Ronald W Irwin1, Alesi R Escobedo1, Jean C Shih2,3. 1. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA. 2. Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA. jcshih@usc.edu. 3. USC-Taiwan Center for Translational Research, Los Angeles, California, USA. jcshih@usc.edu.
Abstract
PURPOSE: The biodistribution imaging kinetics of near-infrared monoamine oxidase inhibitor (NMI) are reported here. METHODS: NMI was administered intravenously or orally to mice and detected by NIR fluorescence optical imaging within minutes and the longitudinal signal distribution was measured for up to 1 week after a single dose. RESULTS: NMI rapidly reached 3.7-fold higher ventral and 3.2-fold higher brain region fluorescent signal intensity compared to oral route at 24 h. Similar patterns of NMI biodistribution were found in mice with or without intracranial implanted GL26 brain tumors. NMI was highly associated with tumors in contrast to adjacent non-tumor brain, confirming diagnostic utility. NMI 5 mg/kg imaging signal in brain at 48 h was optimal (tumor/non-tumor ratio > 3.5) with minimum off-target distribution. Intravenous NMI imaging signal peaked between 24 h and 48 h for lung, liver, kidney, blood, brain, and most other tissues. Clearance (signal weaker, but still present) from most tissues occurred by day 7. Intravenous low dose (0.5 mg/kg) minimally labeled tumor and other tissues, 5 mg/kg showed optimal imaging signal in glioma at a dose we previously reported as efficacious, and 50 mg/kg was tolerable but saturated the tissue signals beyond tumor specificity. Gel electrophoresis showed two major bands present in brain tumor and tissue protein lysates. CONCLUSIONS: Intravenous 5 mg/kg was optimal dose to target brain tumor and identified off-target organs of concern: lungs, liver, and kidneys. These results demonstrate the biodistribution and optimal dose range of NMI for treatment and diagnostic monitoring of glioma.
PURPOSE: The biodistribution imaging kinetics of near-infrared monoamine oxidase inhibitor (NMI) are reported here. METHODS: NMI was administered intravenously or orally to mice and detected by NIR fluorescence optical imaging within minutes and the longitudinal signal distribution was measured for up to 1 week after a single dose. RESULTS: NMI rapidly reached 3.7-fold higher ventral and 3.2-fold higher brain region fluorescent signal intensity compared to oral route at 24 h. Similar patterns of NMI biodistribution were found in mice with or without intracranial implanted GL26brain tumors. NMI was highly associated with tumors in contrast to adjacent non-tumor brain, confirming diagnostic utility. NMI 5 mg/kg imaging signal in brain at 48 h was optimal (tumor/non-tumor ratio > 3.5) with minimum off-target distribution. Intravenous NMI imaging signal peaked between 24 h and 48 h for lung, liver, kidney, blood, brain, and most other tissues. Clearance (signal weaker, but still present) from most tissues occurred by day 7. Intravenous low dose (0.5 mg/kg) minimally labeled tumor and other tissues, 5 mg/kg showed optimal imaging signal in glioma at a dose we previously reported as efficacious, and 50 mg/kg was tolerable but saturated the tissue signals beyond tumor specificity. Gel electrophoresis showed two major bands present in brain tumor and tissue protein lysates. CONCLUSIONS: Intravenous 5 mg/kg was optimal dose to target brain tumor and identified off-target organs of concern: lungs, liver, and kidneys. These results demonstrate the biodistribution and optimal dose range of NMI for treatment and diagnostic monitoring of glioma.