Inflammatory stimuli impact on cellular uptake and biodistribution of perfluorocarbon nanoemulsions

Intravenously administered perfluorocarbon nanoemulsions (PFCs) are taken up by phagocytic immune cells, which enables the noninvasive visualization of inflammatory hot spots by combined 1H/19F magnetic resonance imaging. However, little is known about the influence of inflammatory stimuli on cellular uptake and biodistribution of PFCs. Here, we systematically investigated the impact of inflammation induced by subcutaneous implantation of Matrigel/lipopolysaccharide or myocardial infarction (50 min ischemia reperfusion) on PFC uptake and biodistribution in C57BL/6J mice. We detected strong 19F signals in Matrigel/lipopolysaccharide plugs and infarcted hearts, which were completely absent in controls. Cellular uptake of PFCs was increased in neutrophils isolated from the blood and Matrigel/lipopolysaccharide plugs, whereas uptake by monocytes was only slightly elevated. In contrast, myocardial infarction caused only a moderate early increase of PFC uptake in monocytes and neutrophils. Interestingly, the inflammatory model did also affect the biodistribution of the PFCs. The blood half-life of PFCs was slightly increased after Matrigel/lipopolysaccharide implantation, whereas it was reduced after myocardial infarction. Compared to controls, the 19F signal of the liver was significantly stronger in Matrigel/lipopolysaccharide but not in myocardial infarction animals. Interestingly, stimulation of primary immune cells and RAW264.7 macrophages with lipopolysaccharide had no effect on PFC uptake, whereas C-reactive protein incubation elevated internalization of PFCs at least in RAW264.7 cells. In conclusion, we show that the cellular PFC uptake can differ between individual inflammatory conditions. This is an important aspect that has to be considered for the proper interpretation of 1H/19F magnetic resonance imaging data obtained from inflammatory hot spots.