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Review
. 2024 May 11;14(7):2969-2992.
doi: 10.7150/thno.96403. eCollection 2024.

Actinium-225 targeted alpha particle therapy for prostate cancer

Anil P Bidkar  1 , Luann Zerefa  1 , Surekha Yadav  1 , Henry F VanBrocklin  1   2 , Robert R Flavell  1   2   3
Affiliations
Review

Actinium-225 targeted alpha particle therapy for prostate cancer

Anil P Bidkar et al. Theranostics. .

Abstract

Targeted alpha particle therapy (TAT) has emerged as a promising strategy for the treatment of prostate cancer (PCa). Actinium-225 (225Ac), a potent alpha-emitting radionuclide, may be incorporated into targeting vectors, causing robust and in some cases sustained antitumor responses. The development of radiolabeling techniques involving EDTA, DOTA, DOTPA, and Macropa chelators has laid the groundwork for advancements in this field. At the forefront of clinical trials with 225Ac in PCa are PSMA-targeted TAT agents, notably [225Ac]Ac-PSMA-617, [225Ac]Ac-PSMA-I&T and [225Ac]Ac-J591. Ongoing investigations spotlight [225Ac]Ac-hu11B6, [225Ac]Ac-YS5, and [225Ac]Ac-SibuDAB, targeting hK2, CD46, and PSMA, respectively. Despite these efforts, hurdles in 225Ac production, daughter redistribution, and a lack of suitable imaging techniques hinder the development of TAT. To address these challenges and additional advantages, researchers are exploring alpha-emitting isotopes including 227Th, 223Ra, 211At, 213Bi, 212Pb or 149Tb, providing viable alternatives for TAT.

Keywords: Actinium-225; alpha particle therapy; prostate cancer; targeted alpha therapy.

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Conflict of interest statement

Competing Interests: R.R.F. has filed patent application number 63/344,537 entitled “Radioimmunoconjugates and Therapeutic Uses Thereof.”

Figures

Figure 1
Figure 1
Schematic illustration of radioligand therapy molecules: A. Binding of small molecule PSMA ligands to receptor active site on the cell surface. B. Representation of the use of peptide-based targeting agents. C. Tumor-specific binding of antibodies to the extracellular domain of surface proteins.
Figure 2
Figure 2
Schematic comparison of the distance traveled and Linear Energy Transfers (LETs) of α, β particles, and Auger electrons in tumor and healthy tissues.
Figure 3
Figure 3
Decay scheme of 225Ac showing daughter isotopes, alpha, and beta particle emissions along with the energies.
Figure 4
Figure 4
Chronological sequence of significant milestones spanning from the initial identification of 225Ac to its current role in prostate cancer.
Figure 5
Figure 5
Chemical structures of the chelators used for 225Ac radiolabeling.
Figure 6
Figure 6
Summary of possible combination therapy approaches to enhance the therapeutic effect of TAT.
Figure 7
Figure 7
The decay process of 225Ac, leading to the emission of alpha particles, induces recoiling energy, subsequently causing the redistribution of daughter isotopes. A. Upon injection of the 225Ac-based TAT radiopharmaceutical, accumulation occurs in the tumor tissue. The 225Ac in circulation or tumor tissues decays, producing alpha particles along with recoiled 221Fr and 213Bi. B. The redistribution of the 213Bi contributes to nephrotoxicity.
Figure 8
Figure 8
Strategies to mitigate the toxicity of recoiled daughters. A. Use of rapid uptake and internalizing targets, B. Encapsulation of the TAT radionuclide within nanoparticles, C. pretargeting, D. Intra-tumoral administration of radioactivity via injection.
Figure 9
Figure 9
Schematic presentation of the decay series of Thorium-227 and Radium-223.
Figure 10
Figure 10
Decay scheme of Astatine-211.
See this image and copyright information in PMC

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