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. 2014 Apr;27(4):425-30.
doi: 10.1002/nbm.3078. Epub 2014 Jan 28.

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

Nilesh Mistry  1 , Ashley M Stokes, James Van Gambrell, Christopher Chad Quarles
Affiliations

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

Nilesh Mistry et al. NMR Biomed. 2014 Apr.

Abstract

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.

Keywords: contrast enhanced MRI; drug delivery; iron oxide nanoparticles; nitrite.

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Figures

Figure 1
Figure 1
a: Anatomical image with arrow indicating the location of the tumor. b: CBV map extracted using the change in R2* from baseline images, shows a small necrotic core (arrow), and a surrounding high CBV region indicative of increased vasculature. c: Percent change in R2* after nitrite injection.
Figure 2
Figure 2
Percent change in R2* in normal and tumor tissue in 4 different cohorts of rats including: a) before and after the injection of the CA and saline (N = 5), b) before and after the injection of nitrite without the CA (N = 6), c) before and after the injection of CA and nitrite (N = 8), and d) before and after the injection of CA and nitrite while the animal is breathing 100% O2 (N = 7).
Figure 3
Figure 3
Comparison of the mean percent change in R2* of the last 4 time-points, in normal and tumor tissue in 4 different cohorts of rats including: a) before and after the injection of the CA and saline, b) before and after the injection of nitrite without the CA, c) before and after the injection of CA and nitrite, and d) before and after the injection of CA and nitrite while the animal is breathing 100% O2.
Figure 4
Figure 4
Example (a) anatomic and (b) 18F-FMISO PET late slope map of a C6 bearing rat under normoxia. Arrows indicate the location of the tumor. (c) Plot of 18F-FMISO uptake (as %ID/cc) versus time over the 2 hours post-injection. The uptake in tumor tissue under normoxia continually increases as a result of the tumor hypoxia, while the normal tissue and tumor under hyperoxia have more constant and similar late slopes. (d) Under normoxic conditions, the late slope in tumor was significantly higher than that in normal tissue, whereas there was no difference between normal and tumor tissue late slope under hyperoxia, indicating reduced hypoxia in the tumors.
See this image and copyright information in PMC

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