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

Background: 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. Methods: 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. Results: The ²²⁴Ra-labeled radiopharmaceutical ²²⁴Ra-AEMOF-6@CS demonstrates effective in vivo 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% in vitro 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 in vivo. 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. Conclusion: This discovery provides a potential approach to address the challenges of radioactivity migration of ²²⁴Ra radiopharmaceuticals via radionuclide trap preorganized in nanoscale MOFs, which can also be beneficial to other alpha-emitting radiopharmaceuticals.