Alpha-Emitters and Targeted Alpha Therapy in Oncology: from Basic Science to Clinical Investigations

Abstract

Alpha-emitters are radionuclides that decay through the emission of high linear energy transfer α-particles and possess favorable pharmacologic profiles for cancer treatment. When coupled with monoclonal antibodies, peptides, small molecules, or nanoparticles, the excellent cytotoxic capability of α-particle emissions has generated a strong interest in exploring targeted α-therapy in the pre-clinical setting and more recently in clinical trials in oncology. Multiple obstacles have been overcome by researchers and clinicians to accelerate the development of targeted α-therapies, especially with the recent improvement in isotope production and purification, but also with the development of innovative strategies for optimized targeting. Numerous studies have demonstrated the in vitro and in vivo efficacy of the targeted α-therapy. Radium-223 (Ra) dichloride (Xofigo®) is the first α-emitter to have received FDA approval for the treatment of prostate cancer with metastatic bone lesions. There is a significant increase in the number of clinical trials in oncology using several radionuclides such as Actinium-225 (Ac), Bismuth-213 (Bi), Lead-212 (Pb), Astatine (At) or Radium-223 (Ra) assessing their safety and preliminary activity. This review will cover their therapeutic application as well as summarize the investigations that provide the foundation for further clinical development.

An Appendix of Radionuclides Used in Targeted Alpha Therapy

“…The targeting of cancerous cells relies on the inherent chemistry of radium being similar to calcium and thus accumulate in bone mineralization sites. Several studies are looking into possible ligands for this element such as calix [4]arenes or encapsulation of radium in nanoparticles [23]. Since May 2013, 223 RaCl 2 (Alpharadin, now Xofigo) is authorized to be used to treat castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.…”

“…The interest in radiopharmaceuticals containing radionuclides with suitable emissions for medical therapy (ie, alpha, beta, and Auger emitters) has increased dramatically the past decades. The primary application of these radionuclides is in cancer therapy, but treatment of viral-or bacterial-related diseases has also been studied [1][2][3][4][5][6]. Each radiation particle has different biological effects because of different fundamental nuclear properties.…”

Alphatherapy, the new impetus to targeted radionuclide therapy?

“…The great interest of alpha-emitting radionuclides for therapy is based on a highly cytotoxic effect of alpha particles due to their high linear energy transfer (LET) and a short path length of less than 100 μm as compared to electrons of βemitting radionuclides that have a low LET and a path length of a few mm resulting in radiation exposure to normal tissue and less effective tumour cell killing effect (5). Consequently it is anticipated that alphatherapy could be more efficient and less toxic than conventional therapy using β-emitting radionuclides.…”

“…Four alpha-emitting radionuclides have been used in multiple preclinical studies and in a more limited number of earlystage clinical studies [5]: actinium-225, bismuth-213, astatine-211 and bismuth-212, the daughter of β-emitting lead-212. Each has advantages and drawbacks.…”

“…Up to now and apart from non-tumor-specific radium-223, more than 15 pilot or phase I/II clinical studies involving a total of 185 patients have been performed worldwide using the four aforementioned radionuclides [5]. The upshot of all these studies is a limited toxicity except for hematological malignancies after intravenous injection, and encouraging and documented efficacy.…”