Ji Shundong, Czerwinski Andrzej, Zhou Yang, Shao Guoqiang, Valenzuela Francisco, Sowiński Paweł, Chauhan Satendra, Pennington Michael, Liu Shuang
School of Health Sciences, Purdue University , West Lafayette, Indiana 47907, United States.
Mol Pharm. 2013 Sep 3;10(9):3304-14. doi: 10.1021/mp400085d. Epub 2013 Aug 6.
This study sought to evaluate [(99m)Tc(HYNIC-Galacto-RGD2)(tricine)(TPPTS)] ((99m)Tc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-D-Phe-Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-L-glycero-L-galacto-2,6-anhydro-7-deoxyheptanamide, and PEG2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3',3″-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper(I)-catalyzed 1,3-dipolar azide-alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin αvβ3 binding affinity against (125)I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. (99m)Tc-Galacto-RGD2 was prepared in high specific activity (∼ 185 GBq/μmol) and high radiochemical purity (>95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of (99m)Tc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33, and 5.61 ± 1.52%ID/g at 5, 30, 60, and 120 min p.i., respectively, which was in agreement with high integrin αvβ3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs, and spleen suggests that (99m)Tc-Galacto-RGD2 has advantages over (99m)Tc-3P-RGD2 ([(99m)Tc(HYNIC-3P-RGD2)(tricine)(TPPTS)]: 3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of (99m)Tc-Galacto-RGD2 was integrin αvβ3-specific. (99m)Tc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that (99m)Tc-Galacto-RGD2 is an excellent radiotracer for imaging integrin αvβ3-positive tumors and related metastases.
本研究旨在评估[(99m)Tc(HYNIC-半乳糖-RGD2)(tricine)(TPPTS)]（(99m)Tc-半乳糖-RGD2：HYNIC = 6-肼基烟酰基；半乳糖-RGD2 = Glu[环[精氨酸-甘氨酸-天冬氨酸-D-苯丙氨酸-赖氨酸(SAA-PEG2-(1,2,3-三唑)-1-基-4-甲基酰胺)]]2（SAA = 7-氨基-L-甘油-L-半乳糖-2,6-脱水-7-脱氧庚酰胺，PEG2 = 3,6-二氧辛酸）；TPPTS = 三苯基膦-3,3',3″-三磺酸钠）作为一种用于肿瘤成像的新型放射性示踪剂。半乳糖-RGD2通过铜(I)催化的1,3-偶极叠氮化物-炔烃胡伊斯根环加成反应制备。HYNIC-半乳糖-RGD2通过在二异丙基乙胺存在下使半乳糖-RGD2与6-(2-(2-磺基苯甲醛)腙基)烟酸琥珀酰亚胺酯（HYNIC-OSu）反应制备，并评估其对与U87MG胶质瘤细胞结合的(125)I-echistatin的整合素αvβ3结合亲和力。HYNIC-半乳糖-RGD2的IC50值测定为20±2 nM。(99m)Tc-半乳糖-RGD2以高比活度（约185 GBq/μmol）和高放射化学纯度（>95%）制备，并在携带U87MG胶质瘤异种移植物的无胸腺裸鼠中评估其肿瘤靶向能力和生物分布。(99m)Tc-半乳糖-RGD2在注射后5、30、60和120分钟时的肿瘤摄取分别为10.30±1.67、8.37±2. .13、6.86±1.33和5.61±1.52%ID/g，这与胶质瘤细胞和新生血管上高表达的整合素αvβ3一致。其在肠道、肺和脾脏中的摄取较低，表明(99m)Tc-半乳糖-RGD2在胸部和腹部区域肿瘤成像方面优于(99m)Tc-3P-RGD2（[(99m)Tc(HYNIC-3P-RGD2)(tricine)(TPPTS)]：3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2；PEG4 = 15-氨基-4,7,10,13-四氧杂十五烷酸）。U87MG肿瘤可通过SPECT轻松检测到，且(99m)Tc-半乳糖-RGD2的肿瘤摄取具有整合素αvβ3特异性。(99m)Tc-半乳糖-RGD2还具有非常高的代谢稳定性。基于本研究结果，得出结论：(99m)Tc-半乳糖-RGD2是用于成像整合素αvβ3阳性肿瘤及相关转移灶的优秀放射性示踪剂。
