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,Molecular Pharmaceutics

当前位置： X-MOL 学术 › Mol. Pharmaceutics › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

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
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-10-12 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00536
Zhide Guo _{1,

2} , Linyi You ₁ , Changrong Shi ₁ , Manli Song _{1,

3} , Mengna Gao ₁ , Duo Xu ₁ , Chenyu Peng ₁ , Rongqiang Zhuang ₁ , Ting Liu ₁ , Xinhui Su ₄ , Jin Du ₂ , Xianzhong Zhang ₁

Affiliation

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 ^99mTc 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 ^99mTc-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 ^99mTc-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.

中文翻译：

具有改进的成像对比度的新型FR靶向剂^99m Tc-HYNFA的开发以及^放射性叶酸酯修饰的多聚化和/或PEG化策略的比较

这项研究的目的是开发一种用于SPECT成像的具有新对比度的新型叶酸受体（FR）靶向剂，并评估在开发新的放射性叶酸过程中多聚和/或PEG化的修饰策略。已经合成了一系列新颖的叶酸衍生物，并使用tricine和TPPTS作为大肠菌素，并用^99m Tc进行了放射性标记。为了更好地研究其药代动力学，对细胞摄取，生物分布和microSPECT / CT成像进行了评估。孵育2和4小时后，四个放射性配体显示出高KB细胞摄取。用过量的叶酸（FA）预饱和会在KB细胞中产生明显的阻断作用，表明这些放射性配体对FR具有特异性。KB荷瘤小鼠的生物分布和microSPECT成像研究表明叶酸结合物具有聚（乙二醇）（PEG）和三唑键的^99m Tc-HYNFA表现出最高的肿瘤吸收（在小鼠生物分布中，在2 h pi时为16.30±2.01％ID / g，在4 pi pi时为14.9±0.62％ID / g）和最佳的成像对比度，表明有广阔的应用前景。更有趣的是，这种^99m Tc-HYNFA单体的体内性能比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放射性叶酸设计的可行方法。将来在基于叶酸的放射性药物的开发中应考虑PEG的连接而不是FA的多聚化。

更新日期：2017-10-13

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11