Emergence of a barium metal-organic framework for mitigating off-target effects of alpha radionuclide therapy

<b>Background:</b> ²²⁴Ra, an alpha-emitting radionuclide with a half-life of 3.63 d, holds significant promise in cancer therapy. However, like many other medical alpha-emitters, the development of ²²⁴Ra radiopharmaceuticals has long been impeded by dosimetry limitation caused by the off-target toxicity, which is tightly related to the secondary radioactivity biodistribution. <b>Methods:</b> In this work, we propose leveraging radionuclide trap preorganized in nanoscale barium-based metal-organic framework (AEMOF-6) to overcome the off-target effects of ²²⁴Ra therapy. Functional side chains with high binding affinity towards ²²⁴Ra and its decay daughters were preinstalled inside the cavity of nanoscale AEMOF-6, constructing radionuclide trap capable of inhibiting the radioactivity leaking effectively. <b>Results:</b> The ²²⁴Ra-labeled radiopharmaceutical ²²⁴Ra-AEMOF-6@CS demonstrates effective <i>in vivo</i> radioactivity localization ability, significant antitumor efficacy, and favorable biosafety. It was obtained with a radiochemical yield of 92.87% and a radiochemical purity of 94.75%, maintaining over 87% <i>in vitro</i> stability throughout the observation period. Integrated micro-PET/CT and micro-SPECT/CT imaging, complemented by biodistribution analyses, validated the robust stability and radioactivity localization capability of the AEMOF-6@CS nanocarrier <i>in vivo</i>. A dose-dependent antitumor effect accompanied by excellent biosafety was observed, achieving complete tumor eradication in 20%, 40%, and 60% of mice at 36 d after injection of 18.5, 37.0, and 55.5 kBq of ²²⁴Ra-AEMOF-6@CS, respectively. <b>Conclusion:</b> This discovery provides a potential approach to address the challenges of radioactivity migration of ²²⁴Ra radiopharmaceuticals <i>via</i> radionuclide trap preorganized in nanoscale MOFs, which can also be beneficial to other alpha-emitting radiopharmaceuticals.