Summary

The favorable decay characteristics of ¹⁶¹Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). ¹⁶¹Tb decays with a similar half-life to ¹⁷⁷Lu, but beyond the emission of β⁻-particles and γ-rays, ¹⁶¹Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of ¹⁶¹Tb and ¹⁷⁷Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake.

[¹⁶¹Tb]Tb-SibuDAB and [¹⁶¹Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor–bearing mice. The ¹⁷⁷Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. 

Results from nanoScan^® SPECT/CT

For the dual-isotope SPECT/CT PC-3 PIP/flu tumor–bearing BALB/c nude mice were injected with a mixture of [¹⁶¹Tb]Tb-SibuDAB and [¹⁷⁷Lu]Lu-SibuDAB or [¹⁶¹Tb]Tb-PSMA-I&T and [¹⁷⁷Lu]Lu-PSMA-I&T (20 MBq, 1 nmol per mouse in total).

• The nanoScan® SPECT/CT system made observable the phenomenon that irrespective of whether the prostate-specific membrane antigen (PSMA)–targeting radioligands were labeled with ¹⁶¹Tb or ¹⁷⁷Lu, the resulted in vitro data were similar; and the tissue distribution profiles were directly comparable. As a result of the albumin-binding properties, [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%–69% injected activity per gram at 24 h after injection) than [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-PSMA-I&T (30%–35% injected activity per gram at 24 h after injection).
• The SPECT images reconstructed on the basis of the γ-lines of ¹⁶¹Tb or ¹⁷⁷Lu showed equal distribution in the blood, tumor, and kidneys of the same mouse, irrespective of the used radionuclide. At 1 h after injection of [¹⁶¹Tb]Tb-SibuDAB/[¹⁷⁷Lu]Lu-SibuDAB, blood retention was increased as compared with that of [¹⁶¹Tb]Tb-PSMA-I&T/[¹⁷⁷Lu]Lu-PSMA-I&T, whereas kidney retention appeared somewhat lower for the former. At the 4-h time point, the differences between radiolabeled SibuDAB and PSMA-I&T were less pronounced (Fig. 3).

Figure 3 Dual-isotope SPECT/CT images of mice bearing PC-3 PIP (right shoulder) and PC-3 flu (left shoulder) tumor xenografts 1 and 4 h after injection of 1:1 mixture (20 MBq per mouse) of [¹⁶¹Tb]Tb-SibuDAB and [¹⁷⁷Lu]Lu-SibuDAB (A) or [¹⁶¹Tb]Tb-PSMA-I&T and [¹⁷⁷Lu]Lu-PSMA-I&T (B). Image reconstruction was based on γ-lines of ¹⁶¹Tb (red), ¹⁷⁷Lu (green), or both (red/green overlay). Bl = bladder; Ki = kidneys; PC-3 flu = PSMA-negative tumor xenograft; PC-3 PIP = PSMA-positive tumor xenograft.

Conclusions

In this study the absorbed tumor dose estimated for the ¹⁶¹Tb-based PSMA ligands was 40% higher than that of the ¹⁷⁷Lu-based counterparts. As a result, and in agreement with previous studies using other targeting agents this data showed consistently enhanced antitumor efficacy and prolonged survival in mice treated with the ¹⁶¹Tb-labeled versions of SibuDAB and PSMA-I&T as compared with mice that received their ¹⁷⁷Lu-labeled counterparts. Because the albumin-binding properties of SibuDAB enhanced tumor uptake considerably, [¹⁶¹Tb]Tb-SibuDAB demonstrated an approximately 4-fold higher absorbed tumor dose than [¹⁶¹Tb]Tb-PSMA-I&T. [¹⁶¹Tb]Tb-SibuDAB, applied at the same activity as [¹⁶¹Tb]Tb-PSMA-I&T, thus showed better therapeutic efficacy as demonstrated by the 2.5- to 5-fold enhanced tumor growth inhibition quantified on the basis of the AUC_RTV (area under the curve of the relative tumor volume).

Overall the superior therapeutic efficacy of ¹⁶¹Tb over ¹⁷⁷Lu in combination with PSMA ligands agreed with the increased estimated absorbed tumor dose. The data of this study indicate particularly promising potential for [¹⁶¹Tb]Tb-SibuDAB in the radioligand therapy of prostate cancer patients.

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