Nanoparticle uptake by circulating leukocytes: A major barrier to tumor delivery

Decades of research into improving drug delivery to tumors has documented uptake of particulate delivery systems by resident macrophages in the lung, liver, and spleen, and correlated short circulation times with reduced tumor accumulation. An implicit assumption in these studies is that nanoparticles present in the blood are available for distribution to the tumor. This study documents significant levels of lipoplex uptake by circulating leukocytes, and its effect on distribution to the tumor and other organs. In agreement with previous studies, PEGylation dramatically extends circulation times and enhances tumor delivery. However, our studies suggest that this relationship is not straightforward, and that particle sequestration by leukocytes can significantly alter biodistribution, especially with non-PEGylated nanoparticle formulations. We conclude that leukocyte uptake should be considered in biodistribution studies, and that delivery to these circulating cells may present opportunities for treating viral infections and leukemia. [Display omitted] •Uptake of nanoparticles by circulating leukocytes complicates the traditional measure of bioavailability.•Sequestration by leukocytes prevents particles from passively diffusing into tumors.•PEGylation reduces uptake by leukocytes and allows enhanced accumulation in all tissues, including tumors.•Uptake by leukocytes is part of the innate immune system that is activated in response to infection by foreign materials.