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Background <p>Astatine-211 (<sup>211</sup>At) is a promising radionuclide for targeted alpha therapy (TAT), yet its clinical translation is hindered by poor in vivo stability and pronounced non-target organ accumulation. The fundamental radiochemical mechanisms governing the biodistribution of free <sup>211</sup>At remain insufficiently understood, limiting rational radiopharmaceutical design.</p> Results <p>Comparative in vivo studies revealed that free <sup>211</sup>At and free iodine-131 (<sup>131</sup>I) initially share similar distribution patterns but diverge markedly thereafter, with <sup>211</sup>At exhibiting pronounced accumulation in the stomach, lungs, liver, and spleen. Experimental speciation analyses demonstrated rapid oxidation of At<sup>−</sup> to cationic intermediates in biological environments, followed by hydrolysis and colloid formation. Ultrafiltration and chromatography confirmed the generation of macromolecular species responsible for hepatosplenic retention. Co-administration of ascorbic acid (AA) partially suppressed abnormal organ uptake, supporting a redox-dependent mechanism. Density functional theory (DFT)-based Pourbaix analysis further corroborated the thermodynamic instability of At<sup>−</sup> under physiological conditions and predicted the predominance of oxidized and hydrolyzed species.</p> Conclusions <p>These results identify redox-driven speciation and subsequent hydrolysis/aggregation as key chemical processes contributing to the in vivo behavior of free <sup>211</sup>At. Understanding and controlling astatine redox chemistry is therefore critical for improving the stability, safety, and translational development of <sup>211</sup>At-based radiopharmaceuticals.</p>

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Redox-driven speciation and colloid formation contribute the in vivo chemistry and organ deposition of Astatine-211

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Xiaoxu Dong,
  • Jiaojiao Li,
  • Mumei Chen,
  • Kaiqi Zhang,
  • Xiaozheng Zhang,
  • Fengling Shan,
  • Shuai Xue,
  • Xiao Li,
  • Lan Zhang,
  • Huawei Cai,
  • Jiajun Liu,
  • Qingnuan Li

摘要

Background

Astatine-211 (211At) is a promising radionuclide for targeted alpha therapy (TAT), yet its clinical translation is hindered by poor in vivo stability and pronounced non-target organ accumulation. The fundamental radiochemical mechanisms governing the biodistribution of free 211At remain insufficiently understood, limiting rational radiopharmaceutical design.

Results

Comparative in vivo studies revealed that free 211At and free iodine-131 (131I) initially share similar distribution patterns but diverge markedly thereafter, with 211At exhibiting pronounced accumulation in the stomach, lungs, liver, and spleen. Experimental speciation analyses demonstrated rapid oxidation of At− to cationic intermediates in biological environments, followed by hydrolysis and colloid formation. Ultrafiltration and chromatography confirmed the generation of macromolecular species responsible for hepatosplenic retention. Co-administration of ascorbic acid (AA) partially suppressed abnormal organ uptake, supporting a redox-dependent mechanism. Density functional theory (DFT)-based Pourbaix analysis further corroborated the thermodynamic instability of At− under physiological conditions and predicted the predominance of oxidized and hydrolyzed species.

Conclusions

These results identify redox-driven speciation and subsequent hydrolysis/aggregation as key chemical processes contributing to the in vivo behavior of free 211At. Understanding and controlling astatine redox chemistry is therefore critical for improving the stability, safety, and translational development of 211At-based radiopharmaceuticals.