Pharmacokinetic analysis of intravenously-injected ⁸⁹Zr-labeled nanoparticles reveals monocyte trafficking

Objectives To demonstrate that pharmacokinetic analysis of PET data can show monocyte trafficking after i.v. injection of ⁸⁹Zr-radiolabeled Feraheme (FH) superparamagnetic iron oxide nanoparticles.

Methods Heat induced radiolabeling was used to obtain [⁸⁹Zr]FH which was administered i.v. to mice that underwent longitudinal microPET/CT imaging over 1 week. Blood samples were drawn from a rhesus macaque, once before i.v. injection of FH and again 3h after FH administration. An aliquot of pre-FH blood was used as a control and the remainder was incubated with FH ex vivo for 3h at 20 °C. Each sample underwent Ficoll centrifugation to extract a monocyte-rich buffy coat that was subsequently analyzed by relaxometry.

Results Liver and spleen showed biexponential increases in [⁸⁹Zr]FH. Fast components (t_1/2s = 1.27 & 1.24 h respectively) matched [⁸⁹Zr]FH clearance from plasma determined by direct blood sampling (t_1/2 = 1.02 h), while the second uptake phase had kinetics even slower than the single uptake component observed in popliteal and axillary lymph nodes (t_1/2s = 21.2 h & 20.2 h). Nodal uptake was high with SUV values comparable to liver and spleen. In vivo uptake of FH by circulating monocytes was confirmed by decreased T2 relaxation in the buffy coat; ex vivo incubation gave even greater changes in relaxivity.

Conclusions [⁸⁹Zr]FH given i.v. has an initial vascular phase, a rapid hepatic and splenic uptake phase (from direct phagocytosis of [⁸⁹Zr]FH by resident macrophages), and slower splenic and nodal uptake phases (from trafficking of [⁸⁹Zr]FH-loaded monocytes). These studies add to our understanding of key players in immune function, contribute to our knowledge on the biological fate of nanoparticles after systemic administration, and suggest a path toward monocyte labeling for in vivo tracking.