Hypoxic And Acute Hypoxic Intratumor Mapping By Po(2) Imaging

Hypoxic tumor has a significantly poorer outcome following radiation therapy because hypoxic cells are resistant to radiation. With improvements in radiation treatment planning such as IMRT and Partial RT, it will be possible to precisely deliver appropriate doses to chronically hypoxic and acutely hypoxic area in the tumor when such zones are identified a priori using pO2 imaging techniques. Pulsed electron paramagnetic resonance imaging (EPRI) is a novel imaging method to directly monitor the pO2 in the tumor on a quantitative basis with useful spatial and temporal resolutions. The purpose of this work was to assess the intra-tumor pO2 profiles by EPRI and compare with images representing tumor perfusion by gadolinium-enhanced T1-weighted magnetic resonance imaging (Gd-MRI) findings in murine model of human cancer. HT29 solid tumors were (n = 6) implanted by injecting 5 × 105 cells s.c. into the right hind legs of mice. Experiments were initiated when tumors grew to approximately 1 cm3 in size. Imaging tumor pO2 was accomplished with EPRI using an oxygen-sensitive OX63 as a paramagnetic tracer and dissolved tissue oxygen its contrasting molecule. The dose of OX63 used for imaging (1.125 mmol/kg) was well below the maximally tolerated dose of 2.5-7.0 mmol/kg and the LD50 of 8.0 mmol/kg. Dynamic 3D EPRI were obtained every 3 minutes for 30 minutes. EPRI was done with a 300 MHz pulsed EPRI system, then Gd-MRI was done every 20 seconds for 30 minutes with a controlled 7 T scanner. We defined hypoxia (average pO2 < 8 mm Hg), acute hypoxia (8 mm Hg < average pO2 < 20 mm Hg), and normal regions (20 mm Hg < average pO2) by EPRI, respectively. And one radiologist defined the every pO2 status in Gd-MRI in reference to the value of Gd concentrations. We evaluated the sensitivity and specificity of Gd-MRI by making comparisons with EPRI findings, which served as the gold standard in this analysis. We reliably found chronic hypoxia (15%), acute hypoxia (55%), and normal regions (32%) in the tumor by EPRI. Especially, acute hypoxia was a significant spatiotemporal heterogeneous phenomenon in the dynamics of tumor pO2. We could also define Gd- hypoxia (28%), Gd- acute hypoxia (37%), and Gd- normal regions (36%) in the tumor by Gd-MRI. The sensitivity and specificity of Gd- hypoxia is 31% and 64%, these of Gd- acute hypoxia is 34% and 74%, these of Gd- normal region is 46% and 63%, respectively. We can identify chronically hypoxic, acutely hypoxic and normal region intra-tumor mapping by EPRI. There is a limitation using Gd-MRI to characterize pO2 status. Thus, in the near future, pO2 imaging techniques such as EPRI have a promise to obtain intra-tumor pO2 images rather than Gd-MRI.