Department of Surgery and Cancer, Imperial College London, United Kingdom.
Department of Radiology/Nuclear Medicine, Imperial College Healthcare NHS Trust, London, United Kingdom.
Theranostics. 2020 Jul 9;10(19):8677-8690. doi: 10.7150/thno.47298. eCollection 2020.
: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [F]fluoromethyl-(1,2-H) choline ([F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). : [F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [F]fluorodeoxyglucose ([F]FDG) scans. : Oxidation of [F]D4-FCH to [F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [F]D4-FCH-derived uptake (SUV) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. : [F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.
胆碱及其代谢物在肿瘤中的空间分子分布具有高度异质性。由于缺氧转录信号和其他生存因素对胆碱代谢的调节，我们设想，在患者肿瘤中检测到这种异质性，可以为先进的局部治疗提供基础。然而，目前还没有非侵入性的方法来评估患者的这种现象。我们用[F]氟甲基-(1,2-H)胆碱([F]D4-FCH)和正电子发射断层扫描/计算机断层扫描(PET/CT)研究了非小细胞肺癌(NSCLC)中的这种异质性。给 17 名新诊断的 NSCLC 患者静脉注射[F]D4-FCH(300.5±72.9MBq[147.60-363.6MBq])。同时进行 PET/CT 扫描和放射性血液取样，以便对血液-组织细胞间转运率常数进行数学建模。并与活检得到的胆碱激酶-α(CHKα)表达和诊断性[F]氟脱氧葡萄糖([F]FDG)扫描进行了比较。[F]D4-FCH 氧化为[F]D4-氟代甜菜碱的速度受到抑制(60 分钟时 48.58±0.31%母核)，这可能是由于放射性示踪剂设计中包含的氘同位素效应所致。在 17 名分析患者的 51 个病灶(肿瘤、淋巴结和转移灶)的早期(5 分钟)和晚期(60 分钟)图像中均显示出示踪剂的特异性摄取。17 例原发性病变的[F]D4-FCH 摄取(SUV)值在 2.87-10.13 之间；低于[F]FDG PET 的摄取值[6.89-22.64]。数学模型显示在稳定状态下[F]D4-FCH 有净不可逆摄取，对整个肿瘤的参数成像显示，示踪剂在肿瘤内的保留存在很大的异质性，这可能影响了与活检得到的 CHKα表达的相关性。[F]D4-FCH 可在 NSCLC 中检测到，具有较大的肿瘤内异质性，这可能在未来用于靶向局部治疗。
