| 1. |
- Baum, R. P., et al.
(author)
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First-in-Humans Application of Tb-161: A Feasibility Study Using Tb-161-DOTATOC
- 2021
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 62:10, s. 1391-1397
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Journal article (peer-reviewed)abstract
- Tb-161 has decay properties similar to those of Lu-177 but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply Tb-161 in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of Tb-161-DOTATOC. Methods: Tb-161 was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of Tb-161-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar g-scintigraphy images 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 observed for adverse events after the application of Tb-161-DOTATOC. Results: The radiolabeling of DOTATOC with Tb-161 was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of Tb-161-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of Tb-161-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of Tb-161-DOTATOC using g-scintigraphy and SPECT/CT. On the basis of this essential first step in translating Tb-161 to clinics, further efforts will be directed toward the application of Tb-161 for therapeutic purposes.
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| 2. |
- Muller, C., et al.
(author)
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Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute
- 2019
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 11:9
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Journal article (peer-reviewed)abstract
- Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using Lu-177-folate and Lu-177-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by beta over bar -particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy.
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| 3. |
- Muller, C., et al.
(author)
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Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer
- 2019
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 46:9, s. 1919-1930
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Journal article (peer-reviewed)abstract
- 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 Tb-161 (T-1/2=6.89days; E beta(?)(av)=154keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to Lu-177-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods(161)Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100MBq/nmol. Tb-161-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for Lu-177-PSMA-617. The effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. Tb-161-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results(161)Tb-PSMA-617 and Lu-177-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 Tb-161-PSMA-617 as compared to the effect obtained with the same activities of Lu-177-PSMA-617 over the whole investigated concentration range. Treatment of mice with Tb-161-PSMA-617 (5.0MBq/mouse and 10MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65days) compared to untreated control animals (19days). Therapy studies to compare the effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 indicated the anticipated superiority of Tb-161 over Lu-177.Conclusion(161)Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to Lu-177-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of Tb-161. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of Tb-161-PSMA-617 for the treatment of mCRPC.
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| 4. |
- Siwowska, K., et al.
(author)
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Therapeutic Potential of Sc-47 in Comparison to Lu-177 and Y-90: Preclinical Investigations
- 2019
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 11:8
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Journal article (peer-reviewed)abstract
- Targeted radionuclide therapy with Lu-177- and Y-90-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. Sc-47 is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy beta(-)particles. In this study, Sc-47 was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of Lu-17-folate and Y-90-folate, respectively. In vitro, Sc-47-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to Lu-177-folate, but Y-90-folate was more potent at equal activities due to the higher energy of emitted beta(-)particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (similar to 21 Gy) when treated with Sc-47-folate (12.5 MBq), Lu-177-folate (10 MBq), and Y-90-folate (5 MBq), respectively. The treatment resulted in increased median survival of 39, 43, and 41 days, respectively, as compared to 26 days in untreated controls. There were no statistically significant differences among the therapeutic effects observed in treated groups. Histological assessment revealed no severe side effects two weeks after application of the radiofolates, even at double the activity used for therapy. Based on the decay properties and our results, Sc-47 is likely to be comparable to Lu-177 when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with Sc-44 or Sc-43 as a diagnostic match, enabling the realization of radiotheragnostics in future.
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| 5. |
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| 6. |
- Deberle, L. M., et al.
(author)
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Albumin-Binding PSMA Radioligands: Impact of Minimal Structural Changes on the Tissue Distribution Profile
- 2020
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In: Molecules. - : MDPI AG. - 1420-3049. ; 25:11
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Journal article (peer-reviewed)abstract
- The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of [Lu-177]Lu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177. [Lu-177]Lu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of [Lu-177]Lu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of [Lu-177]Lu-Ibu-PSMA-02 were similar to those previously obtained for [Lu-177]Lu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of [Lu-177]Lu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for [Lu-177]Lu-Ibu-PSMA-01. As a consequence of the high tumor accumulation, [Lu-177]Lu-Ibu-PSMA-02 showed higher tumor-to-background ratios than [Lu-177]Lu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization.
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| 7. |
- Guzik, P., et al.
(author)
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Promising potential of Lu-177 Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model
- 2021
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:4, s. 984-994
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Journal article (peer-reviewed)abstract
- Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [Lu-177]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [Lu-177]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [Lu-177]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 x 200 mu g; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [Lu-177]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [Lu-177]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [Lu-177]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [Lu-177]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.
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| 8. |
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| 9. |
- Muller, C., et al.
(author)
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Promising Prospects for Sc-44-/Sc-47-Based Theragnostics: Application of Sc-47 for Radionuclide Tumor Therapy in Mice
- 2014
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In: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 55:10, s. 1658-1664
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Journal article (peer-reviewed)abstract
- In recent years, Sc-47 has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 key; Ey, 159 key) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of Sc-47 for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. Methods: Sc-47 was produced via the Ca-46(n,gamma)Ca-47 -> Sc beta-47 nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the Sc-47 from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. Sc-47-labeled cm10 was tested on folate receptor-positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor-bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either Sc-47-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. Results: Irradiation of Ca-46 resulted in approximately 1.8 GBq of Ca-47, which subsequently decayed to Sc-47. Separation of Sc-47 from Ca-47 was obtained with 80% yield in only 10 min. The Sc-47 was then available in a small volume (-500 pL) of an ammonium acetate/HCI (pH 4.5) solution suitable for direct radiolabeling. Sc-47-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro 475ccm10 showed folate receptor-specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received Sc-47-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. Conclusion: With this study, we demonstrated the suitability of using Sc-47 for therapeutic purposes. On the basis of our recent results obtained with Sc-44-folate, the present work confirms the applicability of Sc-44/Sc-47 as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.
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| 10. |
- Siwowska, K., et al.
(author)
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Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties
- 2017
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In: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:2, s. 523-532
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Journal article (peer-reviewed)abstract
- Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor a (FR)-positive cancer. Recently, it was shown that modification of radiofolates with an albumin-binding entity increased the tumor-to-kidney ratios of accumulated radioactivity in mice. The goal of this study was to evaluate the lead compound cm10 and compare it with new albumin-binding folate conjugates. Compound cm12 was designed with a long spacer consisting of a PEG-11 entity, and compound cm13 contained a short alkane chain between the albumin-binding moiety and folic acid. All of the derivatives were labeled with Lu-177 (t(1/2) = 6.65 days, E beta(-),(average) = 134 keV; E gamma = 113 keV, 208 keV), a clinically established radionuclide for therapeutic purposes. The evaluation revealed that all of the albumin-binding radiofolates exhibited increased in vitro stability compared with the reference compound (Lu-177-cm14) without albumin binder. Serum protein binding, determined with an ultrafiltration assay, was high (>88%) for the derivatives with albumin-binding entities. The FR-binding affinity was in the same range (K-D = 4.0-7.5 nM) for all of the radiofolates, independent of the albumin-binding entity and spacer length. FR-specific uptake was proven in vitro using FR-positive KB tumor cells. In vivo studies with KB-tumor-bearing mice were performed in order to assess the tissue distribution profile of the novel radiofolates. Lu-177-cm13 showed high tumor uptake at late time points (13.3 +/- 2.94% IA/g, 48 h p.i.) and tumor-to-kidney ratios (0.59 +/- 0.03, 48 h p.i.) in the same range as Lu-177-cm10 (0.55 +/- 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of Lu-177-cm12 (0.28 +/- 0.07, 48 h p.i.) was reduced compared with Lu-177-cm10 and Lu-177-cm13. The results of this study indicate that the spacer entity between folic acid and the albumin binder is of critical importance with regard to the tissue distribution profile of the radiofolate. The PEG spacer compromised the beneficial effects of the lead compound, but the design with a short alkane spacer appeared to be promising. Future studies will focus on the design of radiofolates with lipophilic and more rigid spacer entities, which may allow a further improvement of their tissue distribution profiles.
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