RESUMEN
[123I]ß-methyl-p-iodophenyl-pentadecanoic acid ([123I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [123I]BMIPP in cancer cells. We compared the accumulation of [123I]BMIPP in cancer cells with that of [18F]FDG and found that [123I]BMIPP was a much higher accumulation than [18F]FDG. The accumulation of [123I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [123I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [123I]BMIPP uptake in cancer cells. [123I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [123I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [123I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [123I]BMIPP were similar to those of [18F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [123I]BMIPP administration in the in vivo study. [123I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [123I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [123I]BMIPP is needed.
Asunto(s)
Neoplasias del Colon , Yodobencenos , Animales , Humanos , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ratones , Línea Celular Tumoral , Yodobencenos/química , Antígenos CD36/metabolismo , Radiofármacos/química , Radiofármacos/metabolismo , Radioisótopos de Yodo , Ácidos Oléicos/química , Miocardio/metabolismo , Distribución Tisular , Proteínas de Transporte de Ácidos Grasos/metabolismo , Fluorodesoxiglucosa F18/química , Fluorodesoxiglucosa F18/metabolismo , Ácidos GrasosRESUMEN
Pseudomonas aeruginosa infection is an infectious disease that must be controlled because it becomes chronic and difficult to treat, owing to its unique system of toxin production/injection and elimination of other bacteria. Here, we noninvasively monitored P. aeruginosa using single-photon emission computed tomography (SPECT) imaging. Determining the amount and localization of the P. aeruginosa will enable making faster clinical diagnoses and selecting the most appropriate therapeutic agents and methods. Nonclinically, this information can be used for imaging in combination with biofilms and toxin probes and will be useful for discovering drugs targeting P. aeruginosa. To study P. aeruginosa accumulation, we conducted in vitro and in vivo studies using iodine-123 ß-methyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP), which we previously reported using for Escherichia coli. In vitro, 123I-BMIPP accumulated in P. aeruginosa by being taken up into the bacteria and adsorbing to the bacterial surface. In vivo, 123I-BMIPP accumulated significantly more in infected sites than in noninfected sites and could be quantified by SPECT. These results suggest that 123I-BMIPP can be used as a probe for P. aeruginosa for SPECT. Establishing a noninvasive monitoring method using SPECT will allow further progress in studying P. aeruginosa.
RESUMEN
Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: 123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.