Development of a New FR-Targeting Agent 99mTc-HYNFA with Improved Imaging Contrast and Comparison of Multimerization and/or PEGylation Strategies for Radio-Folate Modification
Development of a New FR-Targeting Agent 99mTc-HYNFA with Improved Imaging Contrast and Comparison of Multimerization and/or PEGylation Strategies for Radio-Folate Modification
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DOI：
10.1021/acs.molpharmaceut.7b00536
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Zhang, Xianzhong
中科院分区：
文献类型：
--
作者：
Guo, Zhide;You, Linyi;Zhang, Xianzhong
本研究旨在开发一种新的叶酸受体（FR）靶向剂，用于SPECT成像，提高对比度，并评估多聚化和/或聚乙二醇化的修饰策略，在新的放射性叶酸的发展。以三羟甲基甘氨酸和TPPTS为共配体，合成了一系列新型叶酸衍生物，并进行了~（99）Tc标记。为了更好地研究其药代动力学，评价了细胞摄取、生物分布和microSPECT/CT成像。4种放射性配体在孵育2和4 h后显示高KB细胞摄取。用过量叶酸（FA）预饱和导致KB细胞中的显著阻断效应，表明这些放射性配体对FR的特异性。在KB荷瘤小鼠中的生物分布和microSPECT成像研究显示，具有聚（乙二醇）（PEG）和三唑键的叶酸缀合物Tc-99 m-HYNFA显示出最高的肿瘤摄取（在2 h p.i.和14.9 +/-0.62%ID/g，在4 h p.i.在小鼠体内的生物分布）和最佳的成像对比度，显示了良好的应用前景。更有趣的是，这种单体Tc-99 m-HYNFA的体内性能比FA多聚体和非PEG化单体的体内性能好得多，这表明多聚化可能不是设计放射性叶酸的可行方法。在未来叶酸类放射性药物的开发中，应考虑PEG连接而不是FA多聚化。
This study aims to develop a new folate receptor (FR)-targeting agent for SPECT imaging with improved contrast and evaluate the modification strategies of multimerization and/or PEGylation in the development of new radio-folates. A series of novel folate derivatives have been synthesized and radiolabeled with Tc-99m using tricine and TPPTS as coligands. To better investigate their pharmacokinetics, cell uptake, biodistribution, and microSPECT/CT imaging were evaluated. Four radioligands displayed high KB cell uptake after incubation for 2 and 4 h. Presaturated with excess folic acid (FA) resulted in a significant blocking effect in KB cells, indicating specificity of these radioligands toward FR. Biodistribution and microSPECT imaging studies in KB tumor-bearing mice showed that the folate conjugate Tc-99m-HYNFA with poly(ethylene glycol) (PEG) and triazole linkage displayed the highest tumor uptake (16.30 +/- 2.01 %ID/g at 2 h p.i. and 14.9 +/- 0.62 %ID/g at 4 h p.i. in mice biodistribution) and best imaging contrast, indicating promising application prospect. More interestingly, the in vivo performance of this monomeric Tc-99m-HYNFA was much better than that of FA multimers and non-PEGylated monomers, suggesting that multimerization may not be a feasible method for the design of radio-folates. PEG linkage rather than FA multimerization should be taken into consideration in the development of folate-based radiopharmaceuticals in the future.