Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
SeeCure LLC, Kaohsiung, Taiwan.
Cancer Biother Radiopharm. 2022 Feb;37(1):30-40. doi: 10.1089/cbr.2021.0169. Epub 2021 Sep 2.
The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases. A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2'-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively. cell uptake and cell/media ratios of Tc-SC-05-L-1 and Tc- SC-05-N-1 in ER (+) ovarian cancer cells (TOV-112D and OVCAR3) were performed. To ascertain the specificity of cell uptake, the cell uptake was blocked with estrone. Tc-SC-05-L-1 or Tc-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to F-fluoro-2-deoxy-d-glucose (F-FDG) positron emission tomography/magnetic resonance imaging (a reference technology). The radiochemical purities of Tc-SC-05-L-1 and Tc-SC-05-N-1 were greater than 99% ( = 10). Tc-SC-05-L-1 had higher cell/media ratios than Tc-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of Tc-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred. Tc-SC-05-N-1 was further selected for imaging studies due to higher maximum tolerated dose and superior water solubility than Tc-SC-05-L-1. Tc-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than F-FDG in tumor-bearing rodents. Tc-SC-05-N-1 showed better differential diagnosis of ovarian tumors than F-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.
通过使用标记的抗雌激素对雌激素受体阳性（ER+）途径激活系统进行鉴别诊断有助于选择对内分泌治疗有最佳反应的患者，并在发生耐药时停止治疗。作者的目的是合成螯合剂-他莫昔芬缀合物以用于成像 ER（+）疾病。在环丙烯或环丙烯二乙酸和他莫昔芬类似物之间引入羟丙基接头，分别产生 SC-05-L-1（Z-1-（1,4,8,11-四氮杂环十四烷-1-基）-3-（（5-（4-（2-（二乙氨基）乙氧基）苯基）-4,5-二苯基戊-4-烯-1-基）氧基）丙-2-醇）和 SC-05-N-1（Z-2,2' -（4-（3-（5-（4-（2-（二乙氨基）乙氧基）苯基）-4,5-二苯基戊-4-烯-1-基）氧基）-2-羟基丙基）-1,4,8,11-四氮杂环十四烷-1,8-二基）二乙酸）。在 ER（+）卵巢癌细胞（TOV-112D 和 OVCAR3）中进行了 Tc-SC-05-L-1 和 Tc-SC-05-N-1 的细胞摄取和细胞/培养基比。为了确定细胞摄取的特异性，用雌酮阻断了细胞摄取。在荷瘤啮齿动物中进行了 Tc-SC-05-L-1 或 Tc-SC-05-N-1 单光子发射计算机断层扫描/计算机断层扫描，并与 F-氟-2-脱氧-d-葡萄糖（F-FDG）正电子发射断层扫描/磁共振成像（一种参考技术）进行了比较。Tc-SC-05-L-1 和 Tc-SC-05-N-1 的放射化学纯度均大于 99%（ = 10）。Tc-SC-05-L-1 在 OVCAR-3 ER（+）细胞中的细胞/培养基比高于 Tc-SC-05-N-1。Tc-SC-05-L-1 的细胞摄取被雌酮阻断 80%，表明发生了雌激素介导的过程。由于 Tc-SC-05-N-1 的最大耐受剂量更高且水溶性优于 Tc-SC-05-L-1，因此进一步选择 Tc-SC-05-N-1 进行成像研究。Tc-SC-05-N-1 在荷瘤啮齿动物中的肿瘤摄取和肿瘤/肌肉计数密度比 F-FDG 更高。Tc-SC-05-N-1 对卵巢肿瘤的鉴别诊断优于 F-FDG，表明螯合剂-他莫昔芬缀合物在 ER 途径导向系统成像方面具有很大的应用前景。
