Neutrophil-Particle Interactions in Blood Circulation Drive Particle Clearance and Alter Neutrophil Responses in Acute Inflammation

Although nano- and micropartide therapeutics have been studied for a range of drug delivery applications, the presence of these particles in blood flow may have considerable and understudied consequences to circulating leukocytes, especially neutrophils, which are the largest human leukocyte population. The objective of this work was to establish if particulate drug carriers in circulation interfere with normal neutrophil adhesion and migration. Circulating blood neutrophils in vivo were found to be capable of rapidly binding and sequestering injected carboxylate-modified particles of both 2 and 0.5 mu m diameter within the bloodstream. These neutrophil-particle associations within the vasculature were found to suppress neutrophil interactions with an inflamed mesentery vascular wall and hindered neutrophil adhesion. Furthermore, in a model of acute lung injury, intravenously administered drug-free particles reduced normal neutrophil accumulation in the airways of C57BL/6 mice between 52% and 60% versus particle-free mice and between 93% and 98% in BALB/c mice. This suppressed neutrophil migration resulted from particle-induced neutrophil diversion to the liver. These data indicate a considerable acute interaction between injected particles and circulating neutrophils that can drive variations in neutrophil function during inflammation and implicate neutrophil involvement in the clearance process of intravenously injected particle therapeutics. Such an understanding will be critical toward both enhancing designs of drug delivery carriers and developing effective therapeutic interventions in diseases where neutrophils have been implicated.