Abstract
BackgroundNon-invasive in vivo imaging strategies are of high demand for longitudinal monitoring of inflammation during disease progression. In this study we present an imaging approach using near infrared fluorescence (NIRF) imaging in combination with a polyanionic macromolecular conjugate as a dedicated probe, known to target L- and P-selectin and C3/C5 complement factors.Methodology/Principal FindingsWe investigated the suitability of dendritic polyglycerol sulfates (dPGS), conjugated with a hydrophilic version of the indocyanine green label with 6 sulfonate groups (6S-ICG) to monitor sites of inflammation using an experimental mouse model of allergic asthma. Accumulation of the NIRF-conjugated dPGS (dPGS-NIRF) in the inflamed lungs was analyzed in and ex vivo in comparison with the free NIRF dye using optical imaging. Commercially available smart probes activated by matrix metalloproteinase's (MMP) and cathepsins were used as a comparative control. The fluorescence intensity ratio between lung areas of asthmatic and healthy mice was four times higher for the dPGS in comparison to the free dye in vivo at four hrs post intravenous administration. No significant difference in fluorescence intensity between healthy and asthmatic mice was observed 24 hrs post injection for dPGS-NIRF. At this time point ex-vivo scans of asthmatic mice confirmed that the fluorescence within the lungs was reduced to approximately 30% of the intensity observed at 4 hrs post injection.Conclusions/SignificanceCompared with smart-probes resulting in a high fluorescence level at 24 hrs post injection optical imaging with dPGS-NIRF conjugates is characterized by fast uptake of the probe at inflammatory sites and represents a novel approach to monitor lung inflammation as demonstrated in mice with allergic asthma.
Highlights
near infrared fluorescence (NIRF) imaging is a common technology in preclinical studies that obtains functional information in vivo over time for assessment of antibody binding, protein expression, enzyme activities, cell tracking etc. [1,2,3]
We present a novel approach for functional in-vivo imaging utilizing a dendritic polyglycerolsulfate conjugated to a NIRF dye related to ICG in combination with optical imaging to monitor sites of inflammation in the lung by applying an experimental model of allergic asthma [12]
We successfully demonstrated that the applied dendritic polyglycerol sulfates (dPGS)-NIRF probe accumulates to inflammatory sites within the lung already 4 hrs after probe administration
Summary
NIRF imaging is a common technology in preclinical studies that obtains functional information in vivo over time for assessment of antibody binding, protein expression, enzyme activities, cell tracking etc. [1,2,3]. Crucial for the success of in vivo NIRF imaging will be the development of dedicated NIRF probes for distinct targets of molecular events characterizing different diseases. These probes, based on their mechanisms of targetdetection can be divided into four groups: passive probes to image areas with increased blood supply [5], target-specific fluorescent probes which are directed against molecular and/or diseasespecific markers [6], fluorescent labels to track injected fluorescence stained cells [7], and application of smart probes activated by enzymes for the detection of molecular events [8]. In this study we present an imaging approach using near infrared fluorescence (NIRF) imaging in combination with a polyanionic macromolecular conjugate as a dedicated probe, known to target L- and P-selectin and C3/C5 complement factors
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