Synthesis and Characterization of PEGylated Trityl Radicals: Effect of PEGylation on Physicochemical Properties
Synthesis and Characterization of PEGylated Trityl Radicals: Effect of PEGylation on Physicochemical Properties
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聚乙二醇化三苯甲基自由基的合成和表征：聚乙二醇化对理化性质的影响
DOI：
10.1021/acs.joc.6b02590
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发表时间：
2017-01-06
影响因子：
3.6
通讯作者：
Liu, Yangping
中科院分区：
文献类型：
--
作者：
Liu, Wenbo;Nie, Jiangping;Liu, Yangping
四硫代三芳基甲基（TAM，trityl）自由基由于其独特的EPR单重态信号和高的生物稳定性，作为自旋探针在生物电子顺磁共振（EPR）光谱和成像领域受到了广泛的关注。然而，它们的体内应用受到短的血液循环寿命和与白蛋白的强结合的限制。我们以前的研究结果表明，聚乙二醇化是一种可行的方法，以克服所面临的问题，在体内应用的TAM自由基。在本研究中，我们合成了一系列新的聚乙二醇化TAM自由基（TTP 1，TPP 2，TNP 1，TNP 2，d-TNP 1和d-TNP 3）含有不同长度和数量的mPEG链。我们的研究结果发现，聚乙二醇化的模式产生的TAM自由基的物理化学性质的重要影响。树枝状PEG化TAM自由基TNP 1和TNP 2比其线性类似物TPP 1和TPP 2具有更高的水溶性和更低的自聚集敏感性。此外，树枝状PEG化TAM自由基对各种生物氧化还原剂以及在大鼠全血、肝匀浆中和在小鼠体内静脉内给药后表现出极高的稳定性。重要的是，氘代衍生物，特别是d-TNP 3，表现出优异的性质，包括尖锐的和O-2-敏感的EPR单线态信号，良好的生物相容性，和延长的动力学，在小鼠中的半衰期>= 10小时。这些PEG化的TAM自由基应该适合于在体内EPR光谱和成像中的广泛应用。
Tetrathiatriarylmethyl (TAM, trityl) radicals have attracted considerable attention as spin probes for biological electron paramagnetic resonance (EPR) spectroscopy and imaging owing to their sharp EPR singlet signals and high biostability. However, their in vivo applications were limited by the short blood circulation lifetimes and strong binding with albumins. Our previous results showed that PEGylation is a feasible method to overcome the issues facing in vivo applications of TAM radicals. In the present study, we synthesized a series of new PEGylated TAM radicals (TTP1, TPP2, TNP1, TNP2, d-TNP1, and d-TNP3) containing various lengths and numbers of mPEG chains. Our results found that the pattern of PEGylation exerts an important effect on physicochemical properties of the resulting TAM radicals. Dendritic PEGylated TAM radicals, TNP1 and TNP2, have higher water solubility and lower susceptibility for self-aggregation than their linear analogues TPP1 and TPP2. Furthermore, dendritic PEGylated TAM radicals exhibit extremely high stability toward various biological oxidoreductants as well as in rat whole blood, liver homogenate, and following in vivo intravenous administration in mice. Importantly, the deuterated derivatives, especially d-TNP3, exhibit excellent properties including the sharp and O-2-sensitive EPR singlet signal, good biocompatibility, and prolonged kinetics with half-life time of >= 10 h in mice. These PEGylated TAM radicals should be suitable for a wide range of applications in in vivo EPR spectroscopy and imaging.