Abstract
There has been considerable interest in the clinical use of exosomes as delivery vehicles for treatments as well as for promising diagnostic biomarkers, but the physiological distribution of exosomes must be further elucidated to validate their efficacy and safety. Here, we aimed to develop novel methods to monitor exosome biodistribution in vivo using positron emission tomography (PET) and optical imaging. Exosomes were isolated from cultured mouse breast cancer cells and labeled for PET and optical imaging. In mice, radiolabeled and fluorescently labeled exosomes were injected both via lymphatic and hematogenous metastatic routes. PET and fluorescence images were obtained and quantified. Radioactivity and fluorescence intensity of ex vivo organs were measured. PET signals from exosomes in the lymphatic metastatic route were observed in the draining sentinel lymph nodes. Immunohistochemistry revealed greater exosome uptake in brachial and axillary versus inguinal lymph nodes. Following administration through the hematogenous metastasis pathway, accumulation of exosomes was clearly observed in the lungs, liver, and spleen. Exosomes from tumor cells were successfully labeled with 64Cu (or 68Ga) and fluorescence and were visualized via PET and optical imaging, suggesting that this simultaneous and rapid labeling method could provide valuable information for further exosome translational research and clinical applications.
Highlights
Exosomes are cell-derived extracellular vesicles containing many functional proteins, mRNAs, and miRNAs [1,2,3], and are considered to be novel messengers in cell-to-cell communication [4,5]
Lipophilic fluorescent tracers, such as DiR (1,1 -dioctadecyl-3,3,3,3 -tetramethylindotricarbocyanine iodide), have been used for optical imaging [9,10], and reporter vectors encoding green fluorescent protein-conjugated exosome-specific proteins have been used for exosome imaging [17,18]. With these imaging methods it has been shown that exosomes localize to the lungs, liver, spleen, and lymph nodes [19]. These optical exosome labeling methods are useful for visualization of exosome localization within in vitro and ex vivo studies [20,21,22], it remains problematic to quantify the biodistribution of exosomes in vivo due to low tissue penetration and sensitivity
We developed a simple exosome radiolabeling method that is less dependent on cell type and utilizes more quantitative positron emission tomography (PET) imaging to better visualize exosome biodistribution in mice
Summary
Exosomes are cell-derived extracellular vesicles containing many functional proteins, mRNAs, and miRNAs [1,2,3], and are considered to be novel messengers in cell-to-cell communication [4,5]. Most previous studies investigated methods to image exosomes in vivo via fluorescence, bioluminescence, radioisotope, MRI, and magnetic particle imaging systems [13,14,15,16] Lipophilic fluorescent tracers, such as DiR (1,1 -dioctadecyl-3,3,3 ,3 -tetramethylindotricarbocyanine iodide), have been used for optical imaging [9,10], and reporter vectors encoding green fluorescent protein-conjugated exosome-specific proteins have been used for exosome imaging [17,18]. With these imaging methods it has been shown that exosomes localize to the lungs, liver, spleen, and lymph nodes [19]. These optical exosome labeling methods are useful for visualization of exosome localization within in vitro and ex vivo studies [20,21,22], it remains problematic to quantify the biodistribution of exosomes in vivo due to low tissue penetration and sensitivity
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