20 results on '"Siwowska, Klaudia"'
Search Results
2. Resting state of the human proton channel dimer in a lipid bilayer
- Author
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Li, Qufei, Shen, Rong, Treger, Jeremy S., Wanderling, Sherry S., Milewski, Wieslawa, Siwowska, Klaudia, Bezanilla, Francisco, and Perozo, Eduardo
- Published
- 2015
3. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs
- Author
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Schniering, Janine, Borgna, Francesca, Siwowska, Klaudia, Benešová, Martina, Cohrs, Susan, Hasler, Roger, van der Meulen, Nicholas P, Maurer, Britta, Schibli, Roger, Müller, Cristina, University of Zurich, and Müller, Cristina
- Subjects
1313 Molecular Medicine ,3002 Drug Discovery ,10051 Rheumatology Clinic and Institute of Physical Medicine ,3003 Pharmaceutical Science ,610 Medicine & health - Published
- 2018
4. Theragnostic Application of Novel Folate Radioconjugates
- Author
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Siwowska, Klaudia, Schibli, Roger, Ametamey, Simon M., and Muller, Cristina
- Subjects
ddc:610 ,Medical sciences, medicine - Published
- 2017
- Full Text
- View/download PDF
5. Diastereomerically Pure 6R- and 6S-3′-Aza-2′-18F-Fluoro-5-Methyltetrahydrofolates Show Unprecedentedly High Uptake in Folate Receptor–Positive KB Tumors..
- Author
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Boss, Silvan D., Müller, Cristina, Siwowska, Klaudia, Schmid, Raffaella M., Groehn, Viola, Schibli, Roger, and Ametamey, Simon M.
- Published
- 2019
- Full Text
- View/download PDF
6. Reduced 18F-Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging.
- Author
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Boss, Silvan D., Müller, Cristina, Siwowska, Klaudia, Büchel, Josephine I., Schmid, Raffaella M., Groehn, Viola, Schibli, Roger, and Ametamey, Simon M.
- Published
- 2018
- Full Text
- View/download PDF
7. Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization.
- Author
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Siwowska, Klaudia, Schmid, Raffaella M., Cohrs, Susan, Schibli, Roger, and Müller, Cristina
- Subjects
- *
FOLIC acid , *GYNECOLOGIC cancer , *CHORIOCARCINOMA , *CANCER chemotherapy , *XENOGRAFTS , *GENE expression , *IN vitro studies , *LABORATORY mice - Abstract
The folate receptor alpha (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates. In this study, a panel of FR-expressing human cancer cell lines-- including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip), choriocarcinoma (JAR, BeWo) and endometrial (EFE-184) tumor cells--was investigated in vitro and for their ability to grow as xenografts in mice. FR-expression levels were compared in vitro and in vivo and the cell lines were characterized by determination of the sensitivity towards commonly-used chemotherapeutics and the expression of two additional, relevant tumor markers, HER2 and L1-CAM. It was found that, besides KB cells, its multiresistant KB-V1 subclone as well as the ovarian cancer cell lines, IGROV-1 and SKOV-3.ip, could be used as potentially more relevant preclinical models. They would allow addressing specific questions such as the therapeutic efficacy of FR-targeting agents in tumor (mouse) models of multi-resistance and in mouse models of metastases formation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
8. A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice.
- Author
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Pellegrini, Giovanni, Siwowska, Klaudia, Haller, Stephanie, Antoine, Daniel J., Schibli, Roger, Kipar, Anja, and Müller, Cristina
- Subjects
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RADIOISOTOPE therapy , *KIDNEY diseases , *PATIENT compliance , *RADIATION-protective agents , *ETHIOFOS , *RADIATION doses , *LABORATORY mice - Abstract
Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that--in this case--cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkersremained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
9. Resting state of the human proton channel dimer in a lipid bilayer.
- Author
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Qufei Li, Rong Shen, Treger, Jeremy S., Wanderling, Sherry S., Milewski, Wieslawa, Siwowska, Klaudia, Bezanilla, Francisco, and Perozo, Eduardo
- Subjects
PROTONS ,PROTON transfer reactions ,VOLTAGE-gated ion channels ,PHAGOCYTOSIS ,CATIONS - Abstract
The voltage-gated proton channel Hv1 plays a critical role in the fast proton translocation that underlies a wide range of physiological functions, including the phagocytic respiratory burst, sperm motility, apoptosis, and metastatic cancer. Both voltage activation and proton conduction are carried out by a voltage-sensing domain (VSD) with strong similarity to canonical VSDs in voltage-dependent cation channels and enzymes. We set out to determine the structural properties of membrane-reconstituted human proton channel (hHv1) in its resting conformation using electron paramagnetic resonance spectroscopy together with biochemical and computational methods. We evaluated existing structural templates and generated a spectroscopically constrained model of the hHv1 dimer based on the Ci-VSD structure at resting state. Mapped accessibility data revealed deep water penetration through hHv1, suggesting a highly focused electric field, comprising two turns of helix along the fourth transmembrane segment. This region likely contains the H
+ selectivity filter and the conduction pore. Our 3D model offers plausible explanations for existing electrophysiological and biochemical data, offering an explicit mechanism for voltage activation based on a one-click sliding helix conformational rearrangement. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
10. Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations.
- Author
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Siwowska, Klaudia, Guzik, Patrycja, Domnanich, Katharina A., Monné Rodríguez, Josep M., Bernhardt, Peter, Ponsard, Bernard, Hasler, Roger, Borgna, Francesca, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Müller, Cristina
- Subjects
- *
PEPTIDE receptors , *ABSORBED dose , *OVARIAN tumors , *TUMOR growth , *RADIOISOTOPES , *DRUG side effects , *CELL survival - Abstract
Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-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, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
11. Therapeutic potential of 47Sc in comparison to 177Lu and 90Y: Preclinical investigations
- Author
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Siwowska, Klaudia, Guzik, Patrycja, Domnanich, Katharina A., Monné Rodríguez, Josep M., Bernhardt, Peter, Ponsard, Bernard, Hasler, Roger, Borgna, Francesca, Schibli, Roger, Köster, Ulli, van der Meulen, Nicholas P., and Müller, Cristina
- Subjects
folate receptor ,SPECT ,47Sc ,radionuclide therapy ,177Lu ,IGROV-1 tumor xenografts ,90Y ,DOTA-folate ,3. Good health ,preclinical therapy - Abstract
Targeted radionuclide therapy with 177Lu- and 90Y-labeled radioconjugates is a clinically-established treatment modality for metastasized cancer. 47Sc is a therapeutic radionuclide that decays with a half-life of 3.35 days and emits medium-energy β−-particles. In this study, 47Sc was investigated, in combination with a DOTA-folate conjugate, and compared to the therapeutic properties of 177Lu-folate and 90Y-folate, respectively. In vitro, 47Sc-folate demonstrated effective reduction of folate receptor-positive ovarian tumor cell viability similar to 177Lu-folate, but 90Y-folate was more potent at equal activities due to the higher energy of emitted β−-particles. Comparable tumor growth inhibition was observed in mice that obtained the same estimated absorbed tumor dose (~21 Gy) when treated with 47Sc-folate (12.5 MBq), 177Lu-folate (10 MBq), and 90Y-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, 47Sc is likely to be comparable to 177Lu when employed for targeted radionuclide therapy. It may, therefore, have potential for clinical translation and be of particular interest in tandem with 44Sc or 43Sc as a diagnostic match, enabling the realization of radiotheragnostics in future., Pharmaceutics, 11 (8)
12. A short-term biological indicator for long-term kidney damage after radionuclide therapy in mice
- Author
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Pellegrini, Giovanni, Siwowska, Klaudia, Haller, Stephanie, Antoine, Daniel J., Schibli, Roger, Kipar, Anja, and Müller, Cristina
- Subjects
Radiofolate ,γ-H2AX ,DNA double-strand breaks ,177Lu ,Kidney ,Radiation nephropathy ,3. Good health - Abstract
Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage., Pharmaceuticals, 10 (2), ISSN:1424-8247
13. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates
- Author
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Müller, Cristina, Guzik, Patrycja, Siwowska, Klaudia, Cohrs, Susan, Schmid, Raffaella M., and Schibli, Roger
- Subjects
folic acid ,albumin-binder ,SPECT ,KB ,radiofolate ,177Lu ,pemetrexed ,3. Good health ,IGROV-1 - Abstract
Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([177Lu]cm13), which is outfitted with an albumin-binding entity. Biodistribution studies were carried out in mice bearing KB or IGROV-1 tumor xenografts, both FR-positive tumor types. SPECT/CT was performed with control mice injected with [177Lu]folate only and with mice that received PMX in addition. Control mice showed high uptake of radioactivity in KB and IGROV-1 tumor xenografts, but retention in the kidneys was also high, resulting in tumor-to-kidney ratios of ~0.85 (4 h p.i.) and ~0.60 (24 h p.i.) or ~1.17 (4 h p.i.) and ~1.11 (24 h p.i.) respectively. Pre-injection of PMX improved the tumor-to-kidney ratio to values of ~1.13 (4 h p.i.) and ~0.92 (24 h p.i.) or ~1.79 (4 h p.i.) and ~1.59 (24 h p.i.), respectively, due to reduced uptake in the kidneys. It was found that a second injection of PMX—3 h or 7 h after administration of the radiofolate—improved the tumor-to-kidney ratio further to ~1.03 and ~0.99 or ~1.78 and ~1.62 at 24 h p.i. in KB and IGROV-1 tumor-bearing mice, respectively. SPECT/CT scans readily visualized the tumor xenografts, whereas accumulation of radioactivity in the kidneys was reduced in mice that received PMX. In this study, it was shown that PMX had a positive impact in terms of reducing the kidney uptake of albumin-binding radiofolates; hence, the administration of PMX resulted in ~1.3–1.7-fold higher tumor-to-kidney ratios. This is, however, a rather moderate effect in comparison to the previously shown effect of PMX on conventional radiofolates (without albumin binder), which led to 5–6-fold increased tumor-to-kidney ratios. An explanation for this result may be the different pharmacokinetic profiles of PMX and long-circulating radiofolates, respectively. Despite the promising potential of this concept, it is believed that a clinical translation would be challenging, particularly when PMX had to be injected more than once., Molecules, 23 (6), ISSN:1420-3049
14. Promising potential of [Lu-177]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model
- Author
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Guzik, Patrycja, Siwowska, Klaudia, Fang, Hsin-Yu, Cohrs, Susan, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina
- Subjects
Folate receptor ,[Lu-177]Lu-DOTA-folate ,CTLA-4 ,Immunotherapy ,3. Good health ,NF9006 breast tumor cells - 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., European Journal of Nuclear Medicine and Molecular Imaging, 48 (4), ISSN:1619-7070, ISSN:1619-7089
15. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates.
- Author
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Müller, Cristina, Guzik, Patrycja, Siwowska, Klaudia, Cohrs, Susan, Schmid, Raffaella M., Schibli, Roger, Brust, Peter, and McPhee, Derek J.
- Subjects
FOLIC acid ,JUNO protein ,PROTEIN binding ,PEMETREXED ,RADIOACTIVITY - Abstract
Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([
177 Lu]cm13), which is outfitted with an albumin-binding entity. Biodistribution studies were carried out in mice bearing KB or IGROV-1 tumor xenografts, both FR-positive tumor types. SPECT/CT was performed with control mice injected with [177 Lu]folate only and with mice that received PMX in addition. Control mice showed high uptake of radioactivity in KB and IGROV-1 tumor xenografts, but retention in the kidneys was also high, resulting in tumor-to-kidney ratios of ~0.85 (4 h p.i.) and ~0.60 (24 h p.i.) or ~1.17 (4 h p.i.) and ~1.11 (24 h p.i.) respectively. Pre-injection of PMX improved the tumor-to-kidney ratio to values of ~1.13 (4 h p.i.) and ~0.92 (24 h p.i.) or ~1.79 (4 h p.i.) and ~1.59 (24 h p.i.), respectively, due to reduced uptake in the kidneys. It was found that a second injection of PMX—3 h or 7 h after administration of the radiofolate—improved the tumor-to-kidney ratio further to ~1.03 and ~0.99 or ~1.78 and ~1.62 at 24 h p.i. in KB and IGROV-1 tumor-bearing mice, respectively. SPECT/CT scans readily visualized the tumor xenografts, whereas accumulation of radioactivity in the kidneys was reduced in mice that received PMX. In this study, it was shown that PMX had a positive impact in terms of reducing the kidney uptake of albumin-binding radiofolates; hence, the administration of PMX resulted in ~1.3–1.7-fold higher tumor-to-kidney ratios. This is, however, a rather moderate effect in comparison to the previously shown effect of PMX on conventional radiofolates (without albumin binder), which led to 5–6-fold increased tumor-to-kidney ratios. An explanation for this result may be the different pharmacokinetic profiles of PMX and long-circulating radiofolates, respectively. Despite the promising potential of this concept, it is believed that a clinical translation would be challenging, particularly when PMX had to be injected more than once. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
16. Diastereomerically Pure 6 R - and 6 S -3'-Aza-2'- 18 F-Fluoro-5-Methyltetrahydrofolates Show Unprecedentedly High Uptake in Folate Receptor-Positive KB Tumors.
- Author
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Boss SD, Müller C, Siwowska K, Schmid RM, Groehn V, Schibli R, and Ametamey SM
- Subjects
- Animals, Biological Transport, Cell Transformation, Neoplastic, Folic Acid pharmacokinetics, Humans, KB Cells, Mice, Positron Emission Tomography Computed Tomography, Radiochemistry, Stereoisomerism, Tissue Distribution, Folate Receptors, GPI-Anchored metabolism, Folic Acid chemistry, Folic Acid metabolism
- Abstract
The aim of this study was to develop the radiosyntheses of diastereomerically pure 6 R - and 6 S -3'-aza-2'-
18 F-fluoro-5-methyltetrahydrofolate (MTHF) (6 R -18 F- 1 and 6 S -18 F- 1 ) using the integrated approach and to compare the in vitro and in vivo performance characteristics of both radioligands with the previously reported 3'-aza-2'-18 F-fluorofolic acid tracer (18 F- 2 ), the oxidized form. Methods: 6 R -18 F- 1, 6 S -18 F- 1, and18 F- 2 were radiolabeled with18 F using aromatic nucleophilic substitution reaction. In vitro cell uptake studies and binding affinity assays were performed using folate receptor (FR)-α-expressing KB cells. PET/CT imaging and biodistribution experiments were performed with KB tumor-bearing mice. Results: Reference compounds 6 R - 1 and 6 S - 1 were obtained after acidic hydrolysis of the corresponding protected intermediates 6 R - 3 and 6 S - 3 in high chemical yields (81%-87%) and chemical purities of more than 95%. 6 R -18 F- 1, 6 S -18 F- 1, and18 F- 2 were obtained after a 2-step radiosynthetic procedure in a decay-corrected radiochemical yield of up to 5% and molar radioactivities ranging from 20 to 250 GBq/μmol. In vitro binding affinity studies using FR-α-positive KB cells gave half-maximal inhibitory concentrations of 27.1 ± 3.7 and 23.8 ± 4.0 nM for 6 R - 1 and 6 S - 1, respectively, which were higher than for the previously reported 3'-aza-2'-fluorofolic acid 2 (1.4 ± 0.5 nM). Comparably high cell uptake values in FR-α-expressing KB cells were found for all 3 radiofolates. In biodistribution studies, exceptionally high KB tumor uptake value of over 32% injected activity per gram of tissue for both 6 R -18 F- 1 and 6 S -18 F- 1 was observed at 180 min after injection, whereas for18 F- 2 only 15% injected activity per gram was found in the KB tumors. Radioactivity uptake in the kidneys, liver, salivary glands, and spleen was substantially different for the 6 R - and 6 S -diastereoisomers and18 F- 2 Excellent KB tumor visualization was found in PET/CT images with 6 R -18 F- 1 and 6 S -18 F- 1, both of which outperformed the corresponding oxidized18 F- 2. Conclusion: We have successfully radiolabeled 6 R - and 6 S -3'-aza-2'-18 F-fluoro-5-MTHF with18 F using the integrated approach. Our results suggest that both 6 R - and 6 S -3'-aza-2'-18 F-fluoro-5-MTHF are promising reduced radiofolates for imaging FR-α-expressing cancers., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
- Full Text
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17. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs.
- Author
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Schniering J, Borgna F, Siwowska K, Benešová M, Cohrs S, Hasler R, van der Meulen NP, Maurer B, Schibli R, and Müller C
- Subjects
- Acute Lung Injury chemically induced, Animals, Aza Compounds chemistry, Bleomycin administration & dosage, Bleomycin toxicity, Capillary Permeability, Disease Models, Animal, Female, Heterocyclic Compounds, 1-Ring chemistry, Humans, Lung blood supply, Lung diagnostic imaging, Lung drug effects, Lung metabolism, Lutetium administration & dosage, Lutetium chemistry, Lutetium pharmacokinetics, Mice, Mice, Inbred C57BL, Positron-Emission Tomography methods, Prealbumin chemistry, Radioisotopes administration & dosage, Radioisotopes chemistry, Radioisotopes pharmacokinetics, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Scandium administration & dosage, Scandium chemistry, Scandium pharmacokinetics, Serum Albumin, Human chemistry, Tissue Distribution, Tomography, Emission-Computed, Single-Photon methods, Acute Lung Injury diagnostic imaging, Molecular Imaging methods, Prealbumin metabolism, Radiopharmaceuticals administration & dosage, Serum Albumin, Human metabolism
- Abstract
Increased vascular permeability is an important hallmark of many diseases, including cancer, cerebral ischemia, and severe inflammatory disorders. In this regard, the noninvasive assessment of pathologically increased vascular permeability in vivo is of great interest. In this study, the potential of albumin- and transthyretin-binding radioligands was evaluated for imaging of vascular hyperpermeability. For this purpose, the bleomycin-induced lung injury model was used as a model of inflammation-associated vascular leakage. The plasma protein-binding ligands, which bind to albumin (DOTA-PPB-01) and transthyretin (DOTA-PPB-03), were radiolabeled and used for nuclear imaging and biodistribution studies. In this regard,
177 Lu was employed as a surrogate nuclide for detailed preclinical investigations, including single-photon emission computed tomography (SPECT) studies, whereas44 Sc was proposed as a radionuclide for positron emission tomography (PET), which may be relevant for future clinical translation. Mice were administered with these radioligands 6-9 days after intratracheal instillation of bleomycin or saline. Bleomycin-treated mice developed pronounced lung inflammation with enhanced vascular permeability that was reflected in significantly increased lung size and weight due to edema and infiltration with inflammatory cells. Biodistribution studies revealed significantly higher accumulation of177 Lu-DOTA-PPB-01 in injured lungs as compared to lungs of control animals at all investigated time points (4-48 h p.i.). The best contrast was achieved at late time points (16.1 ± 2.91% IA/g vs 2.03 ± 1.22% IA/g, 48 h p.i.) when the blood activity levels were ∼7.5% IA/g. Injection of177 Lu-DOTA-PPB-03 also resulted in increased lung accumulation in bleomycin-treated mice at all investigated time points (2-8 h p.i.). The pharmacokinetics was significantly faster, however, resulting in good contrast already at 8 h p.i. (4.32 ± 0.85% IA/g vs 1.06 ± 0.10% IA/g) when blood activity levels were ∼2% IA/g. The absolute lung accumulation of177 Lu-DOTA-PPB-03 was significantly lower than that of177 Lu-DOTA-PPB-01. PET/CT scans performed with44 Sc-DOTA-PPB-01 distinguished injured from healthy lungs only at late time points (20 h p.i.), whereas44 Sc-DOTA-PPB-03 already allowed the differentiation at 4 h p.i. due to its faster clearance. The investigated radioligands,44 Sc/177 Lu-DOTA-PPB-01 and44 Sc/177 Lu-DOTA-PPB-03, hold promise for the visualization of vascular leakage in a variety of pathological conditions.44 Sc would be the radionuclide of choice for clinical application as it can be stably coordinated with a DOTA chelator and enables PET imaging over extended periods.- Published
- 2018
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- View/download PDF
18. Reduced 18 F-Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging.
- Author
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Boss SD, Müller C, Siwowska K, Büchel JI, Schmid RM, Groehn V, Schibli R, and Ametamey SM
- Subjects
- Animals, Endocytosis, Female, Fluorine Radioisotopes pharmacokinetics, Folate Receptor 1 metabolism, Folic Acid pharmacokinetics, Heterografts, Humans, KB Cells, Kidney metabolism, Liver metabolism, Mice, Mice, Nude, Radiopharmaceuticals pharmacokinetics, Stereoisomerism, Tissue Distribution, Fluorine Radioisotopes chemistry, Folic Acid chemistry, Positron-Emission Tomography, Radiopharmaceuticals chemistry
- Abstract
5-Methyltetrahydrofolate (5-MTHF), a reduced folate form, is the biologically active folate involved in many different metabolic processes. To date, there are no studies available in the literature on
18 F-labeled 6 S- and 6 R-5-MTHF radiotracers for imaging folate receptor (FR)-α-positive tissues. Therefore, the goal of this study was to synthesize four18 F-labeled 5-MTHF derivatives conjugated at either the α- or γ-carboxylic functionality of glutamate and to assess their suitability for FR-targeting. Organic syntheses of the precursors and the four reference compounds, namely, 6 S-α, 6 S-γ, 6 R-α, and 6 R-γ-click-fluoroethyl-5-MTHF, were carried out in low to moderate overall chemical yields. The radiosyntheses of the α- and γ-conjugated18 F-labeled folate derivatives were accomplished in approximately 100 min, low radiochemical yields (1-7% d.c.) and high molar activities (139-245 GBq/μmol). Radiochemically pure tracers were obtained after the addition of a mixture of antioxidants consisting of sodium ascorbate and l-cysteine. In vitro, all four 5-MTHF conjugates showed similar binding affinities to FR-α (IC50 = 17.7-24.0 nM), whereas folic acid showed a significantly higher binding affinity to the FR-α. Cell uptake and internalization experiments with KB cells demonstrated specific uptake and internalization of the radiofolate conjugates. Metabolite studies in mice revealed high in vivo stability of the radiotracers in mice. Biodistribution and positron emission tomography (PET) imaging studies in FR-positive KB tumor-bearing mice demonstrated that the 6 S- and 6 R-5-MTHF conjugates exhibited a different accumulation pattern in various organs including the kidneys and the liver, whereas no significant differences in radioactivity accumulation in the kidneys and the liver were found for both the α- and γ-conjugated diastereoisomers. Despite the considerably lower binding affinities of the 5-MTHF derivatives compared to the corresponding folic acid conjugates similar high KB tumor uptake was observed for all the folate conjugates investigated (8-11% IA/g). Based on these results, we conclude that18 F-labeled 5-MTHF conjugates are a promising new class of radiotracers for targeting FR-positive tumor tissues.- Published
- 2018
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19. Preclinical Comparison of Albumin-Binding Radiofolates: Impact of Linker Entities on the in Vitro and in Vivo Properties.
- Author
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Siwowska K, Haller S, Bortoli F, Benešová M, Groehn V, Bernhardt P, Schibli R, and Müller C
- Subjects
- Albumins metabolism, Animals, Cell Line, Tumor, Female, Folate Receptor 1 metabolism, Folic Acid metabolism, Humans, KB Cells, Mice, Mice, Nude, Radioisotopes metabolism, Radiopharmaceuticals metabolism, Tissue Distribution, Albumins chemistry, Folic Acid chemistry, Radioisotopes chemistry, Radiopharmaceuticals chemistry
- Abstract
Tumor targeting with folic acid radioconjugates has been proposed as a promising strategy for radionuclide therapy of folate receptor α (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
177 Lu (t1/2 = 6.65 days, Eβ = 134 keV; E- ,averageγ = 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 (177 Lu-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 (KD = 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.177 Lu-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 as177 Lu-cm10 (0.55 ± 0.07, 48 h p.i.). However, the tumor-to-kidney ratio of177 Lu-cm12 (0.28 ± 0.07, 48 h p.i.) was reduced compared with177 Lu-cm10 and177 Lu-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.- Published
- 2017
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20. (64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate.
- Author
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Farkas R, Siwowska K, Ametamey SM, Schibli R, van der Meulen NP, and Müller C
- Subjects
- Animals, Chelating Agents chemistry, Half-Life, Humans, KB Cells, Mice, Mice, Nude, Positron-Emission Tomography methods, Radiochemistry methods, Acetates chemistry, Albumins chemistry, Folic Acid chemistry, Gallium Radioisotopes chemistry, Heterocyclic Compounds, 1-Ring chemistry, Radiopharmaceuticals chemistry
- Abstract
A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with (64)Cu and (68)Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with (64)Cu and (68)Ga was carried out at room temperature within 10 min resulting in (64)Cu-rf42 and (68)Ga-rf42 with >95% radiochemical purity. (64)Cu-rf42 and (68)Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of (64)Cu-rf42 and (68)Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of (64)Cu-rf42 and (68)Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43-0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of (64)Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of (64)Cu-rf42 and (68)Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with (64)Cu-rf42 and a (64)Cu-labeled DOTA-folate conjugate (cm10) clearly proved the superiority of NODAGA for stable coordination of (64)Cu. (64)Cu-cm10 showed high liver uptake, most probably as a consequence of released (64)Cu(2+). The data reported in this study clearly proved the promising features of (64)Cu-rf42, particularly in terms of favorable tumor-to-kidney ratios. The relatively long half-life of (64)Cu (T1/2 = 12.7 h) matches well with the enhanced circulation time of the albumin-binding NODAGA-folate, allowing PET imaging at longer time points after injection than is possible when using (68)Ga (T1/2 = 68 min).
- Published
- 2016
- Full Text
- View/download PDF
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