To explore stem-cell-targeted radioimmunotherapy with α-particles in acute myelogenous leukemia (AML), pharmacokinetics and dosimetry of the ²¹¹At-labeled anti-C-X-C chemokine receptor type 4 monoclonal antibody (²¹¹At-CXCR4 mAb) were conducted using tumor xenografted mice. The biological half-life of ²¹¹At-CXCR4 mAb in blood was 15.0 h. The highest tumor uptake of 5.05%ID/g with the highest tumor-to-muscle ratio of 8.51 ± 6.14 was obtained at 6 h. Radiation dosimetry estimated with a human phantom showed absorbed doses of 0.512 mGy/MBq in the bone marrow, 0.287 mGy/MBq in the kidney, and <1 mGy/MBq in other major organs except bone. Sphere model analysis revealed 22.8 mGy/MBq in a tumor of 10 g; in this case, the tumor-to-bone marrow and tumor-to-kidney ratios were 44.5 and 79.4, respectively. The stem-cell-targeted α-particle therapy using ²¹¹At-CXCR4 mAb for AML appears possible and requires further therapeutic studies.

Actinium-225 (²²⁵Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although ²²⁵Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free ²²⁵Ac can be released from the drugs and that such free ²²⁵Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of ²²⁵Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free ²²⁵Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free ²²⁵Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced ²²⁵Ac uptake, with an estimated human absorbed dose of 4.76 Sv_RBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced ²²⁵Ac retention in the liver (22% and 30%, respectively). Significant ²²⁵Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free ²²⁵Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free ²²⁵Ac.