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In vivo albumin labeling and lymphatic imaging

Significance The imaging agent we developed in this study can be used for visualization and detection of sentinel lymph nodes (SLNs). After local injection, the imaging probe quickly formed a complex with albumin within the interstitial fluid. Thus, the radioactive signal reflects the behavior of endogenous albumin, avoiding the usage of colloids, nanoparticles, or polymers. The SLNs can be visualized by PET scans before surgery and then removed under the guidance of fluorescence signal and blue color deposit during surgery. The excellent imaging quality, easy preparation, multimodality, and biosafety guarantee the clinical translation to map SLNs and provide intraoperative guidance. The ability to accurately and easily locate sentinel lymph nodes (LNs) with noninvasive imaging methods would assist in tumor staging and patient management. For this purpose, we developed a lymphatic imaging agent by mixing fluorine-18 aluminum fluoride-labeled NOTA (1,4,7-triazacyclononane-N,N',N''-triacetic acid)-conjugated truncated Evans blue (18F-AlF-NEB) and Evans blue (EB) dye. After local injection, both 18F-AlF-NEB and EB form complexes with endogenous albumin in the interstitial fluid and allow for visualizing the lymphatic system. Positron emission tomography (PET) and/or optical imaging of LNs was performed in three different animal models including a hind limb inflammation model, an orthotropic breast cancer model, and a metastatic breast cancer model. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal from EB as well as a high-intensity PET signal from 18F-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. The easy preparation, excellent PET and optical imaging quality, and biosafety suggest that this combination of 18F-AlF-NEB and EB has great potential for clinical application to map sentinel LNs and provide intraoperative guidance.