Table of Contents

    Topic review

    Targeted Alpha Therapy

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    Contributors: Frank Wuest , Bryce Nelson
    Submitted by: Frank Wuest

    Definition

    This article discusses the therapeutic advantages of Targeted Alpha Therapy (TAT), including 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; and the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At.

    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.

    Radioactive Particle

    Decay Characteristics

    Clinical Cancer Applications

    Reference

    Beta particle  (β-)

    Emission energy per decay: 50–2300 keV

    Range: 0.05–12 mm

    Linear Energy Transfer (LET): 0.2 keV/µm

    Metastatic castration resistant prostate cancer, acute myeloid leukemia, neuroendocrine tumors, acute lymphocytic leukemia, ovarian carcinomas, gliomas, metastatic melanoma, colon cancer, bone metastases

    [1][3][4]

    Auger electron (AE)

    Emission energy per decay: 0.2–200 keV

    Range: 2–500 nm

    LET: 4–26 keV/µm

    Advanced pancreatic cancer with resistant neoplastic meningitis, advanced sst-2 positive neuroendocrine and liver malignancies, metastatic epidermal growth factor receptor (EGFR)-positive breast cancer, glioblastoma multiforme

    [1][5]

    Alpha particle (α)

    Emission energy per decay: 5–9 MeV

    Range: 40–100 µm

    LET: 80 keV/µm

    Metastatic castration resistant prostate cancer, relapsed or refractory CD-22-positive

    non-Hodgkin lymphoma, acute myeloid leukemia, neuroendocrine tumors, ovarian carcinoma, gliomas, intralesional and systemic melanoma, colon cancer, bone metastases

    [1][3][4]

    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].

    Parent

    Daughters

    Half-Life

    Emission Type (Energy, Intensity)

    α

    β-

    β+

    γ

    X-Ray

    225Ac

     

    9.9 d

    5.8 MeV, 50.7%

     

     

    100 keV, 1%

    18.6 keV, 13%

     

    221Fr

    4.8 min

    6.3 MeV, 83.3%

     

     

    218 keV, 11.4%

    17.5 keV, 2%

     

    217At

    32.3 ms

    7.1 MeV, 99.9%

     

     

     

     

     

    213Bi

    45.6 min

    5.9 MeV, 1.9%

    492 keV, 66%

     

    440 keV, 26%

    79 keV, 1.8%

     

    213Po

    3.72 μs

    8.4 MeV, 100%

     

     

     

     

     

    209Tl

    2.16 min

     

    178 keV, 0.4%

     

    1567 keV, 99.7%

    75 keV, 9.7%

     

    209Pb

    3.23 h

     

    198 keV, 100%

     

     

     

     

    209Bi

    Stable

     

     

     

     

     

     

     

     

     

     

     

     

     

    224Ra

     

    3.63 d

    5.7 MeV, 95%

     

     

    241 keV, 4.1%

     

     

    220Rn

    55.6 s

    6.3 MeV, 99.9%

     

     

     

     

     

    216Po

    0.15 s

    6.8 MeV, 99.9%

     

     

     

     

     

    212Pb

    10.6 h

     

    93.5 keV, 83%

     

    238 keV, 43.6%

    77 keV, 17.5%

     

    212Bi

    60.6 min

    6.1 MeV, 25%

    834 keV, 55%

     

    727 keV, 6.7%

    15 keV, 7%

     

    212Po

    0.30 μs

    8.8 MeV, 100%

     

     

     

     

     

    208Tl

    3.1 min

     

    650 keV, 49%

     

    2614 keV, 99.9%

     

     

    208Pb

    Stable

     

     

     

     

     

     

     

     

     

     

     

     

     

    227Th

     

    18.7 d

    6.0 MeV, 100%

     

     

    236 keV, 13%

    19 keV, 37%

     

    223Ra

    11.4 d

    5.7 MeV, 100%

     

     

    269 keV, 14%

    83 keV, 25%

     

    219Rn

    3.96 s

    6.8 MeV, 79.4%

     

     

    271 keV, 10%

    16 keV, 1%

     

    215Po

    1.78 ms

    7.4 MeV, 99.9%

     

     

     

     

     

    211Pb

    36.1 min

     

    471 keV, 91%

     

    404 keV, 3.8%

     

     

    211Bi

    2.14 min

    6.6 MeV, 83.5%

    172 keV, 0.3%

     

    351 keV, 13%

     

     

    207Tl

    4.77 min

     

    492 keV, 99.7%

     

     

     

     

    207Pb

    Stable

     

     

     

     

     

     

     

     

     

     

     

     

     

    211At

     

    7.2 h

    5.9 MeV, 42%

     

     

     

    79 keV, 21%

     

    211Po

    0.52 s

    7.5 MeV, 98.9%

     

     

     

     

     

    207Bi

    31.6 y

     

     

     

    570 keV, 97.8%

     

     

    207Pb

    Stable

     

     

     

     

     

     

     

     

     

     

     

     

     

    149Tb

     

    4.1 h

    4.0 MeV, 16.7%

     

    638 keV, 3.8%

    352 keV, 29.4%

    43 keV, 36%

     

    149Gd

    9.3 d

     

     

     

    150 keV, 48%

    42 keV, 55%

     

    149Eu

    93.1 d

     

     

     

     

    40 keV, 40%

     

    149Sm

    Stable

     

     

     

     

     

     

    145Eu

    5.9 d

     

     

    740 keV, 1.5%

    894 keV, 66%

    40 keV, 40%

     

    145Sm

    340.3 d

     

     

     

    61 keV, 12%

    39 keV, 71%

     

    145Pm

    17.7 y

     

     

     

    72 keV, 2%

    37 keV, 40%

     

    145Nd

    Stable

     

     

     

     

     

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

    225Ac (t1/2 = 9.9 d, 5.8 MeV α particle) decays to 209Bi with six intermediate radionuclide progenies. These daughters include 221Fr (t1/2 = 4.8 min; 6.3 MeV α particle and 218 keV γ emission), 217At (t1/2 = 32.3 ms; 7.1 MeV α particle), 213Bi (t1/2 = 45.6 min; 5.9 MeV α particle, 492 keV β- particle and 440 keV γ emission), 213Po (t1/2 = 3.72 μs; 8.4 MeV α particle), 209Tl (t1/2 = 2.2 min; 178 keV β- particle), 209Pb (t1/2 = 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 (t1/2 = 3.63 d, 5.7 MeV α particle, 241 keV γ emission) decays to 208Pb with six intermediate radionuclide progenies. These daughters include 220Rn (t1/2 = 55.6 s, 6.3 MeV α particle), 216Po (t1/2 = 0.15 s, 6.8 MeV α particle), 212Pb (t1/2 = 10.6 h, 93.5 keV β- particle, 238 keV γ emission), 212Bi (t1/2 = 60.6 min, 6.1 MeV α particle, 834 keV β- particle, 727 keV γ emission), 212Po (t1/2 = 0.30 μs, 8.8 MeV α particle), 208Tl (t1/2 = 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 (t1/2 = 18.7 d, 6.0 MeV α particle, 236 keV γ emission) decays to 207Pb with six intermediate radionuclide progenies. These daughters include 223Ra (t1/2 = 11.4 d, 5.7 MeV α particle, and 269 keV γ emission), 219Rn (t1/2 = 3.96 s, 6.8 MeV α particle, 271 keV γ emission), 215Po (t1/2 = 1.78 ms, 7.4 MeV α particle), 211Pb (t1/2 = 36.1 min, 471 keV β- particle, 404 keV γ emission), 211Bi (t1/2 = 2.14 min, 6.6 MeV α particle, 172 keV β- particle, 351 keV γ emission), 207Tl (t1/2 = 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 (t1/2 = 7.2 h, 5.9 MeV α particle) decays to 207Pb with two intermediate radionuclide progenies in separate paths. These daughters include 207Bi (t1/2 = 31.6 y, electron capture) which decays to 207Pb and 211Po (t1/2 = 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 (t1/2 = 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 (t1/2 = 9.28 d), 149Eu (t1/2 = 93.1 d, electron capture), and 149Sm (stable). The other path includes 145Eu (t1/2 = 5.9 d, 740 keV β+ particle, 894 keV γ emission), 145Sm (t1/2 = 340.3 d, electron capture, 61 keV γ emission), 145Pm (t1/2 = 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].

    The entry is from 10.3390/pharmaceutics13010049

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