Abstract
Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.
Highlights
Reactive oxygen species (ROS) are generated as normal byproducts of metabolism in the electron transport chain and play an integral role in the regulation of cell growth, neurotransmission, and the immune response.[1]
Uncontrolled ROS production leads to the oxidation of DNA, proteins, and lipids, underlying the pathogenesis of many cardiovascular and neurodegenerative diseases, as well as cancers and inflammatory conditions.[2−7] In the cardiovascular system, elevated ROS are responsible for tissue injury during ischemia/reperfusion and have been linked to the progression from cardiac hypertrophy to heart failure, the evolution of atherosclerotic plaques, and the cardiac and microvascular dysfunction associated with diabetes
ROS production has been linked to the cardiotoxicity of cancer chemotherapeutic agents, which severely limits their dosimetry and effectiveness.[8−11] Most notably, the cardiotoxicity induced by doxorubicin, a widely used cancer chemotherapy agent, has been linked to ROS generation.[12,13]
Summary
Reactive oxygen species (ROS) are generated as normal byproducts of metabolism in the electron transport chain and play an integral role in the regulation of cell growth, neurotransmission, and the immune response.[1]. 18F-FPBT (∼3.0 MBq) in 5% ethanol in PBS (200 μL) containing sodium ascorbate (0.01 mg/mL) was incubated with rat serum (200 μL) at 37 °C for 1 min or 1 h. Wistar rats that had received either doxorubicin treatment (male, 267 ± 19 g, n = 6) or saline (male, 303 ± 9 g, n = 4) via osmotic pumps for 7 days were injected with 18F-FPBT (2.6 ± 1.5 MBq) via the tail vein on the PET/CT scanner bed. PET scans with the chest area in the field of vision were acquired for 30 min, followed by a CT scan, after which the animals were sacrificed and organs harvested, weighed, and gamma-counted as for the biodistribution protocol. Statistical comparisons between two groups were determined by unpaired t test with Welch’s correction, and comparisons between multiple groups were determined by one-way ANOVA with Tukey’s correction
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