authors.affiliation: Laboratory of Biomedical Imaging and Signal Processing The University of Hong Kong Pokfulam, Hong Kong SAR, China.|Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: Darwin S
authors.initials: DS
authors.lastname: Gao
authors.affiliation: Laboratory of Biomedical Imaging and Signal Processing The University of Hong Kong Pokfulam, Hong Kong SAR, China.|Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: Shu Juan
authors.initials: SJ
authors.lastname: Fan
authors.affiliation: Laboratory of Biomedical Imaging and Signal Processing The University of Hong Kong Pokfulam, Hong Kong SAR, China.|Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: Jerry S
authors.initials: JS
authors.lastname: Cheung
authors.affiliation: Department of Surgery The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Department of Biomedical Engineering Case Western Reserve University Cleveland, Ohio, United States.
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
authors.affiliation: Laboratory of Biomedical Imaging and Signal Processing The University of Hong Kong Pokfulam, Hong Kong SAR, China.|Department of Electrical and Electronic Engineering The University of Hong Kong Pokfulam, Hong Kong SAR, China.
authors.forename: Ed X
authors.initials: EX
authors.lastname: Wu
mesh_terms: D000818:Animals; D003287:Contrast Media; D005353:Fibronectins / Q000378:metabolism; D008103:Liver Cirrhosis / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D025202:Molecular Diagnostic Techniques; D010456:Peptides, Cyclic / Q000378:metabolism
chemical_list: D003287:Contrast Media; D005353:Fibronectins; D010456:Peptides, Cyclic; C510872:cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl)