Nanoparticle mediated microvascular embolization (NME) of tumor tissue may occur after systemic administration of PEM as a result of the nitric oxide sequestration by PEM. Nitric oxide sequestration may cause a reduction in available extracellular nitric oxide in the tumor endothelium, which may prompt a widespread shutdown of vascular flow, hemorrhage, and necrosis. In particular, shutdown of vascular flow may trigger changes in nitric oxide production as well as trigger an acute inflammatory response, which may create reactive nitrogen species that are particularly destructive to the microvasculature. PEM constructs are developed that incorporate large amounts of iron-containing protein, possess high oxygen affinities, and demonstrate delayed nitric oxide binding. Such properties induce selective NME of tumors after extravasation, and will likely enhance the effect of VEGFR TKIs and/or mTOR inhibitors.
