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首页> 外文期刊>Chemistry: A European journal >Release of Toxic Gd~(3+) Ions to Tumour Cells by Vitamin B_(12) Bioconjugates
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Release of Toxic Gd~(3+) Ions to Tumour Cells by Vitamin B_(12) Bioconjugates

机译：维生素B_（12）生物结合物将有毒Gd〜（3+）离子释放至肿瘤细胞

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摘要

Two probes consisting of vitamin B_(12) (CNCbl) conjugated to Gd chelates by esterification of the ribose 5’-OH moiety, Gd–DTPA–CNCbl (1; DTPA=diethylenetriamine- N,N,N’,N’’,N’’-pentaacetic acid) and Gd–TTHA–CNCbl (2; TTHA=tri- ethylenetetramine-N,N,N’,N’’,N’’’,N’’’-hexaacetic acid), have been synthesised and characterised. The crystal structure of a dimeric form of 1, obtained by crystallisation with an excess of GdCl_3, has been determined. The kinetics of binding to and dissociation from transcobalamin II show that 1 and 2 maintain high-affinity binding to the vitamin B_(12) transport protein. Complex 2 is very stable with respect to Gd~(3+) release owing to the saturated co-ordination of the Gd~(3+) ion by four amino and five carboxylate groups. Hydrolysis of the ester functionality occurs on the time scale of several hours. The lack of saturation and the possible involvement of the ester functionality in co-ordination result in lower stability of 1 towards hydrolysis and in a considerable release of Gd~(3+) in vitro. Gd~(3+) ions released from 1 are avidly taken up by the K562 tumour cells to an extent corresponding to approximately 10~(10) Gd~(3+) per cell. The internalisation of toxic Gd~(3+) ions causes a marked decrease in cell viability as assessed by Trypan blue and WST-1 tests. On the contrary, the experiments with the more stable 2 did ot show any significant cell internalisation of Gd3+ ions and any influence on cell viability. The results point to new avenues of in situ generation of cytotoxic pathways based on the release of toxic Gd~(3+) ions by vitamin B_(12) bioconjugates.
机译：两种由通过核糖5'-OH部分的酯化作用结合到Gd螯合物上的维生素B_（12）（CNCbl）组成的探针，Gd-DTPA-CNCbl（1; DTPA = diethylenetriamine- N，N，N'，N''，已合成了N''-五乙酸和Gd-TTHA-CNCbl（2; TTHA =三亚乙基四胺-N，N，N'，N''，N'''，N'''-六乙酸）和表征。已确定通过与过量的GdCl_3结晶获得的二聚体形式1的晶体结构。与反钴胺素II结合和解离的动力学表明，1和2保持与维生素B_（12）转运蛋白的高亲和力结合。由于Gd_（3+）离子被四个氨基和五个羧酸酯基团饱和配位，因此配合物2对Gd_（3+）的释放非常稳定。酯官能团的水解在几个小时的时间范围内发生。饱和度的缺乏和酯官能团可能参与配位导致1对水解的稳定性降低，并在体外大量释放Gd〜（3+）。从1释放的Gd〜（3+）离子被K562肿瘤细胞狂热吸收，其程度相当于每个细胞大约10〜（10）Gd〜（3+）。有毒的Gd〜（3+）离子的内在化会导致细胞活力的显着下降，这是通过台盼蓝和WST-1试验评估得出的。相反，使用更稳定的2进行的实验并未显示Gd3 +离子的任何显着细胞内在化以及对细胞活力的任何影响。结果表明，基于维生素B_（12）生物结合物释放有毒的Gd〜（3+）离子，可就地产生细胞毒性途径的新途径。

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