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Megan E. Capozzi, Patricia K. Russ, John S. Penn, Frederick R. Haselton, Ashwath Jayagopal; Nanotechnology-Guided Molecular Retinal Fluorescence Angiography. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1721.
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Endothelial dysfunction in retinal vasculature disease can be monitored using noninvasive retinal imaging approaches, in conjunction with contrast agents to highlight diseased cells and biomolecules. Nanotechnology holds great potential for interfacing with biomolecular mediators of endothelial dysfunction for purposes of diagnosis or therapy. In this study, we developed nanoscale optical contrast agents for the detection of pathogenic endothelial biomarkers in mouse models of atherosclerotic vascular disease, using a multispectral retinal fluorescence imaging system.
We performed retinal imaging of ApoE-/- mouse models of early and late atherosclerosis and age-matched controls up to 1 year in age. Targets analyzed included endothelial cell adhesion molecules, selectins, and integrins involved in disease pathology. Antibody-functionalized optical contrast agents included molecularly-targeted quantum dot nanocrystals (QD), phycoerythrin (PE) conjugates, as well as indocyanine green (ICG) conjugates. Specificity of contrast agents was validated using conventional molecular biology techniques and histology.
Staging of atherosclerotic disease in mouse models was possible by monitoring inflammatory biomarker expression in the retina of diseased models, including expression of VCAM-1, E-selectin, and ICAM-1. Levels of these markers increased with the severity of disease, indicating that they may serve as retinal surrogate biomarkers of disease progression. Conventional techniques such as RT-PCR and immunofluorescence analysis validated the specificity of molecular targeting. QD offered the highest signal to noise ratio of the imaging approaches tested, although all approaches were highly specific as evaluated by lack of nonspecific IgG-functionalized contrast agents.
The retina is valuable as a continuously accessible, noninvasive imaging window on the circulation. Typically, retinal imaging technology is focused on the assessment of retinal diseases. However, this study suggests that retinal biomarkers hold prognostic value for monitoring other vascular diseases not normally associated with retinal dysfunction. Nanotechnology-based contrast agents such as QD can be combined with retinal fluorescence imaging equipment to perform molecular-level characterization of the vasculature in living subjects for diagnosis and evaluation of therapeutic response.
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