Coordination Confinement on the Decay Chains of Typical Medical α-Radionuclides

The daughter nuclides in the long decay chain have clouded the translation of the corresponding α-radionuclide therapy. To achieve radioactivity confinement is, therefore, pivotal to the development of medical α-radiopharmaceuticals. Here, we proposed coordination confinement on the decay chains of medical α-radionuclides, employing a versatile crown-ether ligand to adaptively chelate with the decay daughters of typical medical α-radionuclides. The coordination interaction between dibenzo-18-crown-6 (dibenzo-18Cr6) and the decay daughters, i.e., Fr (²²¹Fr), At (²¹⁷At), Bi (^211-213Bi), Po (^211-213Po, ^215-216Po), Tl (^207-209Tl), and Pb (^{207-209, 212/213}Pb), from the decay chains of ²¹²Pb/²¹²Bi, ²¹³Bi, ^223/224Ra, and ²²⁵Ac, has been probed through combined computational and experimental chemistry, and all the results suggest that dibenzo-18Cr6 can form a nuclide trap as a multifunctional chelator to capture different decay daughters. Most importantly, dibenzo-18Cr6-mediated coordination confinement on the decay daughters in vivo has been demonstrated via an ²²⁵Ac-labeled radiopharmaceutical, highlighting excellent tumor suppression effects and reliable safety. This work unveils the great potential of decay-chain-adaptive coordination in improving the biosafety of targeted α-therapy, particularly in addressing the unwanted migration of daughter radionuclides of α-emitting endoradiotherapy in clinical practice.