title: Quantitative ultrasound molecular imaging.
abstract: Ultrasound molecular imaging using targeting microbubbles is predominantly a semi-quantitative tool, thus limiting its potential diagnostic power and clinical applications. In the work described here, we developed a novel method for acoustic quantification of molecular expression. E-Selectin expression in the mouse heart was induced by lipopolysaccharide. Real-time ultrasound imaging of E-selectin expression in the heart was performed using E-selectin-targeting microbubbles and a clinical ultrasound scanner in contrast pulse sequencing mode at 14 MHz, with a mechanical index of 0.22-0.26. The level of E-selectin expression was quantified using a novel time-signal intensity curve analytical method based on bubble elimination, which consisted of curve-fitting the bi-exponential equation [Formula: see text] to the elimination phase of the myocardial time-signal intensity curve. Ar and Af represent the maximum signal intensities of the retained and freely circulating bubbles in the myocardium, respectively; λr and λf represent the elimination rate constants of the retained and freely circulating bubbles in the myocardium, respectively. Ar correlated strongly with the level of E-selectin expression (|r|>0.8), determined using reverse transcriptase real-time quantitative polymerase chain reaction, and the duration of post-lipopolysaccharide treatment-both linearly related to cell surface E-selectin protein (actual bubble target) concentration in the expression range imaged. Compared with a conventional acoustic quantification method (which used retained bubble signal intensity at 20 min post-bubble injection), this new approach exhibited greater dynamic range and sensitivity and was able to simultaneously quantify other useful characteristics (e.g., the microbubble half-life). In conclusion, quantitative determination of the level of molecular expression is feasible acoustically using a time-signal intensity curve analytical method based on bubble elimination.
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK; Department of Cardiology, Hammersmith Hospital, London, UK; Imaging Sciences Department, Medical Research Council, Imperial College London, London, UK.
authors.forename: James Shue-Min
authors.initials: JS
authors.lastname: Yeh
authors.affiliation: Imaging Sciences Department, Medical Research Council, Imperial College London, London, UK; Department of Chemistry, Imperial College London, London, UK.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Sennoga
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: McConnell
authors.affiliation: Imaging Sciences Department, Medical Research Council, Imperial College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Eckersley
authors.affiliation: Department of Bioengineering, Imperial College London, London, UK.
authors.forename: Meng-Xing
authors.initials: MX
authors.lastname: Tang
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK; William Harvey Research Institute, Queen Mary, University of London, London, UK.
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
authors.affiliation: Department of Chemistry, Imperial College London, London, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Seddon
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.affiliation: National Heart and Lung Institute, Imperial College London, London, UK; Department of Cardiology, Hammersmith Hospital, London, UK. Electronic address: p.nihoyannopoulos@imperial.ac.uk.
authors.forename: Petros
authors.initials: P
authors.lastname: Nihoyannopoulos
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D019040:E-Selectin / Q000378:metabolism*; D004452:Echocardiography / Q000379:methods*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D051379:Mice; D045423:Microbubbles; D057054:Molecular Imaging / Q000379:methods*; D009206:Myocardium / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D000911:Antibodies, Monoclonal; D019040:E-Selectin
keywords: Contrast agent; Contrast echocardiography; E-Selectin; Echocardiography; Microbubble elimination; Molecular imaging; Quantification; Targeted microbubbles; Time–signal intensity curve; Ultrasound imaging