Attenuated Toxicity and Antitoxic Mechanism via Sodium Iodide Symporter Inhibition-Based Tumor-Selective Delivery in Astatine-211 Radioimmunotherapy

Astatine-211 (²¹¹At) is a promising alpha emitter for cancer treatment, wherein tumor-selective accumulation is pivotal due to its short path length. While sodium ascorbate (SA) successfully protects radioactive antibodies from reactive oxygen species (ROS)-induced denaturation, it does not reduce ²¹¹At distribution in normal organs or mitigate body weight loss. Here, we aimed to attenuate this normal organ uptake. We demonstrated that sodium perchlorate (SP), a competitive inhibitor of the sodium iodide symporter (NIS) expressed in thyroid and gastric mucosal cells, significantly reduced ²¹¹At uptake in the stomach and thyroid in ²¹¹At-radioimmunotherapy (RIT) under SA protection. This favorable biodistribution resulted in significantly milder body weight loss without attenuating the antitumor effect. The combined strategy proved feasible, with no renal toxicity and no exacerbation of transient hematotoxicity or hepatotoxicity. Crucially, NIS inhibition significantly reduced DNA double-strand breaks in stomach and thyroid tissues and helped maintain the thyroid's follicular structure. Overall, we demonstrate that combining SA protection to prevent antibody denaturation with competitive NIS inhibition by SP for greater tumor-selective ²¹¹At delivery is feasible, broadens the therapeutic window, and facilitates the clinical application of ²¹¹At-RIT in cancer treatment.