PurposeThe prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate 161Tb (T1/2 = 6.89 days; Eβ-uperscript>av = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to 177Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods161Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100 MBq/nmol. 161Tb-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for 177Lu-PSMA-617. The effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. 161Tb-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results161Tb-PSMA-617 and 177Lu-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to 161Tb-PSMA-617 as compared to the effect obtained with the same activities of 177Lu-PSMA-617 over the whole investigated concentration range. Treatment of mice with 161Tb-PSMA-617 (5.0 MBq/mouse and 10 MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65 days) compared to untreated control animals (19 days). Therapy studies to compare the effects of 161Tb-PSMA-617 and 177Lu-PSMA-617 indicated the anticipated superiority of 161Tb over 177Lu.Conclusion161Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to 177Lu-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of 161Tb. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of 161Tb-PSMA-617 for the treatment of mCRPC.Electronic supplementary materialThe online version of this article (10.1007/s00259-019-04345-0) contains supplementary material, which is available to authorized users.
Background 161 Tb is an interesting radionuclide for cancer treatment, showing similar decay characteristics and chemical behavior to clinically-employed 177 Lu. The therapeutic effect of 161 Tb, however, may be enhanced due to the co-emission of a larger number of conversion and Auger electrons as compared to 177 Lu. The aim of this study was to produce 161 Tb from enriched 160 Gd targets in quantity and quality sufficient for first application in patients. Methods No-carrier-added 161 Tb was produced by neutron irradiation of enriched 160 Gd targets at nuclear research reactors. The 161 Tb purification method was developed with the use of cation exchange (Sykam resin) and extraction chromatography (LN3 resin), respectively. The resultant product ( 161 TbCl 3 ) was characterized and the 161 Tb purity compared with commercial 177 LuCl 3 . The purity of the final product ( 161 TbCl 3 ) was analyzed by means of γ-ray spectrometry (radionuclidic purity) and radio TLC (radiochemical purity). The radiolabeling yield of 161 Tb-DOTA was assessed over a two-week period post processing in order to observe the quality change of the obtained 161 Tb towards future clinical application. To understand how the possible drug products (peptides radiolabeled with 161 Tb) vary with time, stability of the clinically-applied somatostatin analogue DOTATOC, radiolabeled with 161 Tb, was investigated over a 24-h period. The radiolytic stability experiments were compared to those performed with 177 Lu-DOTATOC in order to investigate the possible influence of conversion and Auger electrons of 161 Tb on peptide disintegration. Results Irradiations of enriched 160 Gd targets yielded 6–20 GBq 161 Tb. The final product was obtained at an activity concentration of 11–21 MBq/μL with ≥99% radionuclidic and radiochemical purity. The DOTA chelator was radiolabeled with 161 Tb or 177 Lu at the molar activity deemed useful for clinical application, even at the two-week time point after end of chemical separation. DOTATOC, radiolabeled with either 161 Tb or 177 Lu, was stable over 24 h in the presence of a stabilizer. Conclusions In this study, it was shown that 161 Tb can be produced in hig...
In this study, it was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β+-emission of 149Tb, tumor localization was feasible using PET/CT after injection of 149Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of 149Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of 149Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand’s tissue distribution.
161 Tb has similar decay properties as 177 Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161 Tb in a clinical setting and to investigate the feasibility to visualize the physiological and tumor biodistribution of 161 Tb-DOTATOC. Methods: 161 Tb was shipped from Paul Scherrer Institute, Switzerland, to Zentralklinik Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In two separate studies, 596 MBq and 1300 MBq 161 Tb-DOTATOC were administered to a 35-year-old male patient with metastatic, well differentiated, nonfunctional malignant paraganglioma and a 70-year-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphies were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed, using a recently-established protocol and visually analyzed. Patients were checked for adverse events after application of 161 Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161 Tb was readily achieved with high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161 Tb-DOTATOC in liver, kidneys, spleen and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in the liver and bones. Application of 161 Tb-DOTATOC was well tolerated and no related adverse events were reported. Conclusion: This study demonstrated the feasibility to image even small metastases after injection of relatively low activities of 161 Tb-DOTATOC using γ-scintigraphy and SPECT. Based on this essential first step to translate 161 Tb to clinics, further efforts will be directed towards the application of 161 Tb for therapeutic purposes.
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