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

Abstract

Besides external high-energy photon or proton beam therapy, targeted radionuclide therapy (TRNT) is an alternative approach to deliver radiation to cancer cells. TRNT is distributed within the body by the vascular system and allows targeted irradiation of a primary tumor and all its metastases, resulting in substantially less collateral damage to normal tissues as compared to ex-ternal beam radiotherapy (EBRT). It is a systemic cancer therapy, tackling systemic spread of the disease, which is the cause of death in most cancer patients. The α-emitting radionuclide bis-muth-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 will provide an overview of preclinical and clinical studies involving 213Bi-radiopharmaceuticals, as well as the future perspectives of this promising cancer treatment option.

Thermodynamic and Kinetic Features of Bi3+ Complexes with the Azamacrocycles H4BATA and H4DOTA

“…The fact that no noticeable dissociation of the Bi 3+ complex with H 4 DOTA was observed at room temperature at pH 1 can be explained by the slow dissociation kinetics of the complex at room temperature, because of which thermodynamic equilibrium under these conditions we not achieved even after several days. This conclusion is consistent with the observations in biological media found in the literature: the Bi 3+ complex with H 4 DOTA is more resistant to transchelation by biomolecules in vivo than, for example, the Bi 3+ complex with H 5 DTPA [39] despite the fact that the thermodynamic stability constant of the [BiDOTA] − is lower than the stability constant of the [BiDTPA] 2− . Another explanation of the high stability of the Bi 3+ complex with H 4 DOTA is the possible existence of protonated forms of the complex at an acidic pH, for which the stability constants have not been determined yet.…”

Neuroendocrine tumor theranostics

“…Alpha‐emitters have received widespread attention as therapeutic drugs for cancer treatment. Alpha particles, consisting of two protons and two neutrons, show a short penetration depth (40‐80 µm, corresponding to 2‐10 cells) and a high‐energy linear transfer compared with beta particles, which then produces minimal damage to the healthy tissue and a high rate of double‐stranded and cluster DNA breaks in cancer cells 62 …”

“…Alpha particles, consisting of two protons and two neutrons, show a short penetration depth (40-80 µm, corresponding to 2-10 cells) and a high-energy linear transfer compared with beta particles, which then produces minimal damage to the healthy tissue and a high rate of double-stranded and cluster DNA breaks in cancer cells. 62 The effect of alpha particles is independent of cell oxygenation, and hypoxic cancer tissue could be resistant to beta particles. Actinium-225 ( 225 Ac, Table 1) is a pure alpha-emitter and is believed to be a promising treatment nucleotide.…”

Rapid EElution of ²²⁶Th from a Two-Column ²³⁰U/²²⁶Th Generator with Diluted and Buffer Solutions

“…A rapid cascade of four α-particles initiated by 226 Th decay deposits totally 27.7 MeV, while 213 Bi emits only one α-particle with an energy of 8.4 MeV. 226 Th-radiopharmaceuticals can be effective for therapy of epithelial or easily accessible tumors [21]. Radioimmunoconjugates Nimotuzumab-p-SCN-Bn-DTPA(DOTA) were synthesized in our previous paper and their specificity towards EGFR overexpressing epidermoid carcinoma A431 cells has been demonstrated [22].…”