Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists
Mengqi Shi1,2 
Vivianne Jakobsson1,3 
Lukas Greifenstein4 
Pek-Lan Khong1,5 Xiaoyuan Chen1,2,5,6,7 
Richard P. Baum4 
Jingjing Zhang1,2,5*- 1Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- 2Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- 3Academy for Precision Oncology, International Centers for Precision Oncology (ICPO), Wiesbaden, Germany
- 4CURANOSTICUM Wiesbaden-Frankfurt, Center for Advanced Radiomolecular Precision Oncology, Wiesbaden, Germany
- 5Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- 6Department of Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore
- 7Agency for Science, Technology, and Research (A*STAR), Institute of Molecular and Cell Biology, Singapore, Singapore
Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells’ DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β– emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 (225Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225Ac-PRRT in NETs, discuss the strengths and challenges of 225Ac complexes being used in PRRT; and envision the prospect of 225Ac-PRRT as a future alternative in the treatment of NETs.
Introduction
Neuroendocrine tumors (NETs) are well-differentiated, low proliferating neuroendocrine neoplasms (NENs) (1), most commonly arising from gastroenteropancreatic structures and the lung, although NEN have been described in almost every tissue. Accounting for only 0.5% of all malignancies, NETs are considered rare (2), however, the incidence/prevalence has been increasing in many epidemiological studies over the last decades (with GEP NETs demonstrating the highest incidence rate with 3.56 cases per 100,000) (2–7). The WHO grading system relies extensively on the proliferation rate to classify low proliferative NETs (NET-G1) with good prognosis, intermediate grade (NET-G2), and high grade (NET-G3) that show poor prognosis (8).
As a heterogeneous disease with very diverse symptomatology, NETs require multidisciplinary treatment and care, including medical control, surgery, chemotherapy, and internal or external radiation therapy (9). The cornerstone of therapy is still surgery with curative intent, whenever possible. However, in the case of metastatic disease, total excision is generally not possible due to the infiltration of other tissues and/or blood vessels or the number of metastatic sites (10, 11).
Systemic chemotherapy provides only modest benefit in rapidly proliferating tumors (grade 3) (12, 13). Therapeutic options such as somatostatin analogs (SSAs) or interferon-α may improve symptoms caused by hormonal excess or even lengthen the time to disease progression by offering hormonal and antiproliferative control over NETs, but rarely lead to partial or complete tumor response (14, 15). External beam radiotherapy (EBRT) unfortunately is not effective for the treatment of metastasized and secondary cancer sites beyond the treatment area (16, 17).
Theranostics, the concept of combining the inevitably intertwined arts of diagnostics and therapy, is a treatment option that has gained momentum over the last two and a half decades. Peptide receptor imaging and peptide receptor radionuclide therapy (PRRT) were the first successful examples of the theranostic concept, for imaging and treating cancer. PRRT has long been considered as a palliative treatment for NETs, but is now attracting more and more attention as a very effective symptomatic and well-tolerated treatment prolonging progression-free (and possibly overall) survival. As a complement to surgery, neoadjuvant therapy can make previously difficult-to-operate tumors operable by shrinking them, and as an adjuvant therapy, it may prevent tumor re-growth after surgical manipulation and growth of pre-existing micrometastases (18, 19).
Unlike chemotherapy and EBRT, PRRT targets disease at the cellular level in the systemic treatment of non-resectable and metastasized NETs (16). The overexpression of somatostatin receptors (SSTRs) of various sub-types in about 80% of NETs provides a continuously evolving way to diagnose and treat NETs (18, 20). The working principle of PRRT is using a therapeutic radionuclide chelated to a SSTR binding peptide and as the compound binds to SSTR expressing tissue, DNA-damaging radiation is delivered nearly exclusively to tumor cells and its microenvironment while sparing the surrounding healthy tissue. Somatostatin, the native peptide, is an obvious example of SSTR-binding peptide (21). However, it is susceptible to fast enzymatic degradation and is thus not suitable for in vivo applications (22). Instead, synthetic peptides, including those based on SSAs, have been developed with the intent to optimize metabolic stability, tumor retention time, and affinity.
History of peptide receptor radionuclide therapy
The first PRRT was performed in the early 1990s (Figure 1). The Rotterdam group successfully developed [111In-DTPA-D-Phe1]-octreotide (111In-pentetreotide) somatostatin scintigraphy (Octreoscan), and subsequently examined its imaging potential in more than 1,000 patients (23–25). Based on high uptake of 111In-pentetreotide by tumors as demonstrated by imaging, Krenning’s team successfully treated a patient with metastatic glucagonoma using a high dose of 111In-pentetreotide, which resulted in a decreased level of circulating glucagon as well as decreased tumor size (26).
Figure 1. History of somatostatin-based peptide receptor radionuclide therapy (PRRT).
This early work set the stage for further development of this exciting new field of radiomolecular precision medicine. For example, guided by the experience with PRRT using 111In-pentetreotide, the need for more suitable radionuclides was identified because the properties of 111In (decay by electron capture with a half-life of 2.8 days) do not provide good tissue penetration which corresponds with a modest or no tumor shrinkage. Improvement of PRRT has been made tremendously since then due to the development and availability of novel peptides, chelators, and radionuclides in various combinations (27).
Derivatizing [Tyr3]-octreotide (Figure 2), which has a higher binding affinity for SSTR2 than the natural somatostatin analog (SSA) octreotide, and combining it with the chelator 1,4,7,10-tetra-azacyclododecane-tetra-acetic acid (DOTA) enabled stable radiolabeling with the high-energy beta particle-emitter Yttrium-90 (90Y-DOTATOC).
Figure 2. Simplified illustration of somatostatin receptor agonists and antagonists. 1-Nal, naphthyl-alanine; Aph(Hor), 4-amino-L-hydroorotyl -phenylalanine; D-Aph(Cbm), D-4-amino-carbamoyl-phenylalanine.
This therapeutic moiety was first applied in a pilot study for the treatment of three patients with abdominal metastases of neuroendocrine carcinoma of unknown localization (28, 29); and its therapeutic potential was evaluated subsequently with larger SSTR-positive patient numbers (30, 31). Treatment with 90Y-DOTATOC stopped rapid tumor progression, decreased the tumor marker neuron-specific enolase (NSE), and allowed disease stabilization (28, 30, 31). DOTATOC has since become a popular theranostics agent, demonstrating superior diagnostic sensitivity compared to Octreoscan, and demonstrating promising therapeutic value for treating SSTR-positive NETs when labeled with β- emitters, particularly Yttrium-90 (90Y) and Lutetium-177 (177Lu).
Another extensively studied SSA is DOTA-[Tyr3]-octreotate (DOTATATE), where the alcohol Thr(ol) of the C-terminus of DOTATOC is replaced by the natural amino acid Thr. This somatostatin analog was developed in 1998 and was found to show an even higher affinity to SSTR2 and a higher uptake in pancreatic tumor cells compared to the previously described SSAs (32).
The first clinical trial with 177Lu-DOTATATE started in 2000 in Rotterdam, The Netherlands, and led to the multinational phase three trial named NETTER-1 (33, 34). In this randomized controlled trial, a significantly higher response rate and extended progression-free survival were demonstrated in patients with advanced progressive SSTR-positive midgut NETs, compared to the double dose of long-acting repeatable (LAR 60 mg) octreotide administrations (18, 27, 34, 35). In January 2018, 177Lu-DOTATATE under the name of Lutathera was approved by the Food and Drug Administration (FDA) for the treatment of SSTR2-positive gastroenteropancreatic NETs (GEP-NETs) in adults (36). The approval of Lutathera in Europe was granted by the European Medicines Agency (EMA) already in September 2017 (37).
Other well-known somatostatin SSAs include lanreotide and vapreotide, but as these are not approved for PRRT of NETs, possibly due to their affinity pattern to SSTR subtypes and mode of action (38–40), they will not be discussed in this review.
Despite the success of [90Y]Y-DOTATOC and [177Lu]Lu-DOTATATE in the treatment of NETs in terms of progression-free survival, there were problems with 90Y concerning renal toxicity and a low rate of complete remissions, suggesting an improvement in PRRT efficacy is required (27, 41) with the main aspects of (1) identification of prognostic and predictive factors; (2) α-PRRT using 225Ac labeled ligands; and (3) shift from using SSAs to somatostatin antagonists.
68Ga-labeled somatostatin analogs for imaging (somatostatin receptor-PET)
Even with the success of DOTATOC and DOTATATE, clinicians need to take the individual variability in the therapy response of patients with seemingly similar profiles into account. 68Ga is a positron emitter that can be chelated to DOTATOC or DOTATATE for PET/CT imaging before therapy. SSTR-PET/CT with 68Ga-labeled DOTATATE and/or DOTATOC showed very promising results (42). All studies agreed on the important role of SSTR-PET using 68Ga for NET imaging and therapy planning, supporting the potent theranostic role of a radiolabeled DOTA-peptide (43–48). As a result, 68Ga-DOTATOC was approved by the FDA in 2019 as the first 68Ga-labeled radiopharmaceutical for imaging of SSTR positive GEP-NET using PET (49).
Choosing a radionuclide for peptide receptor radionuclide therapy
Table 1 lists the physical properties regarding the clinically most frequently used radioisotopes in PRRT of NETs.
Table 1. Physical properties of selected radioisotopes used in PRRT to treat NETs.
While 68Ga is useful for imaging purposes, all other radionuclides in Table 1 are used both for therapy and for single-photon emission computed tomography (SPECT) imaging. Out of these, 90Y and 177Lu are the two favorable isotopes due to their higher particle energies compared to 111In. 90Y (t1/2 = 64.2 h) emits β–-particles with a maximum energy of 2.284 MeV, allowing penetration of soft tissue to a depth of around 11 mm (50, 51). Because of its longer range compared to 177Lu, 90Y-DOTATE/TOC is suggested to be more suitable for bigger lesions, while 177Lu-DOTATATE might be preferred for smaller lesions (52). It has been demonstrated that 90Y-PRRT has a small potential of causing renal toxicity when used without nephroprotection, especially in patients with compromised renal function (53, 54). For 177Lu-DOTATATE or 177Lu-DOTATOC no significant renal damage occurred even in long-term follow up studies. An increasing number of clinical studies suggest that the combination of 90Y and 177Lu could be better than either radionuclide alone for PRRT in NETs, with an improved overall survival (55, 56). In parallel to β–-emitters, radionuclides emitting α-particles recently are gaining special interest for the treatment of NETs.
Why alpha in peptide receptor radionuclide therapy
To date, most PRRTs rely on β-emitters, especially 90Y and 177Lu, because of the availability of these radioisotopes and the proven clinical effect. However, due to the relatively large range of these radionuclides surrounding normal tissues are also exposed to radioactivity. Furthermore, hypoxic cancer tissue could be resistant to β-emitter treatment, causing radiotherapeutic failure of β-PRRT (57, 58).
Targeted α-particle therapy (TAT) offers a therapeutic option for patients resistant to β-irradiation treatments. An α-particle is a helium-4 (4He) nucleus consisting of two protons and two neutrons with an overall charge of +2 (59). Because of the double-positive charge, α-particles deliver dense ionization along a linear track, often described as high linear transfer (LET), ranging from 50 to 230 keV/μm (Figure 3) (60). This high LET renders higher target cell toxicity originating from higher probability of DNA double strand breaks (DSB) compared to β-particles with low LET (0.1–1.0 keV/μm) (61). Moreover, the primary target of high-LET α-particle is DNA, and a low number of particles can result in irreparable DSBs and lack of oxygen effects on cytotoxicity (62–64). Thus, the cytotoxicity of α-particle may be extremely effective and may also be more dose independent than β-emissions with cell death occurring from a single or a few α-particle traversals of the cell nucleus (65, 66). On the other hand, the typical tissue range of α-particles does not exceed 100 μm, which is significantly shorter than that of β-particles (0.05–12 mm) (Figure 3) (16, 58). This allows for selective ablation of the targeted tumor cells whilst minimizing the damage to surrounding healthy tissues (67).
Figure 3. Illustration of the tracks of α-particle, β-particle, and auger election radiation.
Why actinium-225
Considering the half-life, production, availability, and ability to be stably incorporated into a suitable vector, only a handful α-radionuclides have potential for clinical use, including actinium-225, bismuth-213, astatin-211, thorium-227, radium-223, radium-224, lead-212, bismuth-212, and terbium-149 (Table 2) (57, 64, 68–75).
Table 2. Medically relevant α-emitters with their decay properties.
Among all medically relevant α-particles, the generator derived radionuclide 225Ac (and its daughter radionuclide 213Bi) are considered particularly promising. 225Ac was discovered by Andre Debierne in 1899 and Friedrich Giesel in 1902 (76). As a pure α-emitter with a half-life of 9.9 days, the decay of 225Ac produces seven radionuclide daughters in the decay chain to stable 209Bi (Figure 4). From this decay path, a single 225Ac decay yields a total of four α, three β– disintegrations, and two γ emissions. As such, 225Ac is classified as nanogenerator or in vivo generator (77). The relatively long half-life, the multiple α-particle emissions in the decay chain, and the rapid decay to stable 209Bi makes 225Ac a candidate of great potential for application in TAT (78). Moreover, the isomeric γ emissions with energy suitable for SPECT imaging grants 225Ac the theranostic possibility (68, 69). Although the feasibility of using 225Ac for imaging is debatable because the amount administered for therapy may not produce enough gamma emission to be effectively detected by gamma camera.
Figure 4. Decay chain of 225Ac. 225Ac decays to 209Bi with seven intermediate radionuclide progenies, including 221Fr, 217At, 213Bi, 209Tl, 217Ra, 213Po, and 209Pb. Among the decay chain 225Ac and 213Bi are medically relevant and intensively investigated.
The initial focus for harnessing the therapeutic potential of 225Ac was to identify a suitable chelating agent for in vivo delivery of 225Ac to target cells (79, 80). DOTA remains the gold standard for 225Ac labeling for all clinical work. Examples include 225Ac-PSMA-617, 225Ac-DOTATOC, 225Ac-DOTATATE, and 225Ac-DOTA-HuM195 (81). The first-in-human phase I dose escalation trial used 225Ac-DOTA-HuM195, which not only demonstrated the safety of 225Ac and its antileukemic activity, but also suggested that targeted therapy with an in vivo α-particle nanogenerator is a feasible approach in humans (82). With this proof of concept, 225Ac was then attached to PSMA-617 for prostate cancer therapy (83–86) and also bound to SSA-based pharmaceuticals for treating NETs.
Preclinical studies of actinium-225-peptide receptor radionuclide therapy
Several preclinical studies tested the efficacy of α-particle emitting conjugates 225Ac-DOTATATE and 225Ac-DOTATOC in xenografted NET models and tested their toxicity as well as the biological effects of 225Ac. γH2AX was suggested as early key parameter in predicting tumor response to α-PRRT. The great reduction of growth and improved efficacy compared with 177Lu-labeled SSAs suggested that 225Ac-DOTATATE/DOTATOC has significant potential for improving PRRT in NETs and for the clinical translation in NET.
Clinical application of actinium-225-peptide receptor radionuclide therapy
The first clinical study of 225Ac-PRRT in NET treatment was started in 2011 as a collaboration between the Joint Research Centre in Karlsruhe (Germany) and the University Hospital Heidelberg to treat patients with progressive NETs using 225Ac-DOTATOC. Based on 46 treatment cycles in 34 patients, the maximum tolerable dose was determined to be 40 MBq. The treatment was found to be safe with doses of 18.5 MBq every 2 months or 25 MBq every 4 months, and a cumulative activity of 75 MBq in regard to delayed toxicity. Despite the treatment response observed in several patients, further investigations were found to be necessary to improve patient selection and dosage regimens (87). Since then, clinical studies of 225Ac-PRRT in different NETs focused on whole-body SPECT/CT imaging possibility, efficacy and safety, therapeutic effect, as well as comparison to β-PRRT, has burgeoned (Table 3).
Table 3. Actinium-225-peptide receptor radionuclide therapy in NET treatment.
Considering the minimal/acceptable side effects, and the improved therapeutic efficacy and survival, one can conclude that 225Ac-PRRT not only provides an alternative in the treatment of β-radiation-refractory NETs, but also presents as possible frontline in treatment of NETs and can potentially usher a new era in radiopharmaceuticals even in tumors beyond NET.
Challenges of using actinium-225 in peptide receptor radionuclide therapy
Production of actinium-225
Limited 225Ac supply poses the most important challenge for widely implementing 225Ac-based PRRT. For more than two decades, the radiochemical extraction from 229Th, which is originated from the decay of the fissile isotope 233U (Figure 4), has been the most utilized strategy for the production of 225Ac and its daughter 213Bi (88, 89). Even today, 225Ac used in all clinical and virtually all preclinical studies is still obtained from the decay of 229Th. Worldwide, only three sources of 229Th are available (81). The Directorate for Nuclear Safety and Security of the Joint Research Centre (JRC) of the European Commission in Karlsruhe, Germany, the first laboratory to prepare 225Ac/213Bi, has produced approximately 13 GBq 225Ac annually since the 1990s for their center and a wide network of clinical collaborators (89, 90). The Oak Ridge National Laboratory (ORNL), USA produces up to 33 GBq per year for extensive application of treatment (91), while the Institute of Physics and Power Engineering (IPPE) in Russia reported an estimated production of 22 GBq annually (92) with no direct clinical application reported yet to our knowledge. This amounts to a current global production of approximately 68 GBq per year. At this level of supply, 225Ac-based treatments will continue to only be available for some few 100 patients per year, which obviously is insufficient to meet the growing demand of 225Ac labeled compounds in hospitals worldwide (81, 93).
Consequently, multiple accelerator-based routes to scale up 225Ac production have been investigated, including the irradiation of 226Ra target using protons, deuterons or gamma-rays and the spallation of natTh or natU targets with highly energetic protons (Figure 5) (94). Among the routes described so far, the spallation of natTh is currently the most frequently used accelerator-based route. Even though the feasibility of the process has been demonstrated in the USA (95, 96) and Russia (97, 98), the implication of coproducing the long-lived 227Ac (t1/2 = 21.8 years) as impurity is a serious limitation in terms of clinical translation and waste management (99). In addition, issues with licensing and clinical safe handling need to be resolved (81).
Figure 5. Production routes of 225Ac.
Medium-energy proton irradiation of 226Ra in a cyclotron using the reaction 226Ra(p,2n)225Ac offers a number of advantages over the natTh spallation, and is currently the most promising method of large-scale and cost-effective production of 225Ac. Chemical purification of the irradiated targets generates 225Ac with high isotopic purity because there are no other long-lived actinium isotopes, such as 227Ac, co-produced (100). It is important to mention that the availability of appropriate cyclotrons worldwide [energy range 15–25 MeV (101)] makes the production of 225Ac feasible for basic and applied research (94). The downsides of this approach are related to the preparation and safe handling of targets containing milligram of radioactive 226Ra and managing its highly radiotoxic gaseous decay product 222Rn. Further research on the practical implementation of this production route is required to meet the high demand in the mid-term future (81).
The reaction 226Ra(d,3n)225Ac has been suggested as an improved approach for producing 225Ac (102). Model calculations are predicting an increased production yield compared to the 226Ra(p,2n)225Ac reaction. However, deuteron irradiation leads to an enhanced co-production of 226Ac via the 226Ra(d,2n)226Ac reaction, resulting in an extended cooling time necessary to allow for 226Ac decay. Moreover, limited accelerators are available worldwide that can provide deuteron beams of sufficient energy and the complicated handling of 226Ra and its decay product remains an issue (81).
Other production routes being studied involve 226Ra(n, γ)229Th(α)225Ac, 226Ra(γ,n)225Ra(β)225Ac, and 226Ra(n,2n)225Ra(β)225Ac. It is important to point out that the main limitation of all these strategies is the handling of radium target and the generation of long-lived co-products, such as 227Ac (t1/2 = 21.77 years) and 228Ac (t1/2 = 1.9 years). However, preliminary results demonstrated by these above-mentioned methods are promising (94, 100, 103–105). Unfortunately, but understandably, these supply limitations bring about a high cost that is considered unaffordable by many researchers.
Imaging
Clinical imaging using 225Ac also presents challenges. Therefore, post-therapy imaging is usually not done after 225Ac administration for tracer localization. The use of two photopeaks at 218 keV and 440 keV has long been suggested for clinical imaging of α-particles (106), until recently, Rasheed et al. focusing on gamma-ray spectrum for 225Ac showed an additional third photopeak at 78 keV, with higher counting density (107). Although imaging using the additional 78 keV photopeak was suggested to yield higher counts, better images, and more lesion delineations, the literature showing the feasibility of using the three photopeaks is limited to only few clinical case reports (108, 109).
Dosimetry
The short mean free path of 225Ac (110), as well as the complexity and timing of 225Ac decay in relation to its radiopharmaceutical stability, uptake and clearance makes measurement of 225Ac activity very difficult. A number of preclinical studies have estimated 225Ac activity using measurements related to γ-emissions (111). However, a low probability of γ-emission and overlapping Bremsstrahlung due to β-emitters in the 225Ac decay chain preclude simultaneous treatment and dosimetry measurement in a clinical setting (84). Thus, current clinical TAT research relies greatly on indirect approximation by extrapolating pre-existing 177Lu-labeled pharmaceuticals (84, 112, 113). Preclinical studies focusing on 225Ac have used the standard approach described by the Medical Internal Radiation Dose (MIRD) committee. Total dosimetry was calculated from the summation of doses of 225Ac, 221Fr, 217At, 213Bi, and 213Po recorded in a biodistribution study (111). Unfortunately, collection of biodistribution data for dosimetry estimation is not possible for most α-emitters with therapeutic potential. This makes a direct and accurate preclinical dosimetry measurement for 225Ac to be extrapolated into and to guide clinical trials, as well as standardizing α-dosimetry measurement highly demanded in clinical application.
Chelator
Finding a chelator to accommodate 225Ac and its progenies with sufficient stability was proven a great challenge given the range of different periodic properties of the daughters of 225Ac. The recoil effect associated with α-decay of 225Ac imparts an energy that is thousands of times greater than the binding energy of any chemical bond (75), resulting in an inevitable release of the daughter nuclide from the chelate moiety. Subsequently, the unbound α-emitting daughter nuclides are redistributed in vivo causing substantial harm to normal tissue and reducing the therapeutic effect. For example, the renal toxicity induced by 213Bi (in small animals) is considered a critical constraint to clinical use of 225Ac (114). However, recent results indicated that the release of free metals from DOTA may be not as evident as expected shown by fractioned radio-HPLC (115).
Finding a new chelator is one of the strategies to improve 225Ac-TAT. McDevitt et al. presented a comparison of 225Ac radiolabeling efficiency and in vitro stability of multiple chelators including DTPA, DOTA, TETA, DOTPA, TETPA, and DOTMP (116), and concluded that only DOTA and DOTMP showed chelation of 225Ac after 2 h at 37°C with radiochemical yields of >99 and 78%, respectively. Further in vitro serum stability testing showed that the 225Ac-DOTA complex outperformed the rest with >90% of complexes still intact after 10 days (104). Due to its outstanding stability, DOTA remains the gold standard for 225Ac-radiolabeling for all clinical research. However, DOTA has a decreased thermodynamic stability when used with larger metal ions. Moreover, chelation of 225Ac is a slow reaction demanding extensive heating and high amount of ligand for an adequate yield (77, 116, 117). Macropa, crown, and py4pa are new chelators with improved radiochemical yield and specific activity, as well as achievable labeling conditions. However, none of the new chelators was investigated enough so far to confirm in vivo stability, and their potential to translate into clinical application is yet to be assessed (118–122).
Quality control of actinium-225-radiopharmaceuticals
In addition to complicated handling, standardized quality control of radiopharmaceuticals remains a problem in routine clinical production. Because of the complicated decay chain of Ac-225 (Figure 4), special methods must be used for both measurements of the activities and for quality control by radio-thin-layer chromatography (radio-TLC) and radio-high-performance-liquid chromatography (radio-HPLC). Since alpha emitters are difficult to detect directly, indirect measurements are usually used for all measurements by detecting the daughters Fr-221 or Bi-213 (gamma emitters). Fr-221, with its short half-life of 4.9 min, is nearly in radioactive equilibrium after 60–120 min (123). In contrast, Bi-213, with a half-life of 45.6 min, takes hours to reach equilibrium. Thus, measurements of Fr-221 are often used for a faster quality control and release within a clinical environment. When separating free metals and labeled compounds on a TLC plate, the plate is equilibrated for an hour after development before being measured on a TLC scanner. During this period, a constant amount of Fr-221 has formed for both possible species, so comparison is possible, and a labeling yield can be determined. Afterward, an additional distinction must be made between the activity caused by the decay of Fr-221 and the activity of Bi-213. This can typically be differentiated in a gamma spectrometer by splitting the plate. Fr-221 has a line at 218 keV and Bi-213 at 440 keV (122, 124). However, the measurement with radio-TLC is not a valid method to determine the yield and purity of a radiopharmaceutical and additional radio-HPLC methods are required. Two possibilities are conceivable here. Direct detection of Ac-225 by liquid scintillation detection is relatively easy to implement, but may require large activities for injection, which is not always practical and can be very expensive. Therefore, indirect detection of the daughters can be used again by the fractionated collection of the measured sample and subsequent analysis of their components in a gamma spectrometer. In this way, the retention behavior of the compounds on the column can be investigated even when injecting small quantities, and possibly more precise statements can be made about side- or decomposition-products (115).
Future of actinium-225-peptide receptor radionuclide therapy
Combination with somatostatin receptor antagonist
Today, the development of novel SSTR antagonists holds promise for enhanced diagnostic accuracy and efficacy of SSTR-mediated imaging and therapy. SSTR2-selective 111In-DOTA-BASS (125) and SSTR3-selective ODN-8 (126, 127), the first generation of radiolabeled SSTR antagonists all recognized a larger number of binding sites and revealed an in general twofold higher uptake level in vitro than their agonist counterparts (128). Despite this, BASS labeled with 64Cu via the chelator 4, 11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo [6.6.2]hexadecane (CB-TE2A) (64Cu-CB-TE2A-BASS) showed a compromised tumor uptake compared to the agonist 64Cu-CB-TE2A-octreotate in SSTR2-positive AR42J xenografts (129).
This suboptimal tumor uptake triggered the second generation of radiolabeled SSTR antagonists. In 2006, Ginj et al. presented the idea that radiolabeled SSTR antagonists may perform better than agonists despite the lack of receptor-mediated internalization (127). Despite its lack of internalization, SSTR antagonist demonstrated higher tumor uptake with a higher tumor-to-normal ratio and longer tumor retention time than that of agonist, possibly due to its capability to bind larger variety of receptor conformations, than that of SSTR agonists (130). The initial evidence that antagonists are superior to agonists guided the design and development of more potent SSTR2 antagonists with improved affinity (127, 131), with some of the potential antagonists studied as radiotracers. Among all the potential SSTR2 antagonists, LM3 and JR11 were the most interesting, having the highest hydrophilicity and best affinity. These two were evaluated in a comprehensive study, in combination with two chelators DOTA and NODAGA, and multiple radiometals (132, 133). Interestingly, 68Ga-DOTA-JR11 and -LM3, which have drastically lower affinities for SSTR2 (approximately 150-fold and 60-fold, respectively) than 68Ga-DOTATATE, showed higher tumor uptake (132). Likewise, the therapeutic counterpart 177Lu-DOTA-JR11 exhibited a higher tumor uptake, a longer tumor retention time, and an improved tumor-to-kidney ratio compared to 177Lu-DOTATATE (134), and hence led to a delayed tumor growth and an extended median survival period (135).
Lutetium-177-DOTA-JR11 was first compared in a pilot study with 177Lu-DOTATATE. In the same four patients with grade 1–3 metastatic NET, it showed a 1.7–10.6 times higher tumor dose, and at the same time a 1.1–7.2 times higher tumor-to-kidney and tumor-to-bone marrow ratio, compared with 177Lu-DOTATATE (136, 137). A phase I study with 20 grade 1–3 patients reported a best overall response of 45% (RECIST 1.1 criteria) and a median progression-free survival of 21 months (95% CI: 13.6-not reported). Unfortunately, grade 4 hematotoxicity was reported in 4 out of 7 patients after two cycles of 177Lu-DOTA-JR11, resulting in the suspension of this therapy protocol (138). The protocol was under subsequent modification to limit cumulative absorbed bone marrow dose. A phase I/II open-label study (Clinical trial identification: EudraCT: 2015-002867-41; NCT02592707) is currently ongoing to evaluate the safety and efficacy with the adjusted treatment regimen. Hitherto, only one abstract summarizing the promising efficacy and low toxicity is available. In 20 patients with adequate follow-up, no grade 3/4 renal toxicities and a 90% (95% CI: 68.3–98.8%) disease control rate was reported (139).
In parallel to 177Lu-DOTA-JR11, 177Lu-DOTA-LM3 was evaluated in 51 patients with metastatic neuroendocrine neoplasm at the Theranostics Center for Molecular Radiotherapy and Precision Oncology in Wiesbaden, Germany. 177Lu-DOTA-LM3 was reported to have a 3–5.1 times higher absorbed doses and a 22 h longer whole-body effective half-life than the agonist 177Lu-DOTATOC. All patients tolerated therapy well without any serious acute adverse effects, in particular, there was no nephrotoxicity observed (130).
Here we would like to showcase our recent therapeutic result of PRRT using 225Ac-DOTA LM3 to demonstrate the exciting potential of 225Ac labeled SSTR antagonist in NET treatment (Figure 6). A 40-year-old pancreatic-NET patient suffered from bilobar liver metastases and extensive bone metastasis even after multiple cycles of PRRT with 177Lu-DOTATATE, and compromised therapeutic response after one cycle of 177Lu-DOTA-LM3 treatment, was suggested for PRRT with 225Ac-DOTA-LM3. This case with β-radiation refractory metastatic NET demonstrated incredibly auspicious therapeutic response after two cycles of 225Ac-DOTA-LM3, especially concerning the bone metastases. With this successful case reported for the first time, we would like to suggest that PRRT with 225Ac-labeled SSRT antagonist can potentially be a game changer in therapeutic nuclear medicine, and a promising cure for metastasized tumor.
Figure 6. A 40-year-old patient was diagnosed with poorly differentiated non-functioning pancreatic-NET with bilobar liver and extensive bone metastases, Ki-67 index of 25% NEN-G3 without known mutations. The patients had previously undergone laparoscopic subtotal pancreatic resection and splenectomy, CAPTEM chemotherapy, transarterial chemoembolization (TACE) of right liver lobe and resection of abdominal lesion. In addition, the patient had previous ineffective treatment with Lanreotide, Everolimus, and Sunitinib. In total, the patient had received eight cycles of PRRT, and had a very poor prognosis, extensive bone metastases, even after multiple cycles treatment with 177Lu-DOTATATE (A,B, 68Ga-DOTATOC PET/CT before and after 177Lu-DOTATATE treatment). The 9th PRRT cycle was performed with 177Lu-DOTA-LM3 (B,C, PET/CT imaging before and after 177Lu-DOTA-LM3 treatment), and the last two cycles with 225Ac DOTA-LM3 (C,D, PET/CT imaging before and after 225Ac-DOTA-LM3 treatment), 10 MBq in March and 15 MBq in May 2022, respectively. The cumulative administered radio activities are 66.7 GBq of 177Lu and 25 MBq 225Ac. Restaging result in July 2022 showed excellent response to 225Ac-DOTA-LM3 treatment with partial remission according to the THERCIST. As shown in the most recent PET/CT, there is dramatic improvement, especially concerning the previous innumerable bone metastases in the spine, ribs, and pelvis. The primary tumor in the pancreas, and the liver and bone metastases further decreased in size and number, and no new metastatic lesions were noted. The patient felt dramatically better in comparison to the previous treatments. After the last PRRT, he only experienced mild alopecia and mild pain in the upper right abdomen over 1 week, and has been physically active and gained 3 kg body weight over the past 2 months.
Moreover, the pharmacodynamics of SSTR antagonists have been studied as the clinical interest for them is rapidly growing. The antagonist showed faster association, but slower dissociation, as well as longer cellular retention time compared to the agonist. Moreover, antagonists recognize more binding sites than agonists, providing more targeting opportunities (140). Taking the proposed mechanism, preclinical and clinical studies into consideration, it is obvious that using radiolabeled SSTR antagonists, especially LM3 and JR11, may provide more successful imaging and PRRT strategies for neuroendocrine tumors, even those with relatively low SSTR expression (130, 137, 141) compared to agonists.
Cocktail approach
Most PRRTs using radiolabeled SSAs and antagonists has until now depended substantially on the most prominently expressed SSTR2 (142). However, NET expression of SSTR subtypes is heterogeneous, and things are made even more difficult by contradictory expression profiles due to different detection methods (20, 143–153). Also, the downregulation or loss of SSTR2 in advanced stages is inherently associated with worse disease prognosis, compromised image sensitivity, and suboptimal therapy with SSTR2-specific radiolabeled SSAs. Using SSTR agonists and antagonists with affinity to more SSTR subtypes is therefore a proposed method—a cocktail approach—of great clinical interest (154). An impressive clinical case showing the application of this cocktail approach, where six tracers were given to a single patient with prostate cancer, was reported at the 2016 SNMMI Highlights Lecture (155). Inspired by the cocktail approach in treating prostate cancer, using SSTR analogs and antagonists targeting various SSTR subtypes in combination with 225Ac-PRRT is worth exploring.
Conclusion
Peptide receptor radionuclide therapy in NET patients has come a long way since Krenning’s first treatments in the 1990s. Novel radionuclides are constantly being developed and tested, in a race to find the perfect theranostic pair. Modified chelators and new ligands including SSTR antagonists are gaining more and more attention, the latter in particular as they have been revealed to give great tumor uptake, retention time and tumor-to-background ratio. 225Ac in particular is very worth investigating.
The rise of the α-emitters as a compliment or replacement to β-emitters is one of the most exciting recent developments. The shorter range gives “precision” in precision medicine a new meaning: Even less damage to surrounding healthy tissue and even more powerful damage to tumor cells.
To this date, confirmed literature on PRRT using an α-emitter with a SSTR antagonist has yet to be published, and obviously, there are still many hurdles to overcome. Technical ones, such as how to best combine chemical moieties into a stable, pharmacokinetically feasible drug; economical ones, such as how to best implement a global mass production of radionuclides for research and clinical use; clinical ones, such as how to set a dosage of the existing theranostic pairs that minimizes toxicity whilst maximizing tumor uptake. Yet, to have the recent promising clinical studies on 177Lu-DOTA-LM3 and -JR11 in mind at the same time as the potentials of TAT is intriguing; hopefully a new and promising era for NET therapy will see daylight in the foreseeable future.
Author contributions
JZ, XC, and RB: study conception and design. MS, VJ, and RB: data collection. MS and JZ: analysis and interpretation of results. MS and VJ: writing—original draft preparation. JZ, LG, P-LK, RB, and XC: writing—review and editing. All authors reviewed the results and approved the final version of the manuscript.
Funding
This study was supported by the National University of Singapore Start-up grant (NUHSRO/2021/097/Startup/13 and NUHSRO/2020/133/Startup/08), NUS School of Medicine, Nanomedicine Translational Research Program (NUHSRO/202 1/034/TRP/09/Nanomedicine), and the International Centers for Precision Oncology (ICPO) Foundation.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Keywords: actinium-225, neuroendocrine tumor, peptide receptor radionuclide therapy (PRRT), targeted α-particle therapy, SSTR, SSTR antagonist
Citation: Shi M, Jakobsson V, Greifenstein L, Khong P-L, Chen X, Baum RP and Zhang J (2022) Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists. Front. Med. 9:1034315. doi: 10.3389/fmed.2022.1034315
Received: 01 September 2022; Accepted: 21 November 2022;
Published: 07 December 2022.
Edited by:
Maria Picchio, Vita-Salute San Raffaele University, ItalyReviewed by:
Marco Maccauro, Fondazione IRCCS Istituto Nazionale Tumori, ItalyChiara Maria Grana, European Institute of Oncology (IEO), Italy
Copyright © 2022 Shi, Jakobsson, Greifenstein, Khong, Chen, Baum and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jingjing Zhang, j.zhang@nus.edu.sg