Actinium-225/Bismuth-213 as Potential Leaders for Targeted Alpha Therapy: Current Supply, Application Barriers, and Future Prospects

Abstract

Alpha therapy (TAT) relies on combining alpha-emitting radionuclides with specific cell-targeting vectors to deliver a high payload of cytotoxic radiation capable of destroying tumor tissues. TAT efficacy comes from the tissue selectivity of the targeting vector, the high linear energy transfer (LET) of the radionuclide, and the short range of alpha particles in tissues. Recent research studies have been directed to evaluate TAT on a preclinical and clinical scale, including evaluating damage to tumor tissues with minimal toxic radiation effects on surrounding healthy tissues. This review highlights the use of Actinium-225/Bismuth-213 radionuclides as promising candidates for TAT. Herein, we begin with a discussion on the production and supply of [²²⁵Ac]Ac/[²¹³Bi]Bi followed by the formulation of [²²⁵Ac]Ac/[²¹³Bi]Bi-radiopharmaceuticals using different radiolabeling techniques. Finally, we have summarized the preclinical and clinical evaluation of these potential radiotheranostic agents.

Keywords: Actinium-225; Bismuth-213; cancer theranostics; radiolabeling techniques; radionuclide generator; radionuclide production; targeted alpha therapy.

Figure 1

²³³U decay chain.

Figure 2

Growth of [²¹³Bi]Bi activity from [²²⁵Ac]Ac decay after generator elution.

Figure 3

Instability of the daughter radionuclide/chelating agent complex as a result of [²²⁵Ac]Ac α-particle emission (recoil effect).

Figure 4

Chelating agents for [²²⁵Ac]Ac. (a) DOTA [38,80]. (b) MeO-DOTA-NCS [80]. (c) 2B-DOTA-NCS [80]. (d) DO3A [80]. (e) DOTPA [80]. (f) TETPA [80]. (g) DOTMP [80]. (h) DTPA [80]. (i) DTPA-p-Bn-NCS [80]. (j) PEPA [103]. (k) HEHA [104]. (l) HEHA-NCS [104]. (m) CHX-A′′-DTPA [103,105]. (n) CHX-A′′-DTPA-p-Bn-NCS [103,105]. (o) EDTA [105]. (p) t-Bucalix[4]arene-tetracarboxylic acid [24,27,106]. (q) Motexafin [24,107]. (r) L^py [24,107]. (s) Macropid [24,108]. (t) Macropa [24,108]. (u) Macropa-NCS [24,108]. (v) Bispa² [24,108]. (w) EuK-106 [24,108].

Figure 4

Chelating agents for [²²⁵Ac]Ac. (a) DOTA [38,80]. (b) MeO-DOTA-NCS [80]. (c) 2B-DOTA-NCS [80]. (d) DO3A [80]. (e) DOTPA [80]. (f) TETPA [80]. (g) DOTMP [80]. (h) DTPA [80]. (i) DTPA-p-Bn-NCS [80]. (j) PEPA [103]. (k) HEHA [104]. (l) HEHA-NCS [104]. (m) CHX-A′′-DTPA [103,105]. (n) CHX-A′′-DTPA-p-Bn-NCS [103,105]. (o) EDTA [105]. (p) t-Bucalix[4]arene-tetracarboxylic acid [24,27,106]. (q) Motexafin [24,107]. (r) L^py [24,107]. (s) Macropid [24,108]. (t) Macropa [24,108]. (u) Macropa-NCS [24,108]. (v) Bispa² [24,108]. (w) EuK-106 [24,108].