A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89.
A High-Denticity Chelator Based on Desferrioxamine for Enhanced Coordination of Zirconium-89.
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DOI：
10.1021/acs.inorgchem.0c01629
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发表时间：
2020-08-17
影响因子：
4.6
通讯作者：
Price EW
中科院分区：
文献类型：
--
作者：
Sarbisheh EK;Salih AK;Raheem SJ;Lewis JS;Price EW
本文报道了一种基于铁载体去铁胺（DFO）的新型高密度螯合剂。我们设计并合成了一种新的螯合剂-DFO 2-，目的是改善与放射性锆-89的配位化学和放射性标记性能。放射性核素锆-89（[89 Zr]-Zr 4+）在与蛋白质、抗体和纳米颗粒偶联时已被广泛用于正电子发射断层扫描（PET）成像。DFO 2的潜在配位数为12，这为结合大的亲氧金属离子提供了治疗诊断潜力。在合成DFO 2螯合剂和[natZr] Zr-DFO 2络合物之后，我们进行了密度泛函理论计算以研究其配位球，并进行了锆-89放射性标记实验以与“金标准”螯合剂DFO进行比较。DFO（CN = 6）被认为以六齿方式与锆配位，留下两个开放的配位位点，其中水被认为配位（总CN = 8）。DFO 2（电势CN = 12，十二齿）使锆的配位层与四个异羟肟酸基团（CN = 8）饱和，没有水直接配位的空间，并且每个螯合物仅结合单个锆原子。在用锆-89进行定量放射性标记后，对预先形成的[89 Zr]Zr-（DFO）和[89 Zr]Zr-（DFO 2）放射性螯合物进行一系列体外稳定性挑战，包括人血清、脱辅基转铁蛋白、血清白蛋白、铁、羟基磷灰石和EDTA。这些稳定性挑战的一个目的是确定DFO 2相对于DFO的增加的密度是否赋予了改善的螯合物稳定性，另一个目的是确定这些测定中的哪一个与未来的螯合剂最相关。在所有试验中，DFO 2与锆-89显示出上级的稳定性，除了铁挑战，其中DFO 2和DFO是相同的。使用沉淀分析法观察到人血清、脱铁转铁蛋白、羟基磷灰石和EDTA的稳定性存在显著差异。这些结果表明，DFO 2是锆-89螯合剂的有希望的下一代支架，并且具有使用甚至更大的放射性核素的放射化学的希望，这将扩展DFO 2到治疗诊断应用中的效用。TOC简介：DFO 2是一种新的无环螯合剂，含有6个异羟肟酸部分，潜在的配位数为12（十二齿）。这种螯合剂的潜在配位数是去铁胺（DFO，六齿）的两倍，提供了超过锆（IV）典型的标准6-8配位数的有趣的配位选择。这种额外的配位能力使DFO 2具有比DFO更优越的上级放射化学性质，如锆-89实验所证明的，并且将使具有更大放射性金属离子的治疗诊断应用成为可能。
Herein we report a new high-denticity chelator based on the iron siderophore desferrioxamine (DFO). Our new chelator — DFO2 — was designed and synthesized with the purpose of improving the coordination chemistry and radiolabeling performance with radioactive zirconium-89. The radionuclide zirconium-89 ([89Zr]-Zr4+) has found wide-usage for positron emission tomography (PET) imaging when coupled with proteins, antibodies, and nanoparticles. DFO2 has a potential coordination number of twelve, which provides theranostic potential for binding large oxophilic metal ions. Following synthesis of the DFO2 chelator and the [natZr]Zr-DFO2 complex, we performed density functional theory calculations to study its coordination sphere, and zirconium-89 radiolabeling experiments for comparisons with the “gold standard” chelator DFO. DFO (CN = 6) is thought to coordinate with zirconium in a hexadentate fashion leaving two open coordination sites where water is thought to coordinate (total CN = 8). DFO2 (potential CN = 12, dodecadentate) saturated the coordination sphere of zirconium with four hydroxamate groups (CN = 8) with no room left for water to directly coordinate, and only binds a single atom of zirconium per chelate. Following quantitative radiolabeling with zirconium-89, the preformed [89Zr]Zr-(DFO) and [89Zr]Zr-(DFO2) radiometal-chelate complexes were subjected to a battery of in vitro stability challenges including human blood serum, apo-transferrin, serum albumin, iron, hydroxyapatite, and EDTA. One objective of these stability challenges was to determine if the increased denticity of DFO2 over DFO imparted improved chelate stability, and another was to determine which of these assays is most relevant to perform with future chelators. In all assays DFO2 showed superior stability with zirconium-89, except for the iron challenge where both DFO2 and DFO were identical. Substantial differences in stability were observed for human blood serum using a precipitation method of analysis, apo-transferrin, hydroxyapatite, and EDTA. These results suggest that DFO2 is a promising next-generation scaffold for zirconium-89 chelators and holds promise for radiochemisty with even larger radionuclides, which will expand to utility of DFO2 into theranostic applications. TOC synopsis: DFO2 is a new acyclic chelator containing six hydroxamic acid moieties and a potential coordination number of twelve (dodecadentate). This chelator presents double the potential coordination number as desferrioxamine (DFO, hexadentate), providing interesting coordination options beyond the standard 6–8 coordination numbers that are typical for zirconium(IV). This additional coordinating ability has imbued DFO2 with superior radiochemical properties to DFO, as demonstrated by zirconium-89 experiments, and will enable theranostic applications with even larger radiometal ions.
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影响因子：
4.9
作者：
Adams CJ;Wilson JJ;Boros E
通讯作者：
Boros E
影响因子：
3.1
作者：
Escorcia FE;Steckler JM;Abdel-Atti D;Price EW;Carlin SD;Scholz WW;Lewis JS;Houghton JL
通讯作者：
Houghton JL
影响因子：
5.6
作者：
Jauw YW;Menke-van der Houven van Oordt CW;Hoekstra OS;Hendrikse NH;Vugts DJ;Zijlstra JM;Huisman MC;van Dongen GA
通讯作者：
van Dongen GA
DOI：
10.1039/c7cc03572a
发表时间：
2017-07-27
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Allott L;Da Pieve C;Meyers J;Spinks T;Ciobota DM;Kramer-Marek G;Smith G
通讯作者：
Smith G
影响因子：
9.3
作者：
Dijkers, Eli C. F.;Kosterink, Jos G. W.;Lub-de Hooge, Marjolijn N.
通讯作者：
Lub-de Hooge, Marjolijn N.