Molecular Imaging

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1. 

   Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application

   Xiaoping Leng*, Jianjun Wang*, Andrew Carson, Xucai Chen, Huili Fu, Susanne Ottoboni, William R. Wagner, Flordeliza S. Villanueva
   Molecular Imaging, vol. 13, 4, First Published June 1, 2014.
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   Abstract

   Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MB_ESEL). Control MBs had scrambled peptide (MB_CTL) or nonspecific IgG (MB_IgG). MB_ESEL adhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MB_ESEL adhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MB_CTL or MB_IgG adhesion to inflamed versus normal ECs. There was greater adhesion of MB_ESEL to inflamed versus noninflamed microcirculation and minimal adhesion of MB_CTL or MB_IgG under any condition. Ultrasound imaging after injection of MB_SEL demonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MB_ESEL was higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB, p < .02) and higher than that after MB_CTL (4.0 ± 1.0 dB, p < .03) or MB_IgG (1.7 ± 0.1 dB, p < .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.
    
2. 

   The Antiangiogenic Effects of a Vascular Endothelial Growth Factor Decoy Receptor Can Be Monitored in Vivo Using Contrast-Enhanced Ultrasound Imaging

   Flemming Forsberg, Raymond J. Ro, Andrew Marshall, Ji-Bin Liu, See-Ying Chiou, Daniel A. Merton, Priscilla Machado, Adam P. Dicker, Levon N. Nazarian
   Molecular Imaging, vol. 13, 2, First Published March 1, 2014.
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   Abstract

   The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response. We investigated whether the effects of a vascular endothelial growth factor decoy receptor (VEGF Trap, Regeneron Pharmaceuticals, Tarrytown, NY) could be monitored in vivo using contrast-enhanced ultrasonography (CEUS). Twenty nude mice (in two groups) were implanted with a human melanoma cell line (DB-1). The active group received VEGF Trap (4 × 25 mg/kg over 2 weeks), whereas the control group received an inactive protein. An ultrasound contrast agent was injected followed by power Doppler imaging (PDI) and pulse inversion harmonic imaging (PIHI; regular and intermittent). Specimens were sectioned in the same planes as the images and stained for endothelial cells (CD31), cyclooxygenase-2 (COX-2), VEGF, and hypoxia (Glut1). Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis. Mean tumor volume was smaller in the active group than in the control group (656 ± 225 vs 1,160 ± 605 mm³). Overall, PDI and VEGF correlated (r = .34; p = .037). Vascularity decreased from control to treated mice with intermittent PIHI, as did the expression of CD31 and COX-2 (p # .02), whereas VEGF increased (p = .05). CEUS appears to allow in vivo monitoring of the antiangiogenic effects of VEGF Trap in the DB-1 human melanoma xenograft model.
    
3. 

   Ultrasound Backscatter Microscopy Image-Guided Intraventricular Gene Delivery at Murine Embryonic Age 9.5 and 10.5 Produces Distinct Transgene Expression Patterns at the Adult Stage

   Jiwon Jang, Jyhyun Ahn, Nayeon Lee, Seong-Tae Kim, Dae-Hyuk Kweon, Jae Youl Cho, Kye Won Park, Sunyoung Kim, Keejung Yoon
   Molecular Imaging, vol. 12, 8, First Published November 1, 2013.
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   Abstract

   In utero injection of a retroviral vector into the embryonic telencephalon aided by ultrasound backscatter microscopy permits introduction of a gene of interest at an early stage of development. In this study, we compared the tissue distribution of gene expression in adult mice injected with retroviral vectors at different embryonic ages in utero. Following ultrasound image-guided gene delivery (UIGD) into the embryonic telencephalon, adult mice were subjected to whole-body luciferase imaging and immunohistochemical analysis at 6 weeks and 1 year postinjection. Luciferase activity was observed in a wide range of tissues in animals injected at embryonic age 9.5 (E9.5), whereas animals injected at E10.5 showed brain-localized reporter gene expression. These results suggest that mouse embryonic brain creates a closed and impermeable structure around E10. Therefore, by injecting a transgene before or after E10, transgene expression can be manipulated to be local or systemic. Our results also provide information that widens the applicability of UIGD beyond neuroscience studies.
    
4. 

   In Vivo Demonstration of Cancer Molecular Imaging with Ultrasound Radiation Force and Buried-Ligand Microbubbles

   Mark A. Borden, Jason E. Streeter, Shashank R. Sirsi, Paul A. Dayton
   Molecular Imaging, vol. 12, 6, First Published September 1, 2013.
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   Abstract

   In designing targeted contrast agent materials for imaging, the need to present a targeting ligand for recognition and binding by the target is counterbalanced by the need to minimize interactions with plasma components and to avoid recognition by the immune system. We have previously reported on a microbubble imaging probe for ultrasound molecular imaging that uses a buried-ligand surface architecture to minimize unwanted interactions and immunogenicity. Here we examine for the first time the utility of this approach for in vivo molecular imaging. In accordance with previous results, we showed a threefold increase in circulation persistence through the tumor of a fibrosarcoma model in comparison with controls. The buried-ligand microbubbles were then activated for targeted adhesion through the application of noninvasive ultrasound radiation forces applied specifically to the tumor region. Using a clinical ultrasound scanner, microbubbles were activated, imaged, and silenced. The results showed visually conspicuous images of tumor neovasculature and a twofold increase in ultrasound radiation force enhancement of acoustic contrast intensity for buried-ligand microbubbles, whereas no such increase was found for exposed-ligand microbubbles. We therefore conclude that the use of acoustically active buried-ligand microbubbles for ultrasound molecular imaging bridges the demand for low immunogenicity with the necessity of maintaining targeting efficacy and imaging conspicuity in vivo.
    
5. 

   Shear Forces from Flow Are Responsible for a Distinct Statistical Signature of Adherent Microbubbles in Large Vessels

   Shiying Wang, F. William Mauldin, Jr, Alexander L. Klibanov, John A. Hossack
   Molecular Imaging, vol. 12, 6, First Published September 1, 2013.
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   Abstract

   Real-time ultrasound-based targeted molecular imaging in large blood vessels holds promise for early detection and diagnosis of stroke risk by identifying early markers for atherosclerosis prior to plaque formation. Singular spectrum-based targeted molecular (SiSTM) imaging is a recently proposed method that uses changes in statistical dimensionality—quantified by a normalized singular spectrum area (NSSA)—to image receptor-ligand–bound adherent microbubbles. However, the precise physical mechanism responsible for the distinct statistical signature was previously unknown. In this study, in vitro flow phantom experiments were performed to elucidate the physical mechanism in large blood vessel environments. In the absence of flow, an increase in the NSSA of adherent microbubbles with respect to tissue was not observed with increased microbubble concentration or pulse length (p > .23; n = 5) but was observed with increased flow rate (p < .01; n = 10). When observing the dynamics of the adherent microbubble statistics, a good correlation was observed between the NSSA and the derivative of image intensity (R² > .97). In addition, a monotonic relationship between the NSSA and decorrelation was demonstrated. These findings confirm the hypothesis that the statistical signature of adherent microbubbles is derived from frame-to-frame decorrelation, which is induced by flow shear forces.