One of the major obstacles to the use of nanoparticle drug formulations is rapid clearance of these particles by the mononuclear phagocyte system (MPS). To better characterize MPS clearance of nanoparticles, Stephen Jones and colleagues used an intravital microscopy-based assay to quantify nanoparticle clearance and determine the effect of mouse strain and immune system function on particle clearance. The accompanying image shows nanoparticle clearance in 4 different mouse strains at 0, 5, 15, and 60 minutes after administration (left to right). Jones and colleagues found that mouse strains that are prone to a specific type of immune response known as Th2 clear nanoparticles at a faster rate than strains that are prone to Th1 immune responses. These results suggest that global immune status is a critical factor in nanoparticle clearance.
Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopy–based assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte–derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans.
Stephen W. Jones, Reid A. Roberts, Gregory R. Robbins, Jillian L. Perry, Marc P. Kai, Kai Chen, Tao Bo, Mary E. Napier, Jenny P.Y. Ting, Joseph M. DeSimone, James E. Bear