Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

Abstract

This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as in vivo alpha-particle generators. It discusses the production of radionuclides like ²¹¹At, ²²³Ra, ²²⁵Ac/²¹³Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.

Keywords: 223Ra; actinium; alpha particle; astatine; bismuth; decay; in vivo generators; nuclear recoil; radium; targeted alpha therapy.

Figure 1

(a) Log/log plot of linear-energy transfer (LET) of α particles and ²¹⁹Rn ions vs. their path (distance) in water up to the rest; (b) Semi-log 3D plot of final at rest positions of α particles and ²¹⁹Rn ions with their xy, xz and yz plane projections. The recoil, in fact, travels in opposite direction to the emitted α particle (common decay-event origin at x,y,z = 0,0,0).

Figure 2

Chemical formulas of cyclic chelators.

Figure 3

Chemical formulas of TCMC and CHXA”-DTPA chelators.

Figure 4

Selected pharmacokinetics of ²¹³Bi-DOTATATE in H69 (A–C) and CA20948 (D–F) tumor-bearing animals: uptake in tumors (A,D) and kidney (B,E), and radioactivity in blood (C,F) [63].

Figure 5

⁶⁸Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) scans of a patient comparing the initial tumor spread (A); restaging after 2 cycles of β⁻ emitting ¹⁷⁷Lu-PSMA-617 reveals progression (B). In contrast, restaging after second (C) and third (D) cycles of α emitting ²²⁵Ac-PSMA-617 shows impressive response. This research was originally published in JNM. Kratochwil et al. ²²⁵Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J. Nucl. Med. 2016, 57(12), 1941–1944. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. [4].