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Theranostics 2016; 6(10):1611-1618. doi:10.7150/thno.15132 This issue Cite

Research Paper

Comparison between Three Promising ß-emitting Radionuclides, ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb, with Emphasis on Doses Delivered to Minimal Residual Disease

Christophe Champion¹ , Michele A. Quinto¹, Clément Morgat², Paolo Zanotti-Fregonara², Elif Hindié²

1. Université de Bordeaux, CNRS/IN2P3, Centre d'Etudes Nucléaires de Bordeaux Gradignan (CENBG), France;
2. Service de Médecine Nucléaire - CHU de Bordeaux; UMR-CNRS 5287; LabEx TRAIL; Université de Bordeaux, FRANCE.

✉ Corresponding authors: Pr Christophe Champion, PhD. Centre d'Etudes Nucléaires de Bordeaux Gradignan, Chemin du Solarium, BP 120, 33175 Gradignan. Tel.: +33 557120896; Fax: +33 557120801 e-mail: championin2p3.fr Or Pr Elif Hindié, MD, PhD. Service de Médecine Nucléaire, Hôpital Haut-Lévêque, CHU de Bordeaux, 33604 Pessac, France. Tel: +(33)557656838; Fax: +(33)557656839 e-mail: elif.hindiefr. More

Abstract

PURPOSE: Radionuclide therapy is increasingly seen as a promising option to target minimal residual disease. Copper-67, scandium-47 and terbium-161 have a medium-energy β^- emission which is similar to that of lutetium-177, but offer the advantage of having diagnostic partner isotopes suitable for pretreatment imaging. The aim of this study was to compare the efficacy of ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb to irradiate small tumors.

METHODS: The absorbed dose deriving from a homogeneous distribution of ⁶⁷Cu, ⁴⁷Sc or ¹⁶¹Tb in water-density spheres was calculated with the Monte Carlo code CELLDOSE. The diameters of the spheres ranged from 5 mm to 10 µm, thus simulating micrometastases or single tumor cells. All electron emissions, including β^- spectra, Auger and conversion electrons were taken into account. Because these radionuclides differ in electron energy per decay, the simulations were run assuming that 1 MeV was released per µm³, which would result in a dose of 160 Gy if totally absorbed.

RESULTS: The absorbed dose was similar for the three radionuclides in the 5-mm sphere (146-149 Gy), but decreased differently in smaller spheres. In particular, ¹⁶¹Tb delivered higher doses compared to the other radionuclides. For instance, in the 100-µm sphere, the absorbed dose was 24.1 Gy with ⁶⁷Cu, 14.8 Gy with ⁴⁷Sc and 44.5 Gy with ¹⁶¹Tb. Auger and conversion electrons accounted for 71% of ¹⁶¹Tb dose. The largest dose differences were found in cell-sized spheres. In the 10-µm sphere, the dose delivered by ¹⁶¹Tb was 4.1 times higher than that from ⁶⁷Cu and 8.1 times that from ⁴⁷Sc.

CONCLUSION: ¹⁶¹Tb can effectively irradiate small tumors thanks to its decay spectrum that combines medium-energy β^- emission and low-energy conversion and Auger electrons. Therefore ¹⁶¹Tb might be a better candidate than ⁶⁷Cu and ⁴⁷Sc for treating minimal residual disease in a clinical setting.

Keywords: Dose, radionuclide therapy, minimal residual disease, micrometastases, terbium-161, copper-67, scandium-47, lutetium-177.

Introduction

Targeted radionuclide therapy relies on the administration of radiolabeled compounds to irradiate tumors [1]. Iodine-131 has been used since seven decades to prevent recurrence of thyroid cancer after surgery and to treat distant metastases [2-4]. In the past years, several other tumor-targeting radiopharmaceuticals, labeled with iodine-131, yttrium-90, or lutetium-177, have successfully entered into clinical practice. Examples include ¹³¹I-MIBG for neural crest tumors, anti-CD20 antibodies (e.g. ⁹⁰Y-ibritumomab tiuxetan) for lymphomas [5], the somatostatin analogs ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE for neuroendocrine tumors [6] and more recently ¹⁷⁷Lu-labelled PSMA ligands for metastatic prostate cancer [7]. Notably, an ever-increasing number of preclinical studies and clinical trials aim at using radionuclide therapy to treat minimal residual disease: i.e. as adjuvant therapy or for consolidation after remission [8-13].

Many of the novel radiopharmaceuticals for targeted therapy have been armed with lutetium-177 [6-9]. ¹⁷⁷Lu can be stably chelated to various peptides and antibodies [14]. Compared to the high-energy electrons of ⁹⁰Y, the medium-energy β^- emission of ¹⁷⁷Lu allows for a more effective irradiation of small tumors and is associated with a reduced non-specific toxicity [15-18]. Both characteristics are important in the perspective of targeting minimal residual disease. Moreover, ¹⁷⁷Lu emits γ photons which enable post-therapy imaging.

Three other promising medium-energy β^- emitters are: copper-67 [19,20], scandium-47 [21,22] and terbium-161 [23-25]. Their half-lives are suitable for targeted radionuclide therapy with peptides and antibodies (Table 1). The half-life of ¹⁶¹Tb (6.91 d) is similar to that of ¹⁷⁷Lu (6.65 d). The half-lives of ⁶⁷Cu and ⁴⁷Sc are shorter (respectively 2.58 d and 3.35 d) and thus they might be used to label molecules that exhibit a more rapid washout from tumor tissues. Just like ¹⁷⁷Lu, ¹⁶¹Tb is a radiolanthanide that can be stably linked to various molecules using for example DOTA as chelator [24,25]. Chelators that are suitable for stable coordination of copper and scandium are also available [14]. All three radionuclides are amenable to imaging thanks to some gamma photon emissions (Table 1). Photons from ⁶⁷Cu and ⁴⁷Sc (184.6 keV and 159.4 keV, respectively) are better suited to post-therapy imaging with gamma cameras than the photons emitted by ¹⁶¹Tb (whose energy of 74.6 keV is similar to that emitted by the myocardial imaging agent ²⁰¹Tl). On the other hand, the lower proportion of photon emission of ¹⁶¹Tb (~15% of the total emitted energy, compared to ~40% for ⁶⁷Cu or ⁴⁷Sc) minimizes total body dose and allows for treatment on an outpatient basis.

One major advantage of these radionuclides over ¹⁷⁷Lu is the theranostic potential, i.e. the availability of β⁺ (⁶⁴Cu, ⁴³Sc, ⁴⁴Sc, ¹⁵²Tb) or γ-emitting (¹⁵⁵Tb) radioisotopes that enable PET or SPECT pre-therapy imaging and dosimetry [26-30]. Table 2 summarizes the physical properties of these diagnostic radionuclides. The biodistribution of the molecule labeled with the diagnostic radionuclide is expected to faithfully match that of the therapeutic molecule.

The aim of this study was to compare the effectiveness of ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb at irradiating small tumors. Using the Monte Carlo code CELLDOSE [31,32], we assessed the dose deposits from these radionuclides in spheres of various sizes, simulating micrometastases and single tumor cells.

Methods

The absorbed dose in each sphere was assessed with Monte Carlo simulations by taking into account all electron emissions: β-spectra, conversion electrons (CE) and Auger electrons (including Coster-Kronig electrons). Emission data were obtained from the International Commission on Radiological Protection (ICRP) publication ICRP-107 [30]. Photons were neglected. For all simulations, the distribution of radioactivity within spheres was assumed to be homogeneous. This was achieved by random Monte Carlo sampling throughout the sphere volume using a high number of simulations (≥ 1,000,000 per sphere). Decay characteristics of ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb are reported in Table 1. The spectra of electron emissions are shown in Figure 1.

 Figure 1 

Electron emissions of ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb. β-spectra are in red (integral of the curve = 1), conversions electrons (CE) are in blue and Auger electrons (including Coster-Kronig electrons) in green. Conversion and Auger electrons whose probability was <0.0001 [30] were neglected and are not represented.

Event-by-event electron track simulations in CELLDOSE are based on the cross sections of the interactions between the electron and the water molecule, and take into account ionizations, excitations and elastic scattering processes [31-33]. The slowing-down histories for primary and secondary electrons are described until the energy falls to 7.4 eV (electron excitation threshold of the water molecule) [33]. The residual energy is considered to be absorbed locally.

The doses from a single radioactive decay (S-values) for ⁶⁷Cu and ⁴⁷Sc were assessed in spheres of water density and compared with those previously calculated for ¹⁶¹Tb in the same spheres [18]. The diameter of the spheres ranged from 5 mm to 10 µm, thus simulating micrometastases of various sizes and single tumor cells. The relative contribution from the different electron emissions (β^- particles, CE, Auger electrons) was also assessed as previously described with ¹³¹I [31].

In addition to S-values, we calculated the absorbed dose resulting from a uniform concentration of events (1 decay per µm³). Since ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb differ in the total amount of electron energy emitted per decay, the absorbed doses were compared after normalization over a fixed amount of energy released per unit of volume (1 MeV per µm³). If totally absorbed, this concentration would yield 160 Gy. Based on the total electron energy per decay (Table 1), the average number of decays per cubic micrometer (N) that releases 1 MeV of energy is: 6.65 for ⁶⁷Cu, 6.16 for ⁴⁷Sc and 4.94 for ¹⁶¹Tb. Assuming a complete physical decay, no biological elimination, and a tissue density of 1g/cm³, this corresponds to an activity concentration (A₀ = N × ln2 / T) of: 20.71 MBq/g for ⁶⁷Cu, 14.76 MBq/g for ⁴⁷Sc and 5.74 MBq/g for ¹⁶¹Tb.

Finally, we examined the spatial profile of energy deposits around a point source of ⁶⁷Cu, ⁴⁷Sc or ¹⁶¹Tb. Energy deposits (eV per decay) were studied inside concentric 10-µm-thick shells around the point source.

Results

S values for ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb and contribution of the different electron emissions

S-values measured with the Monte-Carlo dose CELLDOSE are reported in Table 3. Results agreed (differences <10%) with those reported by Bardiès for ⁶⁷Cu and ⁴⁷Sc in spheres >20 µm using analytic methods based on scaled dose point kernel [34]. Bardiès and colleagues did not report on smaller spheres and did not study Terbium-161. The relative contributions of β^- particles, CE and Auger electrons are also reported in Table 3. In the case of ⁴⁷Sc, almost all the absorbed dose was due to β^- emission (>99% for all spheres). β^- emission was also the main contributor to the doses delivered by ⁶⁷Cu, with only modest contribution from CE and Auger electrons (10.1 to 29.3%). By contrast, ¹⁶¹Tb displayed a significant contribution from CE and Auger electrons. The combined contribution from ¹⁶¹Tb CE and Auger electrons to the total absorbed dose was 25.9% in the 5-mm sphere and reached 88.3% in the cell-sized 10-µm sphere (Table 3).

Electron dose deposits after normalization

When 1 MeV per µm³ was released, the absorbed dose in the 5-mm sphere was similar for the three radionuclides (146 to 149 Gy). The absorbed dose progressively decreased when the sphere size decreased, but the dose reduction was more abrupt for ⁶⁷Cu and ⁴⁷Sc than for ¹⁶¹Tb (Fig. 2). ¹⁶¹Tb was clearly superior to the other radionuclides for spheres with less than 1mm diameter. For example, in a 100-µm micrometastasis the absorbed dose was 24.1 Gy with ⁶⁷Cu, 14.8 Gy with ⁴⁷Sc and 44.5 Gy with ¹⁶¹Tb (Table 4). The largest dose difference was found in cell-sized spheres: in the 10-µm sphere, the doses delivered by ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb were 3.42 Gy, 1.74 Gy and 14.1 Gy, respectively (Table 4).

 Figure 2 

Electron dose delivered by ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb (considering 1 MeV released per µm³) as a function of sphere size. The maximal value of 160 Gy/MeV/µm³ corresponds to total absorption.

 Figure 3 

Patterns of energy deposit (keV per MeV released) of ⁴⁷Sc and ¹⁶¹Tb over the first 500 µm around a point source.

Electron energy deposit around a point source

The energy deposited by ¹⁶¹Tb (per MeV released) was considerably higher than that deposited by the other radionuclides up to 30 µm around the point source (Fig. 3). This suggests that ¹⁶¹Tb would deliver a higher dose not only to the targeted cell, but also to its immediate neighbors. Beyond this distance, the differences in energy deposits leveled off: the radius within which 50% of the energy is deposited (R50) was 0.17 mm for ⁶⁷Cu, 0.25 mm for ⁴⁷Sc and 0.15 mm for ¹⁶¹Tb. The radius within which 90% of the emitted energy is deposited (R90) was 0.57 mm for ⁶⁷Cu, 0.72 mm for ⁴⁷Sc and 0.63 mm for ¹⁶¹Tb.

Discussion

In many cancers, the prognosis is linked to metastatic relapse, which may occur years after primary surgery [35-37]. Targeted radionuclide therapy may play a major role to treat occult micrometastases in high-risk patients or to eradicate minimal residual disease [2, 8-13]. Several preclinical and clinical studies suggest that radionuclide therapy is more effective when administered at an early stage of the disease [4,6,38,39], probably because the distribution of the radiopharmaceutical in tumors is still relatively homogeneous. However, radionuclides differ in their ability to irradiate micrometastases [16]. In this study we assessed the relative effectiveness of three promising medium-energy β-emitters, i.e. ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb.

Since the electron energy per decay of these three radionuclides differs, we assumed that 1 MeV was released per µm³. If totally absorbed, this energy would always yield a dose of 160 Gy. Absorbed doses of this magnitude were measured in macrometastases of neuroendocrine tumors in patients who responded to ¹⁷⁷Lu-DOTATATE therapy [40]. Smaller and more homogeneous tumors are expected to respond to lower doses.

Our simulations showed that, for the three radionuclides, the doses delivered to a 5‑mm metastasis (146 to 149 Gy) were close to the dose that would result from total absorption. The doses decreased with sphere size, thus underscoring the fact that micrometastases are more difficult to irradiate effectively. The dose delivered by ¹⁶¹Tb was however consistently higher than that delivered by the other radionuclides (Fig. 2). For example, in a 100-µm micrometastasis, the absorbed dose was 44.5 Gy for ¹⁶¹Tb, 24.1 Gy for ⁶⁷Cu and 14.8 Gy for ⁴⁷Sc (Table 4). The largest differences were found in the smallest spheres: in a cell-sized sphere of 10 µm diameter, the dose delivered by ¹⁶¹Tb was 14.1 Gy, compared to 3.42 Gy and 1.74 Gy for ⁶⁷Cu and ⁴⁷Sc. Thus, relatively to the almost pure β^- emission of ⁴⁷Sc, the doses delivered by ¹⁶¹Tb were ~3 times higher in a 100-µm micrometastasis and ~8 times higher in a 10-µm single cell (Table 4). In a previous work, we showed that the dose delivered by ¹⁶¹Tb to small metastases was also higher than that delivered by ¹⁷⁷Lu [18]. In Table 4, the absorbed doses from ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb (for 1 MeV released per µm³) are compared to those from ¹⁷⁷Lu, used as a reference.

Our Monte Carlo study provides a mechanistic framework that explains some recent preclinical findings on tumor-control efficacy [24,25]. Anti-L1CAM antibody labeled with ¹⁶¹Tb inhibited the growth of subcutaneous xenografts of ovarian cancer more effectively than the same antibody labeled with ¹⁷⁷Lu and injected at a comparable activity (corresponding to 50% of the maximum tolerated dose) [25]. In a cell culture study, the radioactivity concentration of folate conjugates required to achieve the half-maximal inhibition of KB cells (human cervical carcinoma) was 4.5 fold lower with the ¹⁶¹Tb-labeled conjugate than with the ¹⁷⁷Lu-labeled conjugate [24]. This difference was smaller (×1.7) for IGROV-1 cells (human ovarian carcinoma), which might be explained by the lower internalization rate of folate conjugates into these cells [24].

The higher efficacy of ¹⁶¹Tb compared to ⁴⁷Sc and ⁶⁷Cu is mainly due to the larger amount of Auger and low-energy conversion electrons (Fig. 1), whose doses are deposited over relatively short distances (Fig. 4). Indeed, CE and Auger electrons accounted for 71% of the radiation dose deposited by¹⁶¹Tb in a 100-µm metastasis and 88% of the dose deposited in a 10-µm cell (Table 3). This contrasts with ⁴⁷Sc data, where >99% of the absorbed energy was due to β^- particles for all spheres. The interpretation of experimental results may be further refined by considering the linear energy transfer (LET) of emitted electrons. Not only emission spectra from ¹⁶¹Tb are rich in Auger electrons, but also the majority of conversion electrons of ¹⁶¹Tb have low energy (< 50 keV) and thus high LET (Table 5).

 Figure 4 

Two-dimensional plots of the tracks of two representative conversion electrons and two representative Auger electrons from ¹⁶¹Tb as simulated with CELLDOSE. Panel A reproduces the full path of the two CE (39.9 keV and 17.87 keV). Panel B is a magnification of the paths of Auger electrons (5.25 keV, 1.02 keV). The solid and open circles represent the ionizing interactions induced by the primary and the secondary electrons, respectively.

Knowledge of the biodistribution of the radiopharmaceutical at the cellular and subcellular level is of paramount importance to rationally choose the most appropriate radionuclide. Radionuclides can be imaged and quantified with techniques such as autoradiography or secondary ion mass microscopy [41]. This distribution may be used as input to derive the dose to tumor cells [32]. The energy deposited by ¹⁶¹Tb (per MeV released) is higher than that deposited by the other radionuclides up to 30 µm around a point source (Fig. 3). Thus, ¹⁶¹Tb would likely deliver a higher dose, not only to the targeted cell, but also to its immediate neighbors. Moreover, the short tracks of energy deposit of Auger electrons and some low energy conversion electrons (Fig. 4) suggest that a putative ¹⁶¹Tb-labeled radiopharmaceutical would be even more effective if transported into the cell and internalized into the nucleus [42]. The impact of Auger electrons on other targets such as the cell membrane also deserves investigation [43]. Our future work will compare the dose distribution of ¹⁶¹Tb to that of other β-, Auger- or α-emitting radionuclides [44] for various cellular distributions. Also, since only limited preclinical work on ¹⁶¹Tb has been done so far [24,25], additional studies should be carried out to establish whether ¹⁶¹Tb is a good candidate for clinical use. Hopefully, preclinical data [24,25], and the theoretical framework provided by our own calculations, will encourage the development of new radiopharmaceuticals labelled with ¹⁶¹Tb.

Finally, the choice of radionuclides for radiopharmaceutical therapy may be driven by logistic issues. Producing ⁶⁷Cu as no-carrier-added in amounts suitable for large clinical use has been difficult [19,20]. The optimal technique to produce ⁴⁷Sc is still debated [21,22]. Preliminary data suggest that ¹⁶¹Tb can be produced in large amounts as no-carrier-added, using for example a gadolinium-160 target (¹⁶⁰Gd(n,γ)¹⁶¹Tb), and with good radionuclide purity (¹⁶⁰Tb to ¹⁶¹Tb activity ratio <0.0001) [45]. The cost for large-scale production is estimated to be comparable to that of no-carrier-added ¹⁷⁷Lu [45].

Conclusion

Radiopharmaceutical therapy can effectively target isolated tumor cells and occult micrometastases, provided that the optimal radionuclide is used. Our investigations on three theranostic radionuclides suggest that ¹⁶¹Tb might be a better choice than ⁶⁷Cu or ⁴⁷Sc. The promising characteristics of this radionuclide justify further preclinical investigations and, hopefully, clinical trials.

Acknowledgements

We thank Pr. Keith Eckerman for helpful discussions regarding the ICRP-107 data files.

Financial support

This work was funded by the Institut National de la Santé et de la Recherche Médicale under contract PhysiCancer “MICRONAUTE project” and by the French Investment for the Future program within LabEx TRAIL ANR-10-LABX-57.

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding authors: Pr Christophe Champion, PhD. Centre d'Etudes Nucléaires de Bordeaux Gradignan, Chemin du Solarium, BP 120, 33175 Gradignan. Tel.: +33 557120896; Fax: +33 557120801 e-mail: championin2p3.fr Or Pr Elif Hindié, MD, PhD. Service de Médecine Nucléaire, Hôpital Haut-Lévêque, CHU de Bordeaux, 33604 Pessac, France. Tel: +(33)557656838; Fax: +(33)557656839 e-mail: elif.hindiefr.

Received 2016-1-29
Accepted 2016-5-1
Published 2016-6-18

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