1. Introduction

Radionuclide therapy has been employed frequently in the past several decades for disease control, curative therapy, and pain management applications ^[1]. Targeted radionuclide therapy (TRT) is advantageous as it delivers a highly concentrated dose to a tumor site—either directly to the tumor cells or to its microenvironment—while sparing the healthy surrounding tissues. It has been clinically demonstrated using a variety of radionuclides to treat malignancies, including polycythemia, cystic craniopharyngioma, hyperthyroidism, synovitis and arthritis, and numerous cancers, such as thyroid cancer, bone tumors and metastasis, hepatic metastasis, ovarian cancer, neuroendocrine tumors, leukemia, lymphoma, and metastatic prostate cancer ^[2][3][4]. Since radionuclide therapy targets diseases at the cellular level, it has advantages for treating systemic malignancies such as tumor metastases over other forms of therapy such as external beam therapy, where full body irradiation is impossible. In addition to being minimally invasive, radionuclide therapy can be shorter in duration than chemotherapy ^[2].

In TRT, therapeutic radionuclides including alpha (α), beta (β^-), and Auger electron emitters are typically conjugated to a targeting vector such as monoclonal antibodies, biomolecules, peptides, nanocarriers, and small-molecule inhibitors. To maximize the therapeutic efficacy of a TRT radiopharmaceutical, its radionuclide decay pathway, particle emission range, and relative biological effectiveness should be matched appropriately for a given tumor mass, size, radiosensitivity, and heterogeneity ^[1].

This review focuses on targeted alpha therapy (TAT), outlined by the graphical abstract in Figure 1. A detailed overview of α-emitting radionuclides currently employed in radiotherapy is presented and compared to radionuclides with different emissions, including β^- particle and auger electron emitters. Production techniques for α-emitters are outlined, including their separation and unique handling requirements, followed by their radiochemistry and targeting characteristics. Preclinical developments and clinical applications of α-emitters are discussed along with current limitations, potential areas for improvement, and anticipated applications.

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.

2. Selecting Radionuclides for Radiotherapy

When selecting a radionuclide for clinical application, the physical and biochemical characteristics must be considered. Physical characteristics include physical half-life, type of emissions, energy of the emissions, daughter products, method of production, and radionuclidic purity. Biochemical characteristics include tissue targeting, retention of radioactivity in the tumor, in vivo stability, and toxicity ^[2]. For radiotherapy, it is desirable to have a high linear energy transfer (LET), where there is a high ionization energy deposited per unit length of travel. Radionuclides with a high LET deposit radioactive emission energy within a small range of tissue, thereby sparing surrounding healthy tissue and keeping the radioactive dose within, as much as possible, the patient’s organ to be treated. It can also be advantageous for the therapeutic radionuclide, or a complementary theranostic radionuclide, to emit positrons (β⁺) or gamma (γ) radiation. This enables positron emission tomography (PET) or single photon emission tomography (SPECT) imaging and visualization of radiopharmaceutical distribution within a patient’s body, permitting treatment monitoring. Table 1 outlines key characteristics of α, β^-, and auger electron emitters, and some clinical applications for cancer TRT that have been explored.

Table 1. Key characteristics of α, β^-, and auger electron emitters and their clinical applications.

β^- emitting radioisotopes have a relatively long pathlength (≤12 mm) and a lower LET of ~0.2 keV/μm, giving them effectiveness in medium–large tumors ^[1]. However, they lack success in solid cancers with microscopic tumor burden. This may be attributed to their emissions releasing the majority of their energy along a several millimeter long electron track, irradiating the surrounding healthy tissue instead of depositing their main energy into the micro-metastatic tumor cells where the radionuclide was delivered ^[6].

Clinical success has been demonstrated with the β^- emitters ⁹⁰Y and ¹³¹I conjugated with anti-CD20 monoclonal antibodies in follicular B-cell non-Hodgkin lymphoma ^[6], ¹⁷⁷Lu-labeled prostate-specific membrane antigen (PSMA) peptides in metastatic, castration-resistant prostate cancer (CRPC) and ¹⁷⁷Lu-DOTATATE for neuroendocrine tumors ^[7][8].

Auger electrons have a medium LET (4–26 keV/μm) ^[1]; however, their short pathlength of 2–500 nm limits the majority of their effects to within single cells, requiring the radionuclide to be transported into the cell and preferably incorporated into DNA to achieve high lethality. They can also kill cancer cells by damaging the cell membrane and kill non-directly targeted cells through a cross-dose or bystander effect ^[9]. Clinical studies with Auger electrons for cancer therapy have been limited; however, some encouraging results were obtained using [¹¹¹In]In-DTPA-octreotide in rats with pancreatic tumors, [¹²⁵I]I-IUdR where tumor remissions were achieved, and [¹²⁵I]I-mAb 425 where the survival of glioblastoma patients improved ^[5][10][11]. However, it has also been determined that some Auger electron emitting compounds, such as [¹²³I]I-IUdR and [¹²⁵I]I-IUdR only kill cells in the S-phase of the cell cycle, highlighting a potential treatment limitation ^[12].

α-particles have a high LET (80 keV/μm) and a moderate pathlength (50–100 μm), giving them an effective range of less than 10 cell diameters. This makes them suitable for microscopic tumor cell clusters, while sparing normal organs and surrounding healthy tissues. Importantly, α-particle lethality is not dependent on the cell cycle or oxygenation, and the DNA damage is often via double strand and DNA cluster breaks and is therefore much more difficult to repair than β^- damage ^[6]. It has been estimated that to attain a single cell kill probability of 99.99%, tens of thousands of β^- decays are required, whereas only a few α-decays at the cell membrane achieves the same kill probability ^[13]. From this, it has been estimated that one α particle transversal can kill a cell ^[14]. Most α-emitters are conjugated to a wide range of targeting vectors for delivery to their target site, though some have intrinsic targeting properties, such as the affinity of ²²³Ra-dichloride for bone ^[1]. Preclinical and clinical studies using α-emitters have been ongoing for a variety of cancers, some of which include recurrent brain tumors, recurrent ovarian cancers, human epidermal growth factor receptor-2 (HER-2) positive cancers, myelogenous leukemia, non-Hodgkin lymphoma, metastatic melanoma, and skeletal metastases in prostate cancer ^[6]. Of these, the most theranostic research is performed on prostate and neuroendocrine tumors (NETs). Examples of studies are numerous—one preclinical study using [²¹²Pb]Pb-trastuzumab found a single injection reduced tumor growth by 60–80%, reduced aortic lymph node metastasis, and prolonged survival or tumor-bearing mice ^[15]. Another study outlined how α-particle radiotherapy for metastatic castration resistant prostate cancer using [²²⁵Ac]Ac-PSMA-617 was able to overcome resistance to [¹⁷⁷Lu]Lu-PSMA-617 β^--particle therapy ^[16]. Additionally, a study using [²¹³Bi]Bi-DTPA and [²¹³Bi]Bi-DOTATATE in mice resulted in a factor of six increase in cell killing compared to [¹⁷⁷Lu]Lu-DOTATATE ^[17][18]. These studies highlight the clinical importance and potential of α-emitters, and their potential to be more efficient and effective than β^-- therapy.

3. Alpha Emitter Decay Properties

As emissions from radioactive decay, α-particles are naked ⁴He nuclei with a +2 charge. They are 7300 times larger than the mass of β^- and Auger electrons, giving them significant emission momentum that reduces deflection and results in a near-linear emission path, as opposed to the winding path of β^- particles. With an emission kinetic energy between 5–9 MeV, coupled with a particle range of 50–100 μm, this classifies α-particles as high LET. The energy distribution between the alpha particle and the recoiling daughter atom is typically 98% to 2%. Upon decay, energy imparted to the daughter recoil atom can reach 100 keV ^[19], which is far higher than the binding energy of the strongest chemical bonds, resulting in release of the daughter isotope from its targeting vector. An example is ²¹⁹Rn, which has a daughter recoil range of 88 nm in a cellular environment ^[19]. These daughters often have a serial decay chain with their own α-emitting progeny, leading to untargeted irradiation of surrounding tissues. As a result, only a limited number of α-emitting radioisotopes are suitable for therapy due to their decay characteristics. The half-life of the radionuclide should be reasonable for therapy; it should not be too short to allow sufficient time for production, radiopharmaceutical synthesis, and delivery to the patient, and it, as well as the half-life of any daughter radionuclide, should not be too long to avoid excess patient dose.

The recoil energy caused by the decay of α-emitters invariably destroys α-emitter-targeting vector chemical bonds, often releasing α-emitting progeny with different chemistries that can lead to undesirable toxicities. The presence of γ-ray emissions in an α-emitter decay chain is also of interest for imaging purposes. Therefore, it is important to understand the half-lives, emissions, and decay characteristics when selecting clinically relevant α-emitters. Figure 2 depicts decay chains that contain some common therapeutic α-emitters, and Table 2 outlines the decay characteristics of some notable α-emitters used in α therapy, including their daughters, half-lives, decay energies, and emissions.

Table 2. Notable α-emitters and their daughters, half-lives, decay energies, and emission types ^[20].

Figure 2. Decay chains of some common therapeutic α-emitters ^[6].

²²⁵Ac (t_1/2 = 9.9 d, 5.8 MeV α particle) decays to ²⁰⁹Bi with six intermediate radionuclide progenies. These daughters include ²²¹Fr (t_1/2 = 4.8 min; 6.3 MeV α particle and 218 keV γ emission), ²¹⁷At (t_1/2 = 32.3 ms; 7.1 MeV α particle), ²¹³Bi (t_1/2 = 45.6 min; 5.9 MeV α particle, 492 keV β^- particle and 440 keV γ emission), ²¹³Po (t_1/2 = 3.72 μs; 8.4 MeV α particle), ²⁰⁹Tl (t_1/2 = 2.2 min; 178 keV β^- particle), ²⁰⁹Pb (t_1/2 = 3.23 h; 198 keV β^- particle) and ²⁰⁹Bi (stable). From this, a single ²²⁵Ac decay yields a total of four α, three β^- disintegrations, and two γ emissions, which classifies ²²⁵Ac as a “nanogenerator” or “in vivo generator”. Therefore, the 9.9 d half-life of ²²⁵Ac, the multiple α particle emissions in its decay chain, and its rapid decay to ²⁰⁹Bi make ²²⁵Ac an attractive candidate for TAT ^[21]. The γ emissions would be useful for SPECT imaging of in vivo radiopharmaceutical distribution, giving the ²²⁵Ac decay series theranostic potential; however, due to the potency of ²²⁵Ac, the small administered doses and correspondingly low γ emissions would make planar SPECT imaging difficult ^[21]. Of note, the intermediate ²¹³Bi possesses attractive potential and can be separated from the ²²⁵Ac decay series for use. However, the short 45.6 min half-life of ²¹³Bi presents challenges for processing, radiolabeling, and radiopharmaceutical administration, resulting in a limited time in circulation to accumulate at its target site and achieve its intended therapeutic effects.

²²⁴Ra (t_1/2 = 3.63 d, 5.7 MeV α particle, 241 keV γ emission) decays to ²⁰⁸Pb with six intermediate radionuclide progenies. These daughters include ²²⁰Rn (t_1/2 = 55.6 s, 6.3 MeV α particle), ²¹⁶Po (t_1/2 = 0.15 s, 6.8 MeV α particle), ²¹²Pb (t_1/2 = 10.6 h, 93.5 keV β^- particle, 238 keV γ emission), ²¹²Bi (t_1/2 = 60.6 min, 6.1 MeV α particle, 834 keV β^- particle, 727 keV γ emission), ²¹²Po (t_1/2 = 0.30 μs, 8.8 MeV α particle), ²⁰⁸Tl (t_1/2 = 3.1 min, 650 keV β^- particle, 2614 keV γ emission), and ²⁰⁸Pb (stable). From this, a single ²²⁴Ra decay yields a total of four α particles, two β^- disintegrations, and six γ emissions, also classifying ²²⁴Ra as a “nanogenerator”. The bone-seeking properties of ²²⁴Ra and its favorable half-life has resulted in its use in α-therapy, and its intermediates ²¹²Pb and ²¹²Bi show potential for TAT, with ²¹²Pb preferable to ²¹²Bi for administration due to the longer half-life of ²¹²Pb, permitting more dose from its ²¹²Bi progeny to be delivered ^[1].

²²⁷Th (t_1/2 = 18.7 d, 6.0 MeV α particle, 236 keV γ emission) decays to ²⁰⁷Pb with six intermediate radionuclide progenies. These daughters include ²²³Ra (t_1/2 = 11.4 d, 5.7 MeV α particle, and 269 keV γ emission), ²¹⁹Rn (t_1/2 = 3.96 s, 6.8 MeV α particle, 271 keV γ emission), ²¹⁵Po (t_1/2 = 1.78 ms, 7.4 MeV α particle), ²¹¹Pb (t_1/2 = 36.1 min, 471 keV β^- particle, 404 keV γ emission), ²¹¹Bi (t_1/2 = 2.14 min, 6.6 MeV α particle, 172 keV β^- particle, 351 keV γ emission), ²⁰⁷Tl (t_1/2 = 4.77 min, 492 keV β^- particle), and ²⁰⁷Pb (stable). ²²⁷Th and ²²³Ra are both nanogenerators, releasing up to four α particles during the decay chain, and their γ emissions allow for imaging ^[1].

²¹¹At (t_1/2 = 7.2 h, 5.9 MeV α particle) decays to ²⁰⁷Pb with two intermediate radionuclide progenies in separate paths. These daughters include ²⁰⁷Bi (t_1/2 = 31.6 y, electron capture) which decays to ²⁰⁷Pb and ²¹¹Po (t_1/2 = 0.52 s, 7.5 MeV α particle, Kα x-rays) which decays to ²⁰⁷Pb. The decay to ²¹¹Po would permit in vivo imaging of ²¹¹At using the emitted Kα x-rays.

¹⁴⁹Tb (t_1/2 = 4.1 h, 4.0 MeV α particle, 638 keV β⁺ particle), decays to ¹⁴⁹Sm and ¹⁴⁵Nd in two separate paths. In one path, its daughters include ¹⁴⁹G (t_1/2 = 9.28 d), ¹⁴⁹Eu (t_1/2 = 93.1 d, electron capture), and ¹⁴⁹Sm (stable). The other path includes ¹⁴⁵Eu (t_1/2 = 5.9 d, 740 keV β⁺ particle, 894 keV γ emission), ¹⁴⁵Sm (t_1/2 = 340.3 d, electron capture, 61 keV γ emission), ¹⁴⁵Pm (t_1/2 = 17.7 y, electron capture, 72 keV γ emission), and ¹⁴⁵Nd (stable) ^[22]. The decay scheme for ¹⁴⁹Tb is quite favorable since it releases short-range α particles from only one radionuclide, with complementary γ emissions and positrons that can be employed for imaging purposes in an “alpha-PET” combination ^[23][24]. Having only one α-emitter in its decay scheme implies a minimal toxicity from daughter recoil during radioactive decay, which should reduce excessive dose burden ^[25].