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- 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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| 2. |
- 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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| 3. |
- Tschan, V. J., et al.
(author)
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Preclinical investigations using Lu-177 Lu-lbu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer
- 2022
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In: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 49, s. 3639-3650
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Journal article (peer-reviewed)abstract
- [Lu-177]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [Lu-177]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [Lu-177]Lu-PSMA-617 and the previously developed [Lu-177]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [Lu-177]Lu-Ibu-DAB-PSMA (similar to 6.6 Gy/ MBq) was more effective to inhibit tumor growth than [Lu-177]Lu-PSMA-617 (similar to 4.5 Gy/MBq) and only moderately less potent than [Lu-177]Lu-PSMA-ALB-56 (similar to 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [Lu-177]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [Lu-177]Lu-Ibu-DAB-PSMA or [Lu-177]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [Lu-177]Lu-Ibu-DAB-PSMA or 30 MBq [Lu-177]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [Lu-177]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [Lu-177]Lu-Ibu-DAB-PSMA over [Lu-177]Lu-PSMA-617 and a more favorable safety profile as compared to that of [Lu-177]Lu-PSMA-ALB-56. Based on these results, [Lu-177]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation.
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