The purpose of dosimetry in radionuclide therapy is to understand or predict the likely biological effects, such as toxicity and efficacy, of a radiopharmaceutical drug on a patient. Evaluating the absorbed dose in relevant organs and tumors requires essential parameters including the spatial and temporal biodistribution of the administered radiopharmaceutical (in order to estimate the total number of radionuclide disintegrations in different tissues and tumors, determined by multi-time-point photon imaging) and information about both the physical properties of the radionuclide and the patient anatomy. In the case of alpha-emitter-labeled radiopharmaceuticals, accurate quantitative imaging is particularly challenging due to the low yield of imageable photons emitted, the very low activity administered, the short path length and heterogeneous distribution in tissue, and the multiple daughter radionuclide redistributions. However, biodistribution and dosimetry research involving
225Ac has emerged in the last few years using different approaches. These include the direct detection of gamma-emissions by gamma-cameras
[86[37][38],
87], dosimetry based on a surrogate nuclide such as
177Lu that can be imaged (particularly for [
225Ac]Ac–PSMA-617 treatment
[88,89][39][40]), pharmacokinetic modeling
[90][41], and small-scale and microdosimetry
[91,92][42][43].
3. Radiochemical and Preclinical Development of [225Ac]Ac–DOTATATE
3.1. Production of Actinium-225
Two isotopes of actinium,
227Ac and
228Ac, exist in nature within the natural decay chain of uranium-235 and thorium-232, respectively
[94][44]. However, neither of these two isotopes is used in the clinic, with
228Ac representing a minimal part of natural actinium and
227Ac having a very long half-life (t
1/2 = 21.77 y). Therefore,
225Ac is the only one of the more than 30 known actinium isotopes to be used in preclinical and clinical studies to date.
The main method for generating
225Ac for clinical use is through radiochemical extraction following the decay of
229Th (t
1/2 = 7397 y), which originates from reactor-bred
233U
[95,96][45][46]. The main sources of
229Th in the world for
225Ac used in preclinical and clinical studies are Oak Ridge National Laboratory (ORNL, Oak Ridge, TN, USA)
[95][45], the Institute of Physics and Power Engineering (IPPE, Obninsk, Russia)
[97][47], and the Directorate for Nuclear Safety and Security of the Joint Research Center of the European commission (JRC, Halstenbek, Germany), formerly the Institute for Transuranium Elements (ITE, Karlsruhe, Germany)
[98][48]. More recently, the Canadian Nuclear Laboratories set up a
225Ac production chain that could supply up to 3.7 GBq of this radioisotope annually
[99][49].
Consequently, accelerator-based production techniques to obtain
225Ac have been developed. The most promising approach to obtain
225Ac at a large scale may be the cyclotron proton irradiation of a
226Ra target, involving the
226Ra(p,2n)
225Ac transformation
[111,112][50][51]. With a high cross-section peak (710 mb) at 16.8 MeV, this convenient method can be performed on low-energy cyclotrons.
3.2. Chemistry of Actinium
3.2.1. Actinium in Aqueous Solution
Actinium is the chemical element with atomic number 89 and the first element of the actinide group, to which it gives its name. Nevertheless, actinium has rather similar chemical properties to lanthanum and other lanthanides. Actinium exists essentially in the +3 oxidation state in aqueous solution; additionally, Ac
3+ is the largest +3 cation in the periodic table. It is also the most basic +3 ion due to its low charge density, directly related to its large size. Although the +3 state is the most stable in aqueous solution, the +2 oxidation state may also be encountered
[120][52]. This second species is assumed because a reduction half-wave potential in a
225Ac
3+ aqueous solution can be observed. The progressive negative shift of this potential in the presence of increasing 18-crown-6 concentrations has been attributed to the formation of a complex between crown ether and divalent actinium
[121][53]. However, without the effect of 18-crown-6 on the reduction of
225Ac
3+, the existence of stable
225Ac
2+ ions in aqueous solution remains unlikely regarding the low extraction yields of actinium using sodium amalgam in aqueous sodium acetate, an extraction technique usually efficient for lanthanides at a stable +2 oxidation state
[122][54].
3.2.2. Coordination Chemistry of Actinium
The usefulness of actinium-225 as a radionuclide for therapeutic purposes has been limited for a long time by the unavailability of chelating agents that are both capable of being compatible with this bulky radionuclide and of controlling the fate of the resulting daughter emitters, particularly with regard to their alpha-recoil, which is related to the conservation of momentum laws that occurs upon release of an alpha-particle
[137][55]. Nevertheless, the coordination chemistry of such a clinically relevant alpha-emitter has recently gained more and more interest
[138][56].
Considering its low polarizability and despite its large ionic radius, the Ac
3+ ion is considered a hard Lewis acid
[139][57], showing a medium absolute chemical hardness value of 14.4 eV
[140][58]. As such, it will complex more easily with hard ligands, such as anionic oxygen donors. The complexation reaction will preferentially occur under charge control and the acid–base bond will be essentially ionic. Indeed, Ac
3+ displays an electrostatic interaction constant (
EA) value of 2.84 and a covalent interaction constant (
CA) value of 0.28
[138][56]. This predominance of charge interactions can be predicted from the character of the frontier molecular orbitals, which are centered on the nuclei of the donor and acceptor atoms; when these atoms are close together in space, the overlaps of the orbitals are negligible while the charge interactions are strong. This is mainly attributed to the density of the charge, which is very significant in ions of hard consistency.
The high ionic radius of the Ac
3+ cation suggests that the most suitable chelators would be polydentate agents, with a high denticity between 8 and 12. Initial works investigated the suitability of linear polyaminocarboxylate chelators, such as CHX-A″-DTPA, for the chelation of the
225Ac
3+ cation
[141,142][59][60]. These efforts were motivated by the advantageous radiolabeling kinetic properties of these ligands; however, the complexes obtained did not show sufficient in vivo stability. Subsequently, large macrocyclic chelators were considered and the 18-membered polyaminocarboxylic acid core HEHA was rapidly identified as particularly suitable for actinium complexation
[142,143][60][61].
3.2.3. Relevance of DOTA in Actinium Radiopharmaceuticals
The in vivo fate of the
225Ac–DOTA complex alone was initially shown to be safe, with only low activity amounts in liver and bone of BALB/c mice
[142][60]. Subsequently, DOTA-bioconjugated constructs (either antibodies or peptides) also showed the sufficient stability of the complex, both in vitro
[162,166,167,173][62][63][64][65] and in vivo
[162,166][62][63]. Nevertheless, early studies raised some concerns about the compatibility of DOTA with actinium
[142,146][60][66]. Indeed, the large ionic radius of the Ac
3+ ion is not in favor of the good thermodynamic stability of the DOTA complex, which may also be subject to transmetalation with other cations. In order to minimize adverse in vivo effects associated with the loss of
225Ac and its daughter radionuclides (especially
213Bi, significantly increasing the kidney-absorbed dose
[194][67]) from DOTA, several approaches have been considered, such as the co-administration of chelating agents or concomitant diuresis
[195,196][68][69].
3.3. Somatostatin Analogs Radiolabeled with
225
Ac: Preclinical Studies
Only a few studies have reported preclinical efficacy results of 225Ac-radiolabeled somatostatin analogues, due to this group of vector molecules having already been widely studied with beta-emitters such as 90Y or 177Lu [197][70].
Activities between 10 and 60 kBq were well-tolerated by the mice; however, activities over 30 kBq induced pathologic changes in the renal cortex, suggesting radiation-induced acute tubular necrosis in both the distal and proximal tubules. Similar results were obtained in another study on Sprague Dawley rats that received 111 or 370 kBq [225Ac]Ac–DOTATOC and developed renal tubular nephrosis or renal glomerulopathy [199][71]. Only a slight accumulation in the liver was objectified, probably due to the release of free 225Ac. After a single administration of the highest non-toxic activity (20 kBq), tumor weights 14 days after treatment were lower with [225Ac]Ac–DOTATOC than with [177Lu]Lu–DOTATOC (1 MBq), in accordance with previous studies investigating [213Bi]Bi–DOTATOC [74,75][30][31].
4. Clinical Use of 225Ac–DOTATATE
To date, [
177Lu]Lu–DOTATATE is considered as the standard PRRT treatment for GEP NETs. In this regard, the phase 3 randomized control trial NETTER-1 specifically demonstrated that [
177Lu]Lu–DOTATATE therapy plus long-acting octreotide was associated with a significantly longer PFS (28.4 vs. 8.5 months) than high-dose long-acting octreotide in advanced midgut GEP NET patients, although the OS endpoint of th
ise study did not reach statistical significance (48 vs. 36.3 months,
p = 0.3)
[62,205][72][73]. Thus, this therapy offers a promising option as an early-line treatment for advanced NET
[60,62][72][74]. Nevertheless, this type of pathology is known to frequently relapse, which may lead to patient retreatment. In this context, several studies have investigated the value of a renewed treatment with β-PRRT; furthermore, TAT protocols using somatostatin analogs, especially
225Ac-based approaches, were also rapidly proposed as an alternative for patients that did not respond to β-PRRT.
Although it was used several years earlier, the first literature report of an alpha-PRRT with [
225Ac]Ac–DOTATOC in human dates from October 2018
[206][75]. Ten patients with metastatic NETs progressing after
90Y– and/or [
177Lu]Lu–DOTATOC therapy were treated with intra-arterial [
225Ac]Ac–DOTATOC (~8 MBq). Overall, the treatment was well-tolerated and effective, demonstrating its potential as a possible therapeutic alternative in advanced NETs resistant to β-PRRT.
Then, two major studies involving
225Ac-labeled octreotide analogs were reported in patients with advanced-stage SSTR-expressing metastatic GEP NETs. These works primarily focused on the hematologic and renal toxicity of [
225Ac]Ac–DOTATOC, and on the long-term outcomes of this therapeutic, respectively.
5. Conclusions
Ahead of other α-emitters, TAT using
225Ac-labeled somatostatin analogs seems to be a promising therapeutic approach for metastatic or inoperable NETs, especially considering its preliminary efficacy and safety results. Efforts to achieve the sufficient production of
225Ac and extensive radiochemistry works aimed at optimizing the chelation of this radioelement reflect the high expectations for its clinical use, including in other pathologies such as prostate cancer with
225Ac-labeled PSMA ligands
[88,233,234,235,236,237][39][76][77][78][79][80], or even in hematological cancers such as acute myeloid leukemia
[238][81]. However, the role of TAT versus β-PRRT in terms of OS, PFS and long-term toxicity is still difficult to define without formal comparative studies. Beforehand, the further investigation into the therapeutic use modalities of
225Ac-radiolabeled somatostatin analogs will be required. Some of these questions may be answered by the ACTION-1 clinical trial (NCT05477576)
[239][82], which is designed to determine the safety, pharmacokinetics, and recommended phase 3 dose of [
225Ac]Ac–DOTATATE and its efficacy compared to the investigator-selected standard of care therapy in patients with inoperable GEP NETs that progressed following
177Lu–somatostatin analogues. Similarly, preliminary data on the efficacy of
225Ac-labeled somatostatin analogs in other cancers such as paragangliomas
[211][83] or pheochromocytomas
[240][84] will need to be further consolidated. From a radiopharmaceutical perspective, the importance of developing a reliable method for measuring the radiochemical purity of
225Ac conjugates produced in-house appears to be crucial and would certainly be a key requirement to obtain approval for clinical use from regulatory agencies. In addition, it will be interesting to develop a standardized dosimetric tool for the accurate estimation of adsorbed doses in target and non-target organs. For the time being, TATs constitute an emerging therapeutic alternative for patients with either highly resistant or late-stage disease, particularly in the context of compassionate access, depending on the country.