亚硝酸钠改变乳腺癌临床前模型中的灌注与缺氧

Breast cancer is known to have high levels of hypoxia, leading to poor prognosis and reduced treatment response. Sodium nitrite is an exogenous agent that has been shown to decrease hypoxia in ischemic limb injury and is being explored to improve hypoxia in the tumor microenvironment. The goal of this study is to use non-invasive imaging to characterize changes in perfusion, hypoxia, and drug delivery in vivo following exposure to sodium nitrite. Mouse models of breast cancer (BT474 human and 4T1 syngeneic cell lines) were treated with saline or sodium nitrite (165μg/kg IP) twice daily. Dynamic contrast-enhanced (DCE) MRI was used to monitor changes 20 minutes after the administration of a single dose of sodium nitrite. [ 18 F]-fluoromisonidazole ([ 18 F]FMISO) positron emission tomography (PET) enabled visualization and quantification of hypoxia within both models, with the BT474 model receiving one week of treatment and the 4T1 model receiving three doses of treatment before imaging. Sodium nitrite-induced changes to drug delivery were measured via dynamic [ 89 Zr]Zr-atezolizumab PET in the 4T1 model, which informed on delivery alterations and the 24-hour retention of an antibody drug delivery. Mice were given sodium nitrite 24 hours, 12 hours, and 20 minutes prior to scan. Modeling of dynamic PET was performed with a two-tissue compartment model to extract biological metrics of perfusion ( K1 ) and retention ( k3 ). For all molecular studies, tracer uptake was quantified using the mean and distribution of the standardized uptake value (SUV) in the tumor. The Wilcoxon rank sum test was used to assess differences in K trans extracted from Kety-Tofts analysis of DCE-MRI data. One-way and two-way ANOVAs were used to determine the effects of treatment. Independent t-tests were used to examine differences between treatment groups. Mice treated with sodium nitrite showed increased perfusion ( K trans from DCE-MRI) compared to those treated with saline (p=0.03). In both models, hypoxia was shown to be significantly reduced with the introduction of sodium nitrate compared to controls, with a decrease observed after 10 doses in BT-474 (p=0.01) and after two doses in 4T1 (p=0.02). Compartmental modeling showed that adding sodium nitrite increased the rate of delivery of the tracer ( K1 ) compared to control (p=0.02) and improved retention ( k3 ) at 24 hours (p=0.015). Non-invasive imaging revealed tumor microenvironment alterations in perfusion and oxygenation following sodium nitrite in two breast cancer models. Further, sodium nitrite was able to increase delivery of an antibody PET tracer, serving as a measure of antibody therapy delivery. As perfusion and hypoxia are key drivers in response to therapy, the addition of sodium nitrite can modulate hypoxia, perfusion, and drug delivery in solid tumors and could potentially offer new therapeutic insights for optimizing treatment in breast cancer.