Astatine-211 and actinium-225: two promising nuclides in targeted alpha therapy

Abstract

Nuclear medicine therapy offers a promising approach for tumor treatment, as the energy emitted during radionuclide decay causes irreparable damage to tumor cells. Notably, α-decay exhibits an even more significant destructive potential. By conjugating α-nuclides with antibodies or small-molecule inhibitors, targeted alpha therapy (TAT) can enhance tumor destruction while minimizing toxic side effects, making TAT an increasingly attractive antineoplastic strategy. Astatine-211 (211At) and actinium-225 (225Ac) have emerged as highly effective agents in TAT due to their exceptional physicochemical properties and biological effects. In this review, we highlight the applications of 211At-/225Ac-radiopharmaceuticals, particularly in specific tumor targets, such as prostate-specific membrane antigen (PSMA) in prostate cancers, cluster of differentiation (CD) in hematological malignancies, human epidermal growth factor receptor-2 (HER2) in ovarian cancers, and somatostatin receptor (SSTR) in neuroendocrine tumors. We synthesize the progress from preclinical and clinical trials to provide insights into the promising potential of 211At-/225Ac-radiopharmaceuticals for future treatments.

1. Introduction

From 1991 to 2021, the cancer mortality rate had a notable reduction of 33%. However, the incidence of cancer continues to increase, with malignant tumors being the second most formidable health threat to humans [1]. Nuclear therapy, particularly radioimmunologic drugs and small-molecule inhibitors, is a promising approach for treating small, diffuse, and micrometastatic tumors. The study of radioactivity originated in 1895 with Roentgen's discovery of X-rays, and groundbreaking discoveries such as the identification of natural radiation, α-rays, and artificial radioactivity laid the foundation for synthesizing and utilizing radionuclides. The use of iodine-131 (131I) marked a pivotal milestone in radiation diagnosis and therapy, and various β-/γ-nuclides, such as fluorine-18 (18F), yttrium-90 (90Y), gallium-68 (68Ga), iodine-125 (125I), iodine-131 (131I) and lutetium-177 (177Lu), have promoted significant advancements in nuclear medicine. Although radium-223 (223Ra) remains the sole α-nuclide approved by the Food and Drug Administration (FDA) for commercial use so far, targeted alpha therapy (TAT) holds immense clinical importance.

Firstly, α-nuclides decay releases energy ranging from 4 to 8 MeV within a limited range of approximately 100 μm, leading to high energy deposition, and the peak relative biological effect (RBE) occurs when the linear energy transfer (LET) approaches ~100 keV/μm [2–4]. Secondly, the average ionization path length of α-particles in cells is closely comparable to the diameter of the deoxyribonucleic acid (DNA) double helix, potentially resulting in irreparable damage to genetic material. Moreover, their cytotoxicity remains unaffected mainly by dose or oxygen level, rendering them highly effective at eliminating hypoxic tumor cells [5]. So α-nuclides are predominantly employed in therapeutic applications, whereas β-particles serve dual roles in diagnosis and treatment. Their energy ranges from 30 keV to 2.3 MeV, with a path length of 0.05 to 12 mm; the low LET of approximately 0.2 keV/μm causes sparse single- and double-strand breaks in DNA. Currently, the utilization of 18F and 68Ga in imaging diagnostics has reached a relatively advanced stage, while 131I is widely applied for treating thyroid diseases. Additionally, a phase III trial involving 831 patients with metastatic castration-resistant prostate cancer (mCRPC) demonstrated that 177Lu-PSMA-617 significantly prolonged their survival [6].

To increase the enrichment of radiopharmaceuticals in tumors, researchers have coupled α-nuclides with antibodies or small-molecule inhibitors via succinimidyl N-2-(4-211At-phenylethyl) succinamate (SAPS), closo-decaborate (2-) (B10), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), their derivatives, and other specific chelators (Figure 1). Radiopharmaceuticals exhibit increased potential as our understanding of tumor molecular mechanisms intensifies and novel targeted vectors arise. Astatine-211 (211At), bismuth-212 (212Bi), lead-212 (212Pb), bismuth-213 (213Bi), thorium-227 (227Th), and actinium-225 (225Ac) have been evaluated in preclinical and clinical studies on the basis of the appropriate half-life, minimally toxic decay products, and relatively uncomplicated production circumstances [7]. Herein, we present a brief overview of the targets and indications for 211At-/225Ac-radiopharmaceuticals, review relevant preclinical studies and clinical trials, and delineate advancements in targeted 211At/225Ac complexes over the past decade. Our objective is to serve as a reference for future research and clinical translation.