||Oxygen Induced Tissue Hypoxia
Ken-ichiro, Matsumoto ,
B. Mitchell, JamesC. Krishna, Murali
Effect of oxygenation challenges to the in vivo pharmacokinetics of nitroxyl contrast agents in squamous cell carcinoma (SCC) tumor tissue and normal muscle were investigated. In addition, difference of T1 relaxivity (ΔR1) in the normal muscle and the SCC tumor tissues were compared under several gas-challenging conditions. SCC tumor cells were injected into the right thighs of C3H/Hen MTV- female mice and allowed to grow for 9 days, which resulted in a tumor of approximate size of 0.7 cm3. Pharmacokinetic profiles of three nitroxyl contrast agents, 3-carboxy-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CxP), 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (CmP), and 4-hydroxy-tetramethylpiperidine-N-oxyl (TPL), having different lipophilicities were compared using MR redox imaging. To perform T1 mapping, spin echo images were obtained using a multi-slice multi-echo (MSME) sequence with 5 TRs (repetition time: 4800, 3200, 1600, 800 and 400 ms). Exposure to 100% oxygen resulted in a rapid decay rate of TPL in tumor tissue, while no effect or slightly slower decay rate was observed in normal muscle. The 100% oxygen breathing also made distribution of nitroxyl probes into tissue lower. As a result, 100% oxygen breathing can make relatively large difference of TPL concentration between normal and tumor tissue. Carbogen and 1.5 atm hyperbaric oxygen (HBO) challenges could increase ΔR1 in the tissue, while 100% oxygen breathing could not increase but decrease the ΔR1 in both the normal and the tumor tissue. The pO2 in the healthy muscle tissue during 100% oxygen breathing measured by the EPR method also showed lower or similar values compared to the air breathing. Pimonidazole staining area, i.e. hypoxic area, in the tumor tissue was spread by 100% oxygen breathing. Those results suggest that breathing 100% oxygen can make tissue hypoxic. A combination of 100% oxygen with TPL has a potential to enhance the radioprotection effect selective to normal tissue without oxygenation of tissues.
The Society for Redox Biology and Medicine's 24th Annual Meeting (SfRBM 2017)