Abstract
Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, and emphasizes the need to directly measure intra-tumor drug concentration. In the era of precision medicine and with the advent of powerful imaging and proteomics technologies, there is an opportunity to better understand drug resistance, by exploiting these techniques to provide new knowledge on drug-target interactions. Here, we are contributing to this endeavor by reporting on the development of a fluorine-18 labeled carboplatin derivative (18F-FCP) that can be used to potentially image drug uptake and retention, including intra-tumoral distribution, by positron emission tomography (PET). Methods: Fluorinated carboplatin (19F-FCP) was synthesized using 2-(5-fluoro-pentyl)-2-methyl malonic acid (FPMA) as the labeling agent to coordinate with the cisplatin aqua complex. It was then used to treat cell lines and compared with cisplatin and carboplatin at different concentrations. Manual radio synthesis and characterization of 18F-FCP was performed using 18F-FPMA with coordination with cisplatin aqua complex. Automated radiosynthesis of 18F-FCP was optimized based on the manual synthetic procedures. Stability of 18F-FCP was verified using high performance liquid chromatography. 18F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor animals as well as in KB 3-1 and COLO205 tumor xenograft bearing nude mice. Results: In vitro cytotoxicity studies demonstrated that 19F-FCP has similar anti-tumor activity profile as the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact 18F-FCP at 24-hour post injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in kidneys, indicating substantial renal clearance of 18F-FCP. Using 18F-FCP PET, we could image and identify intra-tumor drug profile. Conclusion: Our results demonstrate that 19F-FCP derivative, like carboplatin, retains anti-tumor activity in various cell lines. 18F-FCP could be a useful imaging tool to measure intra-tumor drug distribution. This strategy of using new therapeutic carboplatin derivative to quantify and track platinum drugs in tumor using PET could potentially translate into a clinically useful imaging tool for individual patients.
- Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.