²¹¹At radiolabeled APBA-FAPI for enhanced targeted-alpha therapy of glioma

Fibroblast activation protein-α (FAPα) is highly expressed in tumor-associated cells and has become one of the most attractive targeting sites in cancer diagnosis and therapy. To ameliorate the rapid metabolism of FAPα inhibitor (FAPI), here, a multifunctional binding agent was introduced to simultaneously achieve ²¹¹At radiolabeling and tumor retention prolongation of corresponding radiolabeled drug. ²¹¹At-APBA-FAPI was successfully synthesized by conjugating ²¹¹At with the designed FAPI carrier in satisfactory radiochemical yield (>60 %). ²¹¹At-APBA-FAPI exhibited excellent in vitro stability, significant tumor affinity and specific killing effect on FAPα-positive U87MG cells. Molecular docking reveals that FAPI decorated with albumin binder can bind with FAPα protein via multiple intermolecular interactions with a considerable binding energy of -9.66 kcal/mol ²¹¹At-APBA-FAPI exhibits good targeting in murine xenograft models, showing obviously longer tumor retention than previously-reported radioastatinated compound. As a result, ²¹¹At-APBA-FAPI presents pronounced therapeutic effect with ignorable normal organs/tissues biotoxicity. All these indicate that introducing a multifunctional binding agent can effectively enhance the availability of FAPI for ²¹¹At conjugation and tumoricidal effect, providing vital hints for the translation of targeted-alpha therapy based on radiolabeled FAPI derivatives.