Nitrite induces the extravasation of iron oxide nanoparticles in hypoxic tumor tissue

Nitrite undergoes reconversion to nitric oxide under conditions characteristic of the tumor microenvironment, such as hypoxia and low pH. This selective conversion of nitrite into nitric oxide in tumor tissue has led to the possibility of using nitrite to enhance drug delivery and the radiation response. In this work, we propose to serially characterize the vascular response of brain tumor-bearing rats to nitrite using contrast-enhanced R2 * mapping. Imaging is performed using a multi-echo gradient echo sequence at baseline, post iron oxide nanoparticle injection and post-nitrite injection, whilst the animal is breathing air. The results indicate that nitrite sufficiently increases the vascular permeability in C6 gliomas, such that the iron oxide nanoparticles accumulate within the tumor tissue. When animals breathed 100% oxygen, the contrast agent remained within the vasculature, indicating that the conversion of nitrite to nitric oxide occurs in the presence of hypoxia within the tumor. The hypoxia-dependent, nitrite-induced extravasation of iron oxide nanoparticles observed herein has implications for the enhancement of conventional and nanotherapeutic drug delivery.