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Essentials of radionanotargeting usingoligodeoxynucleotides

机译：放射性纳米靶向用寡聚脱氧核苷酸的要点

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Antisense oligomers may be used for carrying radiation source into a specific location inside a tumour cell. Effects of radioactive labeled oligos may be exerted both via direct antisense inhibition and radiation. This radionanotargeting approach may provide several benefits to conventional treatment modalities, and radiation is minimized in adjacent tissue. In addition, a combination of radiation and antisense activity of oligodeoxynucleotide may result in synergistic interaction, as there are two different treatment modalities hitting a single mechanism of action. We have previously shown that oligonucleotide therapy is effective with internally labeled oligodeoxynucleotide phosphorothioates P-32, P-33 and S-35. Here, we review our results and discuss the role of radionanotargeting. We refer to our previous results of a large selection of radionuclides; we have calculated in vivo subcellular tissue distribution for oligodeoxynucleotide phosphorothioates using decay characteristics of ten β- and Auger-emitting radionuclides. The absorbed nuclear doses of these radiolabelled oligonucleotides were estimated in different cellular dimensions using the subcellular biodistribution data. These results indicate that Auger-emitter isotopes do not give higher absorbed cell nuclear doses than the isotopes suitable for internal labeling of oligo phosphorothioates. The best isotopes for subcellular targeting were P-33 and S-35 giving smallest variation of nuclear dose in the cell dimensions we studied (nuclear diameter 6-16 μm, cellular diameter 12-20 μm). Therefore, we conclude that radionanotargeting by oligonucleotides may provide synergistic interaction and should be carried on with short rangeβ-emitters suitable for internal labelling of oligonucleotides unless relative biological effectiveness of Auger-emitters could be remarkably improved. Further preclinical evaluation of radionanotargeting based on radio-oligos should be continued.
机译：反义寡聚物可用于将辐射源带入肿瘤细胞内部的特定位置。放射性标记的寡核苷酸可以通过直接的反义抑制和辐射来发挥作用。这种放射性纳米靶向的方法可以为常规治疗方式提供一些好处，并且可以使相邻组织的辐射最小化。另外，寡脱氧核苷酸的放射和反义活性的组合可能导致协同相互作用，因为有两种不同的治疗方式达到单一作用机理。先前我们已经表明，寡核苷酸疗法对于内部标记的寡脱氧核苷酸硫代磷酸酯P-32，P-33和S-35是有效的。在这里，我们回顾我们的结果并讨论放射性纳米靶向的作用。我们参考以前选择大量放射性核素的结果;我们利用十种发射β-和Auger的放射性核素的衰变特征计算了寡脱氧核苷酸硫代磷酸酯的体内亚细胞组织分布。使用亚细胞生物分布数据，在不同细胞尺寸中估计了这些放射性标记寡核苷酸的吸收核剂量。这些结果表明，俄歇-发射极同位素没有比适合内部标记硫代磷酸酯的同位素提供更高的吸收细胞核剂量。亚细胞靶向的最佳同位素是P-33和S-35，在我们研究的细胞尺寸（核直径6-16μm，细胞直径12-20μm）中，核剂量的变化最小。因此，我们得出结论，寡核苷酸的放射纳米靶向可能提供协同相互作用，并且应使用适合于寡核苷酸内部标记的短程β-发射子进行，除非可以显着提高俄歇发射子的相对生物学有效性。应继续进行基于放射性寡核苷酸的放射性纳米靶向的进一步临床前评估。

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