Abstract
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Objectives The ability to accurately and easily locate sentinel lymph nodes (SLNs) with non-invasive 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 conjugated truncated Evans blue (18F-AlF-NEB) and Evans blue (EB) dye. While PET provides a pre-surgical evaluation of SLNs, fluorescence signal and visible blue color afford guidance for surgery.
Methods The radiochemical yield for 18F-AlF-NEB was around 60% with a total synthesis and work-up time of 20-30 min. PET and/or optical imaging of lymph nodes was performed in three different animal models including hind limb inflammation model, orthotropic breast cancer model, and metastatic breast cancer model. Magnetic Resonance Imaging (MRI) was performed to provide anatomical references of LNs. BLI and immunostaining were performed to confirm tumor metastasis to LNs.
Results 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. In all three models, the LNs can be distinguished clearly by the apparent blue color and strong fluorescence signal from EB as well as high intensity PET signal from 18F-AlF-NEB. The lymphatic vessels between the LNs can also be optically visualized. In hind limb inflammation model induced by turpentine injection, the imaging results corroborate with the size and flow changes during local inflammatory responses. In both the orthotropic breast tumor and the tumor metastaisis models, SLNs were successfully detected by 18F-AlF-NEB PET with excellent image quality. An overlay of the PET and optical images provided high positional correlation of the LNs.
Conclusions The radioactive signal reflects the behavior of endogenous albumin, avoiding the usage of colloids, nanoparticles, and polymers. 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 SLNs and provide intraoperative guidance.
Research Support The research was supported by Intramural Research Program of National Institute of Biomedical Imaging and Bioengineering