A generic Zr labeling method to quantify the in vivo pharmacokinetics of liposomal nanoparticles with positron emission tomography.

Liposomal nanoparticles are versatile drug delivery vehicles that show great promise in cancer therapy. In an effort to quantitatively measure their in vivo pharmacokinetics, we developed a highly efficient Zr liposome-labeling method based on a rapid ligand exchange reaction between the membrane-permeable Zr(8-hydroxyquinolinate) complex and the hydrophilic liposomal cavity-encapsulated deferoxamine (DFO). This novel Zr-labeling strategy allowed us to prepare radiolabeled forms of a folic acid (FA)-decorated active targeting Zr-FA-DFO-liposome, a thermosensitive Zr-DFO-liposome, and a renal avid Zr-PEG-DFO-liposome at room temperature with near-quantitative isolated radiochemical yields of 98%±1% (n=6), 98%±2% (n=5), and 97%±1% (n=3), respectively. These Zr-labeled liposomal nanoparticles showed remarkable stability in phosphate-buffered saline and serum at 37°C without leakage of radioactivity for 48 h. The uptake of Zr-FA-DFO-liposome by the folate receptor-overexpressing KB cells was almost 15-fold higher than the Zr-DFO-liposome in vitro. Positron emission tomography imaging and ex vivo biodistribution studies enabled us to observe the heterogeneous distribution of the Zr-FA-DFO-liposome and Zr-DFO-liposome in the KB tumor xenografts, the extensive kidney accumulation of the Zr-FA-DFO-liposome and Zr-PEG-DFO-liposome, and the different metabolic fate of the free and liposome-encapsulated Zr-DFO. It also unveiled the poor resistance of all three liposomes against endothelial uptake resulting in their catabolism and high uptake of free Zr in the skeleton. Thus, this technically simple Zr-labeling method would find widespread use to guide the development and clinical applications of novel liposomal nanomedicines.