自组装铁(III)配位笼作为MRI活性载体用于金(I)药物

Self-Assembled Iron(III) Coordination Cage as an MRI-Active Carrier for a Gold(I) Drug

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BIOCONJUGATE CHEMISTRY

影响因子:3.9

分区:化学2区 / 生化研究方法2区有机化学2区生化与分子生物学3区化学：综合3区

发表日期:2024 Sep 20

作者: Priya Ranjan Sahoo, Joseph A Spernyak, Steven G Turowski, Janet R Morrow

DOI: 10.1021/acs.bioconjchem.4c00391

摘要

一种基于具有四个铁(III)中心的自组装配位笼的T1 MRI探针，作为金(I)抗癌药物Au(PEt3)Cl水解产物的载体。对包裹在配位笼的二氟镓(III)类似物（Ga(III)模拟物）中的金复合物进行的1H核磁共振（NMR）表征显示，失去氯离子形成水合金(Au(PEt3)(OH2)+)，很可能在笼内形成。该金复合物在Ga(III)笼中表现出pH依赖的物种变化，在微酸性pH条件下从Ga(III)和Fe(III)笼中释放。与人血清白蛋白（HSA）共同存在时，包裹金复合物的NMR研究表明其在Ga(III)笼中能保持数小时，不易释放，也不与HSA的半胱氨酸残基结合。MRI显示，含有包裹金复合物的Fe(III)笼增强血管造影对BALB/c小鼠中的CT26肿瘤的摄取。铁(III)笼能够使金复合物溶解，便于静脉注射，而游离复合物必须腹腔注射。经体外分析，1-48小时内，包裹和游离的金复合物在肿瘤中均有积累。与游离复合物相比，包裹在Fe(III)笼中的金复合物在小鼠体内的组织分布有所调节，验证了笼作为载体的功能。

Abstract

A T1 MRI probe based on a self-assembled coordination cage with four iron(III) centers acts as a host for the hydrolysis product of the gold(I) anticancer drug, Au(PEt3)Cl. 1H NMR characterization of the gold complex encapsulated within the diamagnetic Ga(III) analog of the coordination cage is consistent with loss of chloride to give aquated gold complex, most likely [Au(PEt3)(OH2)]+ within the cage. The gold complex undergoes pH-dependent speciation changes in the Ga(III) cage and is released at mildly acidic pH from both the Ga(III) and Fe(III) cages. NMR spectroscopy studies of the encapsulated gold complex in the presence of human serum albumin (HSA) show that the gold complex remains inside of the Ga(III) cage for several hours, resisting release and binding to cysteine residues of HSA. The Fe(III) cage with encapsulated gold complex shows enhanced contrast of the vasculature and uptake into CT26 tumors in BALB/c mice as shown by MRI. The gold complex is solubilized by the iron(III) cage for intravenous injection, whereas the free complex must be injected intraperitoneally. Gold complex accumulates in the tumor for both caged and free complex over 1-48 h as measured by ex-vivo analysis. Encapsulation in the Fe(III) cage modulates the biodistribution of the gold complex in mice in comparison to the free complex, consistent with the function of the cage as a carrier.