Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside

Abstract

In contrast to external high energy photon or proton therapy, targeted radionuclide therapy (TRNT) is a systemic cancer treatment allowing targeted irradiation of a primary tumor and all its metastases, resulting in less collateral damage to normal tissues. The α-emitting radionuclide bismuth-213 (²¹³Bi) has interesting properties and can be considered as a magic bullet for TRNT. The benefits and drawbacks of targeted alpha therapy with ²¹³Bi are discussed in this review, covering the entire chain from radionuclide production to bedside. First, the radionuclide properties and production of ²²⁵Ac and its daughter ²¹³Bi are discussed, followed by the fundamental chemical properties of bismuth. Next, an overview of available acyclic and macrocyclic bifunctional chelators for bismuth and general considerations for designing a ²¹³Bi-radiopharmaceutical are provided. Finally, we provide an overview of preclinical and clinical studies involving ²¹³Bi-radiopharmaceuticals, as well as the future perspectives of this promising cancer treatment option.

Keywords: bifunctional chelator; bismuth-213; radiopharmaceutical; targeted alpha therapy; targeted radionuclide therapy; vector molecule.

Figure 1

General concept of TRNT. ROS = reactive oxygen species, SSB = single strand break, DSB = double strand break, APC = antigen presenting cells, CD6 = cluster of differentiation 6. The DNA structure was reproduced from Gill and Vallis 2019, with permission from the Royal Society of Chemistry [9], Royal Society of Chemistry, 2019.

Figure 2

Decay chain of thorium-229 to ²²⁵Ac and ²¹³Bi.

Figure 3

(A) Production routes for ²²⁵Ac and (B) the ²²⁵Ac/²¹³Bi generator.

Figure 4

Some structures of bifunctional chelators currently used for ²¹³Bi (A) DTPA and 1B4M-DTPA (B) CHX-A’’-DTPA, (C) DOTA, (D) Me-DO2PA, (E) PEPA, (F) H4neunpa, (G) 3p-C-NETA (H) 3p-C-DEPA and (I) C-NE3TA.

Figure 5

Crystal structure of NaBiDOTA·H₂O. Reprinted (adapted) from E. Brücher et al., 2003, with permission from [58]; American Chemical Society, 2003.

Figure 6

The size of the vector molecule determines the residence time of blood, tumor accumulation, radiotoxicity, target-to-blood ratio, and imaging contrast of the radiopharmaceutical. Image was adapted from Hong H. et al., 2008 and modified with permission from [79], SAGE Journals, 2008.