225Ac as a Potential Theranostic Radionuclide: Comparison
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α radioisotopes can offer a treatment choice to individuals who are not responding to β− or gamma-radiation therapy or chemotherapy drugs. Only a few α-particle emitters are suitable for targeted alpha therapy (TAT) and clinical applications. The majority of available clinical research involves 225Ac and its daughter nuclide 213Bi. Additionally, the 225Ac disintegration cascade generates γ decays that can be used in single-photon emission computed tomography (SPECT) imaging, expanding the potential theranostic applications in nuclear medicine. Despite the growing interest in applying 225Ac, the restricted global accessibility of this radioisotope makes it difficult to conduct extensive clinical trials for many radiopharmaceutical candidates.

  • targeted alpha therapy
  • 225Ac
  • physical properties
  • production routes
  • theranostic application

1. Introduction

At the end of the 1800s, Pierre and Marie Curie, along with Alexander Graham Bell in the early 1900s, conducted research linked to cancer-targeted α therapy (TAT), which represented one of the earliest non-surgical cancer treatments [1]. Furthermore, α-particle emitters have significant curative effects, particularly in patients with limited therapeutic options and metastatic spread [2,3,4][2][3][4]. They can target very small clusters of metastatic cancer cells.
There are many benefits of using these radioisotopes in cancer therapy over common methods. α particles can selectively destroy tumour cells while preserving adjacent normal tissues due to their narrow extent in human tissue, corresponding to less than 0.1 mm [5]. Meanwhile, highly efficient cell destruction through DNA double-strand and DNA cluster damage is caused by the high energy of α emitters, in addition to the strong linear energy transfer (LET) (80 keV/µm) that goes along with it. These effects are mainly unaffected by the state of the cell cycle and oxygenation [6,7,8][6][7][8]. Thus, α radioisotopes can provide a therapeutic option for patients who are resistant to therapy with β− or gamma radiation or chemotherapeutic medications [9,10,11][9][10][11]. According to research estimations, tens of thousands of β− particles are needed to reach a single-cell killing rate of 99.99%, whereas only a few α decays are needed to accomplish a similar killing potential [4,12][4][12].
The high-LET radiation’s biological efficacy is explained by its tendency to cause complex multiple clusters and double-strand or single-strand breaks in a target cells’ DNA, rendering cellular repair mechanisms ineffective [4,13][4][13]. Additionally, reactive oxygen species (ROS), which are produced when emitted particles interact with water, can react with biomolecules such as proteins, phospholipids, RNA, and DNA, leading to permanent cell deterioration [14]. Moreover, during this type of therapy, the primary tumour and any additional cancerous lesions in the body that the radiation did not directly target may decrease as a result of “the abscopal effect” [14]. It is thought that the immune system is a key player in this process, even though the precise biological mechanisms underlying the phenomenon are as yet unknown [4,15,16][4][15][16] (Figure 1).
Figure 1. Schematic representation of the biological effects following the use of α-particle emitter radiopharmaceutical for cancer therapy. SSD = Single-Strand Break, DSB = Double-Strand Break, ROS = Reactive Oxygen Species.
Considering the clinical application of TAT, only a limited number of α-particle emitters are appropriate [17]. The use of 225Ac and its short-lived daughter nuclide 213Bi represents the vast majority of available experience in clinical research [5]. Furthermore, applying γ decays, which are produced during the radioactive 225Ac cascade [5] in SPECT imaging, raises the possibility of theranostic nuclear medicine applications.
Although interest in using 225Ac as an α-emitting radiolabel has been steadily increasing [18], substantial clinical investigations of many radiopharmaceutical candidates cannot be supported due to 225Ac’s limited worldwide accessibility [19]. Notwithstanding the significant financial investments made by numerous laboratories to establish production pathways, the widespread use of 225Ac-labeled radiopharmaceuticals in human patients is still not achievable [19]. This ongoing shortage in 225Ac supply can be explained by the practical production techniques that need difficult logistical tasks, such as using controlled nuclear materials or highly irradiating radioactive accelerator targets [19].

2. 225Ac: Physical Characteristics

Actinium is a radioactive component with atomic number 89 [20]. Only two of its 32 isotopes, 228Ac and 227Ac, are naturally produced as a result of the disintegration of 232Th and 235U, respectively [20,21][20][21]. With its long half-life of 21.7 years and predominant β− emissions decay, 227Ac represents the most common actinium isotope. However, 228Ac, which is also a β− emitter, is highly uncommon [20,21][20][21]. 225Ac is the initial element in the actinide family, and its radioactive parents are parts of the now-extinct “neptunium series” [19,21][19][21]. This α-emitter isotope has a long half-life of 9.9 days [5,22][5][22]. Starting from 225Ac to reach 209Bi (T1/2 = 1.9 × 1019 y), the decay series includes six short-lived radionuclide daughters [5,23][5][23]. This radioactive cascade is represented by 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) [24] (Figure 2) [14].
Figure 2.
The decay chain of
233
U to
225
Ac and
213
Bi.

3. 225Ac and Its Potential Theranostic Use

225Ac is considered a “nanogenerator”, since one decay of this element produces a total of four α and three β particles, in addition to two γ emissions [24]. Taking into account its α particle emissions, along with the fact that the non-tumour binding activity can be eliminated before most of its dose is deposited in organs, 225Ac is considered an appealing choice for TAT [24,25][24][25]. However, it is important to give attention to the notable 225Ac cytotoxicity, including renal toxicity [26], due to its extended half-life and the various α particles produced throughout its decay chain [5]. A theranostic-based approach, characterised by the imaging–therapeutic duality, is the process of obtaining positron emission tomography (PET) and SPECT scans by exchanging the therapeutic α-emitting radionuclide with a positron or gamma diagnostic imaging radionuclide. Significant information on dosimetry and TAT reactions is obtained from these relevant nuclear medicine images. Chemical characteristics, half-life, radioactive emission type and intensity, related dosimetry, ease and scalability of production, radionuclidic purity, economics, and radionuclide progeny considerations are the factors that determine “the ideal” imaging surrogates for targeted alpha therapy [27,28][27][28]. Therapeutic use of 225Ac is often paired with imperfect PET imaging surrogates, such as 68Ga, 89Zr, or 111In, despite significant differences in their half-lives or chelation chemistry [29]. Studies are being conducted to address the limitations of imaging radionuclides by utilising lanthanum (La) as a potential alternative, especially 132La (T1/2 = 4.8 h, 42% β+) and 133La (T1/2 = 3.9 h, 7% β+) [30,31][30][31]. However, the half-lives of these isotopes are much shorter than that of 225Ac, limiting their applicability in PET imaging [29]. In this regard, the production of 134Ce (T1/2 = 3.2 d) has recently been started by the U.S. Department of Energy (DOE) Isotope Program [32]. The long 134Ce T1/2 and the similar chemical properties of 225Ac and 134Ce were considered potential benefits for monitoring in vivo pharmacokinetics. For PET imaging of the chelate and the antibody trastuzumab, 134Ce has been demonstrated to bind with diethylenetriamine pentaacetate (DTPA) [32] and dodecane tetraacetic acid (DOTA) [33]. On the other hand, greater molar ratios and higher temperatures are needed for isotope combinations with DOTA and DTPA [29]. In contrast, N, N′-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa) has shown great stability for nonradioactive cerium and better chelate characteristics for 225Ac [34], indicating that it might be useful for the theranostic development of 134Ce/225Ac [35]. The potential use of γ disintegrations, obtained by the decay of the intermediate 221Fr (218 keV, 11.6% emission probability) and 213Bi (440 keV, 26.1% emission probability) [5], in SPECT in vivo imaging could lead the 225Ac radioactive cascade to a possible theranostic prospective in nuclear medicine applications. Nonetheless, planar SPECT imaging would be challenging because of the effectiveness of 225Ac, which results in modest administered doses (~50–200 kBq/kg [5]), along with low γ emissions [24,25][24][25]. As a possible solution to this limitation, we can notice the suitable use of 213Bi, which can be isolated from the 225Ac decay cascades [24]. Nevertheless, it is mandatory to consider the short half-life of 213Bi (45.6 min), which poses difficulties for processing, radiolabelling, and radiopharmaceutical delivery [24]. In addition, it is necessary to point out that these radiations make reaction monitoring complicated. Moreover, the secular equilibrium must be attained (for at least 6 h) before measuring a trustworthy radiochemical yield (RCY) [21]. Actinium’s chemistry lacks advancement because of its restricted availability; all Ac isotopes need specific management and facilities [20].

4. Radiochemistry

During the production of radionuclides, it is mandatory to take into consideration a set of important aspects, such as safety, the co-generation of a few long-lived radionuclidic impurities, and adjustability, to enable delivery through clinical sites [27]. Once the target material has been irradiated, potent chemical purification methods are required to isolate the radioisotope [27,36,37,38][27][36][37][38]. Furthermore, the alpha particle may radiolytically damage the radiopharmaceutical itself, reducing in vivo targeting and producing more radioactive deposits in nontarget tissue. [27]. Since radiopharmaceuticals are considered typical pharmaceuticals, special manuals have been developed in the European Pharmacopoeia to deal with quality control issues [39]. Additionally, optimised protocols for preparing 225Ac agents in therapeutic doses have been established [40] (Table 1).
Table 1.
Research on
225
Ac chemistry. RCY = Radiochemical yield, RCP = Radiochemical purity, TLC = Thin-layer chromatography, ITLC = Instant thin-layer chromatography.

Study

Preparation Method

Radiopharmaceutical

RCY/RCP

Abou. et al., 2022 [41]

❖

The labelling of the DOTA-conjugated peptide was carried out under good manufacturing practice within a shielded hot cell using a multifunctional automated radiosynthesis module (Trasis, AllinOne mini).

❖

46.6 MBq of the 225Ac source dissolved in 0.2 M HCl was loaded under vacuum in the initial vial for radiolabelling with the DOTA-conjugated precursor (200 µg) on day 5 postsource purification. The source was transferred to the one-pot radiolabelling reactor cassette, in which the reaction occurred in Tris buffer (1 M, pH 7.2) at 85 °C for 70 min in the presence of 20% v/v L-ascorbic acid at pH 6–8. The radiolabelled peptide was transferred in saline and passed through a 0.2 µm sterilizing filter, resulting in a final volume of 9.7 mL.

❖

The radiolabelled products were characterised using thin-layer chromatography, high-pressure liquid chromatography, gamma counting, and high-energy resolution gamma spectroscopy.

225Ac-DOTA-conjugated peptide

>99%/>95%

Dumond. et al., 2022 [42]

❖

PSMA-617 precursor was dissolved in 25 μL metal-free water (0.67 mg/mL) and combined with 500 μL 0.05M Tris buffer, pH 9. 225Ac solution (~65 μCi in 15 μL) was added and the reaction was heated at 120 °C for 40–50 min. The resulting reaction was cooled and 0.6 mL gentisic acid solution (4 mg/mL in 0.2 M NH4OAc) was added. To formulate the dose for injection, sterile saline (8 mL) was added and the pH was adjusted by the addition of 100 μL 0.05 M Tris buffer (pH 9) to give a final pH of ~7.2. The final solution was filtered using a 0.22 μm GV sterile filter into a sterile dose vial.

❖

Radiochemical purity was determined by radio-TLC (eluent: 50mM sodium citrate, pH 5), and plates were analysed using an AR2000 scanner.

225Ac-PSMA-617

>99%/98 ± 1%

Thakral. et al., 2021 [43]

❖

225Ac-PSMA-617 was prepared by adding the peptidic precursor-PSMA-617 (molar ratios, 225Ac: PSMA-617 = 30:1) in 1 mL ascorbate buffer to 225Ac and heating the reaction mixture at 90 °C for 25 min.

❖

pH was determined using pH paper.

❖

RCP of 225Ac-PSMA-617 was determined by ITLC.

225Ac-PSMA-617

85–87%/97–99%

Kelly. et al., 2021 [44]

❖

225Ac (9.25 MBq) was obtained from a thorium generator at Canadian Nuclear Laboratories and supplied as the dried [225Ac]AcCl3 salt. The [225Ac]AcCl3 was dissolved in 1 mL 1 M NH4OAc, pH 7.0, transferred by pipette to a 50 mL centrifuge tube, and diluted to 45 mL in 1 M NH4OAc. Stock solution (1 mL), containing approximately 205 kBq [225Ac]Ac(OAc)3, was transferred by pipette to a plastic Eppendorf tube placed on a digital TermoMixer heating block. Then, 20 µL of the ligand stock solution (0.01–1 mg/mL of PSMA or DOTA or macropa) was added and the reaction was shaken at 300 rpm at either 25 °C or 95 °C. A 3 µL aliquot of the reaction mixture was withdrawn and deposited on the origin of a silica-gel-60-coated aluminium plate (Sigma Aldrich) after incubating the reaction for 1 min, 5 min, and 15 min.

❖

A TLC method was developed to separate the metal complexed ligand from uncomplexed 225Ac and its daughter radionuclides.

225Ac-PSMA conjugated peptide/

225Ac-DOTA conjugated peptide/

225Ac-macropa conjugated peptide

2.7 ± 0.55%–98.8 ± 0.09%/1.8–99.5%

Hooijman. et al., 2021 [45]

❖

225Ac was diluted into 0.1 M HCl. Stock solutions (10 mL) were proceeded in quartz-coated sterile vials. All purchased chemicals were prepared with Milli-Q water. Stock solutions prepared the day before labelling were 1 M HCl (from 37% HCl), 10 M NaOH, and 0.1 M TRIS-buffer pH 9. Two stock solutions were prepared on the day of labelling: First, 20% ascorbic acid was prepared; the ascorbic acid solution was transformed to ascorbate by the addition of 10 M NaOH to a pH 5.8. Secondly, PSMA-I&T (250 µg) was dissolved in 0.1 M TRIS buffer (pH 9) to a concentration of 600 µg/mL. Directly after labelling, 4 mg/mL diethylenetriaminepentaacetic acid (DTPA) was added to the labelling mixture. A solution for injection was prepared by the addition of ascorbate (50% v/v) and ethanol (6% v/v, 96%) into saline.

225Ac-PSMA-I&T

>95%/>90%

5. 225Ac Radiopharmaceuticals and Clinical Applications

The delivery of the radiopharmaceutical via the circulatory system enables the targeting of both the main tumour and its metastases. Whether a radiopharmaceutical is intended for therapeutic or diagnostic purposes depends on the decay properties of the linked radioisotope. For the purpose of curing, controlling, or palliating symptoms, TAT aims to provide an adequate amount of ionising radiation to intended malignities areas [27]. This means that any TAT agent must have a thorough understanding of its stability, pharmacokinetics, and dosimetry. Investigations on 225Ac have shown potential in treating neuroendocrine tumours, acute myeloid leukaemia, and metastatic prostate cancer, and more radiopharmaceuticals are being developed for other cancer types [46,47,48,49,50,51,52][46][47][48][49][50][51][52] (Table 2).
Table 2.
Clinical research based on
225
Ac.

Disease

Study

Radiopharmaceutical

Prostate cancer

Parida et al., 2023 [53]

225Ac-PSMA RLT
 

Ma et al., 2022 [54]

225Ac-PSMA-617
 

Sanli et al., 2021 [55]

225Ac-PSMA-617
 

Sen et al., 2021 [56]

225Ac-PSMA-617
 

Zacherl et al., 2021 [50]

225Ac-PSMA-I&T
 

Feuerecker et al., 2021 [57]

225Ac-PSMA-617
 

Van Der Doelen et al., 2021 [58]

225Ac-PSMA-617
 

Sathekge et al., 2020 [51]

225Ac-PSMA-617
 

Yadav et al., 2020 [59]

225Ac-PSMA-617
 

Satapathy et al., 2020 [60]

225Ac-PSMA-617
 

Sathekge et al., 2019 [61]

225Ac-PSMA-617
 

Kratochwil et al., 2018 [62]

225Ac-PSMA-617

Neuroendocrine tumours

Ballal et al., 2022 [63]

225Ac-DOTATATE
 

Yadav et al., 2022 [48]

225Ac-DOTATATE
 

Kratochwil et al., 2021 [64]

225Ac-DOTATATE
 

Ballal et al., 2020 [65]

225Ac-DOTATATE
 

Kratochwil et al., 2015 [66]

225Ac-DOTATOC

Acute myeloid leukaemia

Rosenblat et al., 2022 [67]

225Ac-lintuzumab
 

Jurcic, 2018 [68]

225Ac-lintuzumab
 

Jurcic et al., 2016 [69]

225Ac-lintuzumab
 

Jurcic et al., 2011 [70]

225Ac-lintuzumab
The use of 225Ac in clinical practice is limited by its low availability. Breaking through this barrier would allow 225Ac therapy to spread widely. Automated synthesis and consistent patient doses are essential, regardless of the production route chosen for this α-isotope acquisition. 225Ac can be adapted for the commonly accessible DOTA-conjugated peptides for therapy [41], which are already capable of labelling 177Lu or 90Y. Marc Pretze et al. [71] studied the effectiveness and consistency of the radiosynthesis process for creating 225Ac-labelled DOTA-conjugated peptides. Additionally, the research aimed to establish whether this process could be adapted for clinical production purposes through an automated synthesis platform (cassette-based module—Modular-Lab EAZY, Eckert & Ziegler) [72]. After comparing two purification methods, the researchers obtained 225Ac-labelled peptides in an RCY of 80–90% for tumour therapy in patients [71]. Thus, the whole process was meticulously validated in accordance with the regulations of the German Pharmaceuticals Act §13.2b, knowing that the estimated costs for the automated synthesis of 1 MBq 225Ac is around EUR 300–390, taking into account that the peptides would cost EUR 600–1000, the cassettes would cost EUR 180–200, and the ML EAZY would cost EUR ~30,000 [71].

6. The Production Routes of 225Ac

As already mentioned, 225Ac is part of the 237Np disintegration family that has vanished in nature. This radioactive element could be artificially reproduced [21]. In addition to direct production paths, 225Ac is conveniently reachable at numerous points along the decay chain, in particular via 233U (T1/2 =159200 y, 100% α), 229Th (T1/2 = 7340 y, 100% α), and 225Ra (T1/2 = 14.9 d, 100% β−) [19]. 225Ac possesses many fewer nucleons than other actinide nuclei that are more stable to be employed as production targets, such as 232Th and 226Ra [19]. Thus, production methods should, with rare exceptions, rely on radioactive decay or greater energy bombardments. The available production routes of 225Ac and its parents are listed below (Figure 3) [14]:
Figure 3.
The principal production routes for
225
Ac.

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