Effect of coligands on biodistribution characteristics of ternary ligand 99mTc complexes of a HYNIC-conjugated cyclic RGDfK dimer
Effect of coligands on biodistribution characteristics of ternary ligand 99mTc complexes of a HYNIC-conjugated cyclic RGDfK dimer
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DOI：
10.1021/bc0501653
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发表时间：
2005-11-01
影响因子：
4.7
通讯作者：
Mohammed, SI
中科院分区：
文献类型：
--
作者：
Liu, S;Hsieh, WY;Mohammed, SI
本文报道了三种三元配体配合物[TC-99m(SQ168)(三碱)(L)](SQ168=[2-[[[5-[carboonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu-(cyclo{Lys-Arg-Gly-ASP-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}；L=三苯基膦-3，3‘，3“-三磺酸三钠)、异烟酸(异烟酸)和2，5-吡啶二甲酸(PDA)在荷人乳腺癌裸鼠体内的分布特征。合成了三元配合物[TC-99m(SQ168)(Tricine)(L)](L=TPPTS、ISONIC和PDA)，并用反相高效液相色谱法对其进行了分析。令人惊讶的是，尽管高效液相保留时间表明[TC-99m(SQ168)(Tricine)(PDA)]和[TC-99m(SQ168)(Tricine)(ISONIC)]比[TC-99m(SQ168)(Tricine)(TPPTS)]更亲水，但配体对其三元配体Tc-99m络合物的logP值几乎没有影响。生物分布研究结果表明，~(99m)Tc标记的环状RGDfK二聚体的排泄动力学可以通过选择配基来改变。这三种放射性示踪剂在2小时的研究期间都显示出很高的肿瘤摄取能力，这表明结肠素对标记的环状RGDfK二聚体的肿瘤靶向能力的影响很小。阻断实验结果表明，99m标记的环状RGDfK二聚体的肿瘤定位是整合素α(V)β(3)介导的。根据它们的肝脏摄取和肿瘤/肝脏比率，我们认为PDA在标记HYNIC-生物分子偶联物方面优于TPPTS和ISONIC。
This report describes biodistribution characteristics of three ternary ligand complexes [Tc-99m(SQ168)(tricine)(L)] (SQ168 = [2-[[[5-[carboonyl]-2-pyridinyl]hydrazono]methyl]-benzenesulfonic acid]-Glu-(cyclo{Lys-Arg-Gly-ASP-D-Phe})-cyclo{Lys-Arg-Gly-Asp-D-Phe}; L = TPPTS (trisodium triphenylphosphine-3,3',3"-trisulfonate), ISONIC (isonicotinic acid) and PDA (2,5-pyridinedicarboxylic acid)) in athymic nude mice bearing MDA-MB-435 human breast cancer xenografts. Ternary ligand complexes [Tc-99m(SQ168)(tricine)(L)] (L = TPPTS, ISONIC and PDA) were prepared and were analyzed by a reversed HPLC method. Surprisingly, coligands have little impact on log P values of their ternary ligand Tc-99m complexes even though HPLC retention times suggest that [Tc-99m(SQ168)(tricine)(PDA)] and [Tc-99m(SQ168)(tricine)(ISONIC)] are more hydrophilic than [Tc-99m(SQ168)(tricine)(TPPTS)]. The results from biodistribution studies indicated that excretion kinetics of the Tc-99m-labeled cyclic RGDfK dimer can be modified by the choice of coligand. The fact that all three radiotracers show high tumor uptake during the 2 h study period suggests that the coligand has minimal effect on the tumor targeting capability of the Tc-99m-labeled cyclic RGDfK dimer. Results from the blocking experiment suggest that the tumor localization of the Tc-99m-labeled cyclic RGDfK dimer is integrin alpha(v)beta(3)-mediated. On the basis of their liver uptake and tumor/liver ratios, we believe that PDA has the advantage over TPPTS and ISONIC for the Tc-99m-labeling of HYNIC-biomolecule conjugates.