Targeted Alpha Therapy: Progress in Radionuclide Production, Radiochemistry, and Applications

Abstract

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including ²²⁵Ac, ²¹³Bi, ²²⁴Ra, ²¹²Pb, ²²⁷Th, ²²³Ra, ²¹¹At, and ¹⁴⁹Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT.

Keywords: actinium-225; alpha particle therapy; astatine-211; bismuth-213; radium-223; targeted alpha therapy; targeted radionuclide therapy; terbium-149; theranostics; thorium-227.

Figure 1

Key aspects of targeted alpha therapy: (a) radionuclide production via cyclotron, nuclear reactor or generator decay, and shielded automated processing; (b) radiolabeling the alpha-emitting radionuclide to a suitable targeting vector to form a bioconjugate; and (c) targeted alpha radiotherapy precisely destroys tumor cells while sparing surrounding healthy tissue.

Figure 2

Decay chains of some common therapeutic α-emitters. Reproduced from [6], Frontiers, 2014.

Figure 3

Several commonly employed radiometal chelators.

Figure 4

(A) Tumor sizes of control and [²²⁵Ac]Ac-E4G10 treated glioblastoma-bearing mice before and after 10 days, imaged by MRI. (B) Mean tumor volumes for control and [²²⁵Ac]Ac-E4G10-treated mice. Reproduced from [81], JNM, 2016.

Figure 5

Survival curve of mice injected with 5T33 cells at day 0. 3.7 MBq of ²¹³Bi-9E7.4 antibodies was injected for alpha therapy (n = 20), and NaCl was injected into the control group (n = 44). Reproduced from [96], Frontiers, 2015.

Figure 6

(A,B) Maximal intensity projections and (C) sections of positron emission tomography (PET)/CT images of an AR42J tumor-bearing mouse 2h after injection with 7 MBq of [¹⁴⁹Tb]Tb-DOTANOC. Reproduced from [59], Frontiers, 2017.

Figure 7

[⁶⁸Ga]Ga-PSMA-11 PET/CT scans of a patient with castration-resistant prostate cancer (CRPC). (A) Initial tumor burden (B) Progression despite 2 cycles of β⁻-emitting [¹⁷⁷Lu]Lu-PSMA-617 (C,D) Impressive decrease in tumor burden after two cycles of α-emitting [²²⁵Ac]Ac-PSMA-617. Reproduced from [6], Frontiers, 2014.

Figure 8

(a) Patient with an extensive liver metastases tumor burden imaged with [⁶⁸Ga]Ga-DOTATOC. (b) After injection of 10.5 GBq of [²¹³Bi]Bi-DOTATOC, liver metastases shrunk significantly. Reproduced from [75], Springer, 2014.

Figure 9

(a) Deeply infiltrating squamous cell carcinoma of the scalp showing complete response to diffusing alpha emitters therapy (DaRT) by day 30. (b) Kaplan-Meier local progression-free survival stratified by complete and partial response. Reproduced with permission from Popovtzer, A., published by Elsevier, 2020 [94].