PET Imaging with Pegylated [64Cu]Cu2Se Nanoparticles Reveals Live Lymphatic Dynamics

Abstract The lymphatic system is vital for immune regulation, tissue fluid balance, and lipid metabolism, and its dysfunction contributes to cardiovascular disease, cancer metastasis, and metabolic disorders. Yet, unlike the blood vasculature, there is no clinically available imaging method for quantitative assessment of lymphatic dynamics, an urgent unmet need in lymphatic disease management. Positron emission tomography (PET), with its high sensitivity and quantitative whole-body imaging capability, offers a promising solution. Here, we report a lymphatic PET radiotracer based on PEGylated [64Cu]Cu2Se nanoparticles, engineered for selective lymphatic entry and dynamic whole-body imaging. The platform integrates a positron-emitter of copper radionuclides, 64Cu (t1/2 = 12.7 h), within a biodegradable Cu2Se matrix, which releases biocompatible copper and selenium only upon degradation. In vivo PET imaging in normal and diseased mouse models revealed lymphatic flows with unprecedented clarity, including the direct observation of pulsatile lymph-node dynamics and collateral lymphatic remodeling in a lymphedema model. Taken together, these results establish a solid foundation for future translational studies of such nanoparticle-based lymphatic imaging approaches.