Progress in the application of ¹⁷⁷Lu- and ²²⁵Ac-targeted radionuclide therapy in pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by the limited efficacy of current therapies and an urgent need for novel treatment strategies. Targeted radionuclide therapy (TRT) enables the selective delivery of radionuclides to tumor sites via specific ligands, integrating molecular targeting with cytotoxic radiation. Among these radionuclides, ¹⁷⁷Lu, a β-emitter with moderate energy and suitable tissue penetration, offers a distinct advantage in theranostics, whereas ²²⁵Ac, an α-emitter with high linear energy transfer (LET) and an ultrashort path length, demonstrates superior efficacy against hypoxic and treatment-resistant tumor cells. Although no TRT agents have yet been approved for PDAC, multiple emerging targets are under active investigation, with several candidates entering early-phase clinical trials. This review systematically summarizes recent advances in ¹⁷⁷Lu- and ²²⁵Ac-labeled radiopharmaceuticals for PDAC, comparing their physicochemical properties, biological effects, and translational potential. Future perspectives for TRT development are also discussed to facilitate its clinical application in PDAC.