Molecular imaging of inflammation in inflammatory bowel disease with a clinically translatable dual-selectin-targeted US contrast agent: comparison with FDG PET/CT in a mouse model.
OBJECTIVE
To develop and test a molecular imaging approach that uses ultrasonography (US) and a clinically translatable dual-targeted (P- and E-selectin) contrast agent (MBSelectin) in the quantification of inflammation at the molecular level and to quantitatively correlate selectin-targeted US with fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in terms of visualization and quantification of different levels of inflammation in a murine acute colitis model.


METHODS
Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care at Stanford University. MBSelectin was developed by covalently binding an analog of the naturally occurring binding ligand P-selectin glycoprotein ligand 1 fused to a human fragment crystallizable(or Fc) domain onto the lipid shell of perfluorobutane and nitrogen-containing MBs. Binding specificity of MBSelectin was assessed in vitro with a flow chamber assay and in vivo with a chemically induced acute colitis murine model. US signal was quantitatively correlated with FDG uptake at PET/CT and histologic grade. Statistical analysis was performed with the Student t test, analysis of variance, and Pearson correlation analysis.


RESULTS
MBSelectin showed strong attachment to both human and mouse P- and E-selectin compared with MBControl in vitro (P ≤ .002). In vivo, US signal was significantly increased (P < .001) in mice with acute colitis (173.8 arbitrary units [au] ± 134.8 [standard deviation]) compared with control mice (5.0 au ± 4.5). US imaging signal strongly correlated with FDG uptake on PET/CT images (ρ = 0.89, P < .001). Ex vivo analysis enabled confirmation of inflammation in mice with acute colitis and high expression levels of P- and E-selectin in mucosal capillaries (P = .014).


CONCLUSIONS
US with MBSelectin specifically enables detection and quantification of inflammation in a murine acute colitis model, leveraging the natural pathway of leukocyte recruitment in inflammatory tissue. US imaging with MBSelectin correlates well with FDG uptake at PET/CT imaging.
Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Dr, Room H1307; Stanford, CA 94305-5621, USA.
Huaijun
H
Wang
Steven
S
Machtaler
Thierry
T
Bettinger
Amelie M
AM
Lutz
Richard
R
Luong
Philippe
P
Bussat
Sanjiv S
SS
Gambhir
François
F
Tranquart
Lu
L
Tian
Jürgen K
JK
Willmann
D000704:Analysis of Variance; D000818:Animals; D003287:Contrast Media; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D019788:Fluorodeoxyglucose F18; D007074:Immunoglobulin G; D015212:Inflammatory Bowel Diseases / Q000000981:diagnostic imaging*; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods*; D064847:Multimodal Imaging; D019007:P-Selectin / Q000378:metabolism; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D014057:Tomography, X-Ray Computed; D014463:Ultrasonography
D003287:Contrast Media; D019040:E-Selectin; D007074:Immunoglobulin G; D019007:P-Selectin; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18