Volume 42 Issue 5
Oct.  2018
Article Contents

Citation:

Biological evaluation of PET/CT imaging agent 18F-fluoropropionic acid in hepatocellular carcinoma

  • Corresponding author: Sheng Liu, liusheng_gz@126.com ; Ganghua Tang, gtang0224@126.com
  • Received Date: 2018-05-23
    Fund Project:

    Science and Technology Planning Project Foundation of Guangzhou 201510010145

    Science and Technology Foundation of Guangdong Province 2013B021800264

    Science and Technology Foundation of Guangdong Province 2016B090920087

    National Natural Science Foundation of China 81671719

    Science and Technology Planning Project Foundation of Guangzhou 201604020169

    National Natural Science Foundation of China 81571704

  • Objective To evaluate the potential of 18F-fluoropropionic acid (18F-FPA) as a PET/CT tracer in the imaging of hepatocellular carcinoma (HCC) and to identify the mechanism underlying 18F-FPA uptake.Methods (1) 18F-FPA was synthesized from the precursor methyl-2-bromopropionate. (2) 18F-FPA uptake by SK-Hep 1 HCC cells was quantified in vitro at different time points. To further investigate the mechanism underlying 18F-FPA uptake, the inhibitory effects of the fatty acid synthase inhibitor Orilistat and the acetyl-CoA carboxylase inhibitor 5-tetradecyloxy-2-furoic acid on 18F-FPA uptake were observed. (3) Micro-PET/CT imaging results for 18F-FPA and 18F-FDG for mouse models of human hepatocellular carcinoma SK-Hep 1 were obtained and compared. Mthe radioactivity uptake ratios of 18F-FDA and 18F-FDG were compared and analyzed with t test.Results(1) 18F-FPA was synthesized with a yield of 45±2% through a simple process. (2) 18F-FPA uptake ratio by SK-Hep 1 cells gradually increased from (1.3±0.4)% after 5 min to (4.6 ±0.2)% after 120 min. In the cell uptake inhibition experiments, 18F-FPA uptake by SK-Hep 1 cells gradually decreased as inhibitor concentration increased. Under Orilistat and TOFA concentrations of 400 μmol, 18F-FPA uptake by SK-Hep 1 cells decreased by (40.3±4.0)% and (26.0±6.0)%, respectively. (3) 18F-FPA showed rapid and accurate tumor localization in mouse models of human hepatocellular carcinoma SK-Hep 1 with a tumor/liver ratio of 1.63±0.26. When used in 18F-FDG PET/CT imaging, the tumor/liver ratio of 18F-FPA reached 1.09±0.21. The imaging results provided by 18F-FPA were superior to those provided by 18F-FDG (t=4.055, P=0.047).Conclusion 18F-FPA can be used as an alternative radiotracer in the detection of hepatocellular carcinoma, its uptake is related to fatty acid synthesis.
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  • [1] Sun H, Song T. Hepatocellular carcinoma:Advances in diagnostic imaging[J]. Drug Discov Ther, 2015, 9 (5):310-318. DOI:10.5582/ddt.2015.01058.
    [2] Haug AR. Imaging of primary liver tumors with positron-emission tomography[J]. Q J Nucl Med Mol Imaging, 2017, 61 (3):292-300. DOI:10.1053/j.sult.2012.11.006.
    [3] Sun DW, An L, Wei F, et al. Prognostic significance of parameters from pretreatment 18F-FDG PET in hepatocellular carcinoma:a meta-analysis[J]. Abdom Radiol (NY), 2016, 41 (1):33-41. DOI:10.1007/s00261-015-0603-9.
    [4] Deford-Watts L M, Mintz A, Kridel S J. The potential of 11C-acetate PET for monitoring the Fatty acid synthesis pathway in Tumors[J]. Curr Pharm Biotechnol, 2013, 14 (3):300-312. DOI:10.2174/1389201011314030006.
    [5] Grassi I, Nanni C, Allegri V, et al. The clinical use of PET with 11C-acetate[J]. Am J Nucl Med Mol Imaging, 2012, 2 (1):33-47.
    [6] Schiepers C, Huang SC, Dahlbom M. Dynamic PET/CT with 11C-acetate in prostate cancer[J]. J Nucl Med, 2013, 54 (2):326. DOI:10.2967/jnumed.112.112532.
    [7] Ponde DE, Dence CS, Oyama N, et al. 18F-fluoroacetate:a potential acetate analog for prostate tumor imaging-in vivo evaluation of 18F-fluoroacetate versus 11C-acetate[J]. J Nucl Med, 2007, 48 (3):420-428.
    [8] Wang H, Tang G, Hu K, et al. Comparison of three 18F-labeled carboxylic acids with 18F-FDG of the differentiation tumor from inflammation in model mice[J]. BMC Med Imaging, 2016, 16:2. DOI:10.1186/s12880-016-0110-7.
    [9] Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis[J]. Nat Rev Cancer, 2007, 7 (10):763-777. DOI:10.1038/nrc2222.
    [10] Calvisi DF, Wang C, Ho C, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma[J]. Gastroenterology, 2011, 140 (3):1071-1083. DOI:10.1053/j.gastro.2010.12.006.
    [11] Brogsitter C, Zophel K, Kotzerke J. 18F-Choline, 11C-choline and 11C-acetate PET/CT:comparative analysis for imaging prostate cancer patients[J]. Eur J Nucl Med Mol Imaging, 2013, 40 (Suppl 1):S18-27. DOI:10.1007/s00259-013-2358-2.
    [12] Yamamoto Y, Nishiyama Y, Kameyama R, et al. Detection of hepatocellular carcinoma using 11C-choline PET:comparison with 18F-FDG PET[J]. J Nucl Med, 2008, 49 (8):1245-1248. DOI:10.2967/jnumed.108.052639.
    [13] Yoshii Y, Furukawa T, Oyama N, et al. Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome[J/OL]. Plos one, 2013, 8 (5): e64570[2018-05-22]. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064570. DOI:10.1371/journal.pone.0064570.
    [14] Kornberg A, Küpper B, Thrum K, et al. Increased 18F-FDG Uptake of hepatocellular carcinoma on positron emission tomography independently predicts tumor recurrence in liver transplant patients[J]. Transplantat Proc, 2009, 41 (6):2561-2563. DOI:10.1016/j.transproceed.2009.06.115.
    [15] Dang YH, Cai J, Li X, et al. Imaging Potential and Biodistribution in vivo of 2-[18F]Fluoropropionic Acid in Breast Cancer-bearing Mice[J]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 2015, 37 (3):320-324.DOI:10.3881/j.issn.1000-503X.2015.03.014.
    [16] Pillarsetty N, Punzalan B, Larson SM. 2-18F-Fluoropropionic Acid as a PET Imaging Agent for Prostate Cancer[J]. J Nucl Med, 2009, 50 (10):1709-1714. DOI:10.2967/jnumed.109.064212.
    [17] 张占文, 胡平, 唐刚华.肿瘤短链脂肪酸代谢PET显像剂研究进展[J].国际放射医学核医学杂志, 2017, 41 (6):430-436. DOI:10.3760/cma.j.issn.1673-4114.2017.06.009.Zhang ZW, Hu P, Tang GH. Progress on short-chain fatty acid tumor molecular probes for PET imaging[J]. Int J Radiat Med Nucl Med, 2017, 41 (6):430-436. doi: 10.3760/cma.j.issn.1673-4114.2017.06.009
    [18] Wehrle JP, Ng CE, McGovern KA, et al. Metabolism of alternative substrates and the bioenergetic status of EMT6 tumor cell spheroids[J]. NMR Biomed, 2000, 13 (6):349-360. DOI:10.1002/ijc.23835.
    [19] Ricks CA, Cook RM. Regulation of volatile fatty acid uptake by mitochondrial acyl CoA synthetases of bovine liver[J]. J Dairy Sci, 1981, 64 (12):2324-2335. doi: 10.3168/jds.S0022-0302(81)82854-8
    [20] Carvalho MA, Zecchin KG, Seguin F, et al. Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model[J]. Int J Cancer, 2008, 123 (11):2557-2565. DOI:10.1002/IJC.23835.
    [21] Wysham WZ, Roque DR, Han J, et al. Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines[J]. Target Oncol, 2016, 11 (6):763-769. DOI:10.1007/s11523-016-0442-9.
    [22] Ricks CA, Cook RM. Regulation of volatile fatty acid uptake by mitochondrial acyl CoA synthetases of bovine liver[J]. J Dairy Sci, 1981, 64 (12):2324-2335. DOI:10.3168/jds.S0022-0302 (81)82854-8.
    [23] Wysham WZ, Roque DR, Han J, et al. Effects of Fatty Acid Synthase Inhibition by Orlistat on Proliferation of Endometrial Cancer Cell Lines[J]. Target Oncol, 2016, 11 (6):763-769. DOI:10.1007/s11523-016-0442-9.
    [24] Xiao X, Liu H, Li X. Orlistat treatment induces apoptosis and arrests cell cycle in HSC-3 oral cancer cells[J]. Microb Pathog, 2017, 112:15-19. DOI:10.1016/j.micpath.2017.09.001.
    [25] Sokolowska E, Presler M, Goyke E, et al. Orlistat Reduces Proliferation and Enhances Apoptosis in Human Pancreatic Cancer Cells (PANC-1)[J]. Anticancer Res, 2017, 37 (11):6321-6327. DOI:10.21873/anticanres.12083.
    [26] Li S, Qiu L, Wu B, et al. TOFA suppresses ovarian cancer cell growth in vitro and in vivo[J]. Mol Med Rep, 2013, 8 (2):373-378. DOI:10.3892/mmr.2013.1505.
    [27] Guseva NV, Rokhlin OW, Glover RA, et al. TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status[J]. Cancer Biol Ther, 2011, 12 (1):80-85. DOI:10.4161/cbt.12.1.15721.
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Biological evaluation of PET/CT imaging agent 18F-fluoropropionic acid in hepatocellular carcinoma

    Corresponding author: Sheng Liu, liusheng_gz@126.com
    Corresponding author: Ganghua Tang, gtang0224@126.com
  • 1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation/Department of Nuclear Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
  • 2. Department of Nuclear Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
  • 3. Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
  • 4. Department of Radiation Oncology, The First Affiliated Hospital, SunYat-sen University, Guangzhou 510080, China
Fund Project:  Science and Technology Planning Project Foundation of Guangzhou 201510010145Science and Technology Foundation of Guangdong Province 2013B021800264Science and Technology Foundation of Guangdong Province 2016B090920087National Natural Science Foundation of China 81671719Science and Technology Planning Project Foundation of Guangzhou 201604020169National Natural Science Foundation of China 81571704

Abstract: Objective To evaluate the potential of 18F-fluoropropionic acid (18F-FPA) as a PET/CT tracer in the imaging of hepatocellular carcinoma (HCC) and to identify the mechanism underlying 18F-FPA uptake.Methods (1) 18F-FPA was synthesized from the precursor methyl-2-bromopropionate. (2) 18F-FPA uptake by SK-Hep 1 HCC cells was quantified in vitro at different time points. To further investigate the mechanism underlying 18F-FPA uptake, the inhibitory effects of the fatty acid synthase inhibitor Orilistat and the acetyl-CoA carboxylase inhibitor 5-tetradecyloxy-2-furoic acid on 18F-FPA uptake were observed. (3) Micro-PET/CT imaging results for 18F-FPA and 18F-FDG for mouse models of human hepatocellular carcinoma SK-Hep 1 were obtained and compared. Mthe radioactivity uptake ratios of 18F-FDA and 18F-FDG were compared and analyzed with t test.Results(1) 18F-FPA was synthesized with a yield of 45±2% through a simple process. (2) 18F-FPA uptake ratio by SK-Hep 1 cells gradually increased from (1.3±0.4)% after 5 min to (4.6 ±0.2)% after 120 min. In the cell uptake inhibition experiments, 18F-FPA uptake by SK-Hep 1 cells gradually decreased as inhibitor concentration increased. Under Orilistat and TOFA concentrations of 400 μmol, 18F-FPA uptake by SK-Hep 1 cells decreased by (40.3±4.0)% and (26.0±6.0)%, respectively. (3) 18F-FPA showed rapid and accurate tumor localization in mouse models of human hepatocellular carcinoma SK-Hep 1 with a tumor/liver ratio of 1.63±0.26. When used in 18F-FDG PET/CT imaging, the tumor/liver ratio of 18F-FPA reached 1.09±0.21. The imaging results provided by 18F-FPA were superior to those provided by 18F-FDG (t=4.055, P=0.047).Conclusion 18F-FPA can be used as an alternative radiotracer in the detection of hepatocellular carcinoma, its uptake is related to fatty acid synthesis.

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  • 近几十年来,原发性肝癌的全球发病率逐渐上升,早期发现和诊断对其治疗及预后至关重要。与大多数恶性肿瘤相比,肝癌的诊断可以完全依据影像学表现。然而,推荐用于病灶成像的增强CT或MRI的灵敏度较低,分别为76%和61%[1]18F-FDG PET可为肝脏手术、移植和姑息治疗提供有价值的预后信息,但在肝细胞癌的诊断中作用有限[2-3]。乙酸盐和胆碱能显像剂对18F-FDG显像具有重要的互补作用[4]。虽然11C-乙酸盐的摄取机制尚不清楚,但最新研究发现大多数前列腺肿瘤脂肪酸合成代谢活跃,推测这是由于肿瘤中11C-乙酸盐摄取增加,即以乙酸盐为底物合成短链脂肪酸[5]11C-乙酸盐在肝癌成像方面显示出很好的前景,但是11C的半衰期(20.4 min)短,限制了它的广泛应用。为此,开发了18F-氟乙酸(18F-fluoroacetic acid, 18F-FAC)作为11C-乙酸盐的替代物。18F-FAC的缺点在于其被骨骼大量吸收,放射性示踪剂的脱氟特性限制了它的使用[6-7]。因此,需要开发或寻找新的PET示踪剂以克服现有的缺点或补充现有的示踪剂。因此,我们制备了18F-氟丙酸(18F-fluoropropionic acid, 18F-FPA),探讨18F-FPA在人肝癌SK-Hep 1细胞中的摄取情况和在荷肝癌肿瘤模型中的显像效果,并对其摄取机制进行了初步探索。

1.   材料与方法

    1.1.   试剂与仪器

  • 人肝癌SK-Hep 1细胞系来自中国科学院细胞库(上海),无特定病原体级雄性Bclb/c裸鼠,4~6周龄,体质量20~25 g,购自广州中山大学医学院实验动物中心。4,7,13,16,21,24-六氧-1,10-二氮双环[8.8.8]二十六烷(K222)购自法国ABX公司;乙腈和二甲基亚砜(DMSO)购自美国Aldrich公司;甲基-2-溴丙酸乙酯购自阿拉丁试剂(上海)有限公司;奥利司他(Orilistat)购自美国Sigma-Alrich公司;5-十四烷氧基-2-呋喃甲酸(5-Tetradecyloxy-2-furoic acid, TOFA)购自美国Cayman Chemical公司;其余试剂均为国产分析纯或化学纯。Sep Pak QMA、C18 plus柱购自美国Waters公司;micro PET/CT显像仪购自德国Bruker公司,由中山大学中山医学院实验平台提供。

  • 1.2.   细胞培养和动物模型的建立

  • 人肝癌SK-Hep 1细胞培养基使用DMEM,采用含10%胎牛血清,于37℃、5% CO2的细胞培养箱中培养。培养基每周例行更换3次,选择处于指数增长的肿瘤细胞用于实验。所有实验均在中山大学动物实验中心批准的方案下进行,常规消毒后每只Bclb/c裸鼠腋窝皮下注射5×106个/mL肿瘤细胞100 μL,其中含细胞培养悬液50 μL、基质胶50 μL。荷人肝癌SK-Hep 1小鼠在无特定病原体级环境中培养,食物充足。每周测量2次体质量和肿瘤体积。待肿瘤体积长到500~1000 mm3时进行实验。

  • 1.3.   18F-FPA的合成

  • 18F-FPA的合成是基于文献[8]和既往的合成方法。回旋加速器通过180(p,n)18F核反应生产得到18F离子,18F离子通过QMA柱俘获后用K222溶液淋洗到反应瓶中;利用氮气在116 ℃加热条件下除去溶剂;将甲基-2-溴丙酸乙酯加入含有[18F]KF/K222的反应瓶中,在密闭的反应管内加热至100 ℃并持续15 min。冷却后,用8 mL水将中间体挂在HLB柱子上。用2 mol/L的NaOH通过HLB固相萃取小柱,室温下水解5 min。用1 mL灭菌水通过HLB-Al2O3-SCX柱将产品洗至产品瓶中,调节pH值至中性或弱酸性,用生理盐水配成溶液通过0.22 μm无菌滤膜后使用。使用高效液相色谱测定18F-FPA的放射性化学纯度。

  • 1.4.   体外实验

    1.4.1.   细胞结合实验
  • 将人肝癌SK-Hep 1细胞悬液于实验前一天铺于24孔板中(1×107个/孔),将细胞培养基倒掉,用PBS清洗细胞2次,加入18F-FPA(约2 mL,0.074 MBq/孔),于37℃、5%CO2细胞培养箱分别孵育5、30、60、90和120 min后,用PBS冲洗细胞2次,再加入1 mol/L的NaOH 500 μL,裂解20 min,收集细胞裂解液,用γ计数仪测细胞放射性活度。结果以平均值±标准差表示,每次实验重复4次。

  • 1.4.2.   细胞结合抑制实验
  • 将人肝癌SK-Hep 1细胞悬液接种于24孔板,于37℃、5%CO2培养箱中孵育1 d,将细胞培养基倒掉,用PBS清洗2次,然后将细胞悬液分为对照组和实验组,对照组加入200 μL PBS;实验组共分为5组,分别加入不同浓度梯度(25、50、100、200、400 μmol/L)的抑制剂奥利司他或TOFA 200 μL,孵育30 min后加入18F-FPA(约2 mL,0.074 MBq/孔),孵育60 min后用PBS冲洗细胞2次,用1 mol/L NaOH 500 μL,裂解20 min,收集细胞裂解液,用γ计数仪测细胞放射性活度。结果以平均值±标准差表示,每次实验重复4次。实验组得出的数据与对照组相比,观察在不同浓度的抑制剂条件下细胞对18F-FPA的摄取抑制情况。

  • 1.5.   荷人肝癌SK-Hep 1小鼠micro PET/CT显像

  • 将荷人肝癌SK-Hep 1小鼠禁食4 h,小鼠在注射放射性示踪剂前用2%戊巴比妥钠(40 mg/kg)麻醉,并在整个研究过程中保持麻醉状态,然后经尾静脉给予100~120 μL 18F-FPA溶液,约3.70~4.44 MBq。给药60 min后行全身microPET/CT显像。先行15 min的静态PET扫描,然后用CT扫描对病变部位进行校正和定位。同一只荷人肝癌SK-Hep 1小鼠,完成18F-FPA显像后放置24 h,在与18F-FPA同样的注射剂量、扫描条件下给小鼠尾静脉注射18F-FDG进行显像。使用Albira PET系统和PMOD 3.7版软件进行图像重建,由2名核医学科医师在肿瘤和肌肉组织上绘制ROI,获得肿瘤及组织器官的每克组织百分注射剂量率(ID%/g值),并对所获得的数据进行分析。

  • 1.6.   肿瘤组织苏木精-伊红法染色

  • PET/CT显像完成后,处死荷人肝癌SK-Hep 1小鼠,分离肿瘤组织,用冷的PBS溶液冲洗细胞3次,部分肿瘤组织用4%甲醛溶液浸泡,然后用石蜡切片,每片厚5 μm,脱蜡、水化,苏木精染色5 min后伊红染色2 min,在光学显微镜下观察肿瘤细胞形态。

  • 1.7.   统计学分析

  • 应用SPSS18.0软件进行统计学分析。所有数据均用平均数±标准差(x±s)表示,计数数据符合正态分布且方差齐,18F-FPA和18F-FDG在肿瘤中的放射性摄取率的比较采用t检验。P<0.05表示差异有统计学意义。

2.   结果

    2.1.   18F-FPA合成结果

  • 18F-FPA的合成在40 min内完成,经高效液相色谱分析测定,产物的放射性化学纯度>95%,比活度>37 GBq/μmol,合成最终产率为(45±2)%。

  • 2.2.   体外细胞实验结果

  • 18F-FPA在人肝癌SK-Hep 1细胞中的摄取率从5 min的(1.3±0.4)%上升到120 min的(4.6±0.2)%,30~60 min放射性摄取增加速度最快(图 1)。不同浓度梯度抑制剂奥利司他和TOFA分别对人肝癌SK-Hep 1细胞摄取抑制的实验结果见图 2。由图 2可见,随着抑制剂浓度的增高,人肝癌SK-Hep 1细胞的放射性摄取率表现出逐渐降低的趋势。与对照组比较,当抑制剂奥利司他和TOFA的浓度分别为400 μmol/L时,人肝癌SK-Hep 1细胞对18F-FPA的摄取率分别下降了(40.3±4.0)%和(26.0±6.0)%。

    Figure 1.  The cellular uptake rate of 18F-fluoropropionic acid by human hepatocellular carcinoma SK-Hep 1 cells at different time points

    Figure 2.  Different concentrations of Orilistat and TOFA presented a inbibitive effect on of 18F-fluoropropionic acid in SK-Hep 1 cells

  • 2.3.   荷人肝癌SK-Hep 1小鼠的microPET/CT显像结果

  • 荷人肝癌SK-Hep 1小鼠注射18F-FPA后行microPET/CT显像结果见图 3。由图 3可见,静脉注射18F-FPA 60 min后,microPET/CT显像显示在荷人肝癌SK-Hep 1小鼠中表现出快速且准确的肿瘤定位,相应的肿瘤摄取值为(8.15±0.13)%ID/g,肿瘤/肝放射性比值为1.63±0.26。18F-FDG PET/CT显像中,肿瘤摄取值为(3.25±0.50)%ID/g,肿瘤/肝放射性比值为1.09±0.21。18F-FPA的肿瘤/肝放射性比值高于18F-FDG,差异有统计学意义(t=4.055,P=0.047)。

    Figure 3.  micro PET/CT imaging of 18F-FDG and 18F-fluoropropionic acid in human hepatocellular carcinoma SK-Hep 1 mice

  • 2.4.   病理学结果

  • 人肝癌SK-Hep 1细胞肿瘤组织病理图见图 4。图中可见大量异性细胞,证明成功建立了肿瘤动物模型。

    Figure 4.  Histopathology of SK-Hep 1 tumor tissue(HE, ×200)

3.   讨论
  • 物质代谢异常是恶性肿瘤的重要标志,除了已知的糖酵解外,恶性肿瘤会有脂质代谢紊乱的表现[9-10]。放射性核素标记的小分子,如葡萄糖、乙酸酯、FAC已被广泛用于各种肿瘤的检测,包括肝癌、前列腺癌和乳腺癌等[11-13]18F-FDG PET可为肝脏手术、移植和姑息治疗提供有价值的预后信息,但其在肝癌诊断中的作用有限[16]11C-乙酸酯和11C-胆碱PET对肝细胞肝癌的诊断有较高的灵敏度,在18F-FDG PET/CT中联合11C-乙酸酯和11C-胆碱显像可提高诊断原发性肝癌的整体灵敏度,但也存在一些缺点和局限性。本研究对短烷基羧酸18F-FPA进行了实验研究,结果表明,18F-FPA合成简便,产率高,是一种非常有前景的肿瘤PET显像剂。本研究结果与以往研究结果相符合[15-18]

    丙酸钠、钾和钙盐通常被广泛用于食品添加剂。代谢研究表明,丙酸可作为脂肪酸、糖原、氨基酸等合成的前体。有研究结果显示,丙酸可取代乙酸,成为心脏和肿瘤细胞首选的能量基质[18]。丙酸首先由线粒体丙酰基-辅酶A合成酶催化转变为丙酰基辅酶A,这是脂肪酸代谢的第一个共同步骤[19]。在本研究的抑制细胞实验中,我们推断18F-FPA可能有类似于18F-FAC的代谢机制,参与脂肪酸代谢。奥利司他和TOFA分别抑制脂肪酸合成酶、乙酰辅酶A羧化酶[20-22]。奥利司他可以特异性地抑制脂肪酸合成酶,它对不同的肿瘤细胞的增殖有潜在的抑制作用,并可抑制肿瘤的生长[23-25]。TOFA对肝细胞、大鼠肝脏或雄性大鼠肝脏的脂肪酸合成有抑制作用,降低内源性脂肪酸从而对细胞膜磷脂组分产生影响。已有研究证明,TOFA对肺癌、结肠癌和前列腺癌细胞均有细胞毒性[26-27]。在本研究中,脂肪酸合成关键酶抑制剂能够不同程度地抑制18F-FPA在人肝癌SK-Hep 1细胞中的摄取,证明18F-FPA的摄取参与脂肪酸代谢途径。

    本研究中,18F-FPA的体外细胞摄取及荷人肝癌SK-Hep 1小鼠PET/CT显像结果表明,18F-FPA在人肝癌SK-Hep 1细胞中具有较高地摄取,且可清晰地显示肿瘤。与传统显像剂18F-FDG相比,18F-FPA具有更好的显像效果,是一种具有前景的肿瘤PET/CT显像剂。

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