Lamichhane Narottam, Dewkar Gajanan K, Sundaresan Gobalakrishnan, Wang Li, Jose Purnima, Otabashi Muhammad, Morelle Jean-Luc, Farrell Nicholas, Zweit Jamal
Center for Molecular Imaging, Department of Radiology, Virginia Commonwealth University, Richmond, Virginia.
Trasis SA, Ans, Belgium; and.
J Nucl Med. 2017 Dec;58(12):1997-2003. doi: 10.2967/jnumed.117.191965. Epub 2017 Jul 20.
Increasing evidence indicates that reduced intracellular drug accumulation is the parameter most consistently associated with platinum drug resistance, emphasizing the need to directly measure the intratumor 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 contribute to this endeavor by reporting on the development of an F-labeled carboplatin derivative (F-FCP) that has the potential to image drug uptake and retention, including intratumoral distribution, by PET. Fluorinated carboplatin (F-FCP) was synthesized using F-labeled 2-(5-fluoro-pentyl)-2-methyl malonic acid (F-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 radiosynthesis and characterization of F-FCP were performed using F-FPMA for coordination with the cisplatin-aqua complex. Automated radiosynthesis of F-FCP was optimized on the basis of manual synthesis procedures. The stability of F-FCP was verified using high-performance liquid chromatography. F-FCP was evaluated using ex vivo biodistribution and in vivo PET imaging in non-tumor-bearing animals as well as in KB-3-1 and COLO-205 tumor xenograft-bearing nude mice. In vitro cytotoxicity studies demonstrated that F-FCP has an antitumor activity profile similar to that of the parent drug carboplatin. In vivo plasma and urine stability analysis showed intact F-FCP at 24 h after injection. PET imaging and biodistribution studies showed fast clearance from blood and major accumulation in the kidneys, indicating substantial renal clearance of F-FCP. Using F-FCP PET, we could image and identify the intratumor drug profile. Our results demonstrated that F-FCP, like carboplatin, retains antitumor activity in various cell lines. F-FCP could be a useful imaging tool for measuring the intratumor drug distribution. This strategy of using a new therapeutic carboplatin derivative to quantify and track platinum drugs in tumors using PET has the potential to translate into a clinically useful imaging tool for individual patients.
越来越多的证据表明，细胞内药物蓄积减少是与铂类药物耐药性最始终相关的参数，这凸显了直接测量肿瘤内药物浓度的必要性。在精准医学时代，随着强大的成像和蛋白质组学技术的出现，有机会通过利用这些技术来更好地理解耐药性，以提供关于药物-靶点相互作用的新知识。在此，我们通过报道一种F标记的卡铂衍生物（F-FCP）的研发来为这一努力做出贡献，该衍生物有潜力通过正电子发射断层扫描（PET）对药物摄取和滞留情况进行成像，包括肿瘤内分布。使用F标记的2-(5-氟戊基)-2-甲基丙二酸（F-FPMA）作为标记剂与顺铂水合物配合物反应合成了氟化卡铂（F-FCP）。然后将其用于处理细胞系，并与不同浓度的顺铂和卡铂进行比较。使用F-FPMA与顺铂水合物配合物反应进行F-FCP的手动放射性合成和表征。基于手动合成程序对F-FCP的自动化放射性合成进行了优化。使用高效液相色谱法验证了F-FCP的稳定性。在无肿瘤动物以及携带KB-3-1和COLO-205肿瘤异种移植的裸鼠中，使用F-FCP进行了体外生物分布和体内PET成像评估。体外细胞毒性研究表明，F-FCP具有与母体药物卡铂相似的抗肿瘤活性谱。体内血浆和尿液稳定性分析显示注射后24小时F-FCP保持完整。PET成像和生物分布研究表明，F-FCP从血液中快速清除，主要蓄积在肾脏中，表明F-FCP有大量经肾清除。使用F-FCP PET，我们能够对肿瘤内药物情况进行成像和识别。我们的结果表明，F-FCP与卡铂一样，在各种细胞系中都保留抗肿瘤活性。F-FCP可能是一种用于测量肿瘤内药物分布的有用成像工具。这种使用新型治疗性卡铂衍生物通过PET来量化和追踪肿瘤中铂类药物的策略有可能转化为对个体患者有用的临床成像工具。
