On the prevention of kidney uptake of radiolabeled DARPins
Abstract Background Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14–18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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SpringerOpen
2020-02-01
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| Series: | EJNMMI Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13550-020-0599-1 |
| _version_ | 1819058794953441280 |
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| author | Mohamed Altai Javad Garousi Sara S. Rinne Alexey Schulga Sergey Deyev Anzhelika Vorobyeva |
| author_facet | Mohamed Altai Javad Garousi Sara S. Rinne Alexey Schulga Sergey Deyev Anzhelika Vorobyeva |
| author_sort | Mohamed Altai |
| collection | DOAJ |
| description | Abstract Background Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14–18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [99mTc]Tc(CO)3-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney. Results Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Administration of sodium maleate before the injection of [99mTc]Tc(CO)3-G3 reduced the kidney-associated activity by 60.4 ± 10.3%, while administration of fructose reduced it by 46.9 ± 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [99mTc]Tc(CO)3-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [99mTc]Tc(CO)3-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups. Conclusion Common clinical strategies were not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition. |
| first_indexed | 2024-12-21T14:00:52Z |
| format | Article |
| id | doaj.art-1cdec13355ae4c87aaae315f15791931 |
| institution | Directory Open Access Journal |
| issn | 2191-219X |
| language | English |
| last_indexed | 2024-12-21T14:00:52Z |
| publishDate | 2020-02-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Research |
| spelling | doaj.art-1cdec13355ae4c87aaae315f157919312022-12-21T19:01:22ZengSpringerOpenEJNMMI Research2191-219X2020-02-011011810.1186/s13550-020-0599-1On the prevention of kidney uptake of radiolabeled DARPinsMohamed Altai0Javad Garousi1Sara S. Rinne2Alexey Schulga3Sergey Deyev4Anzhelika Vorobyeva5Department of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Immunology, Genetics and Pathology, Uppsala UniversityDepartment of Medicinal Chemistry, Uppsala UniversityShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of SciencesDepartment of Immunology, Genetics and Pathology, Uppsala UniversityAbstract Background Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14–18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [99mTc]Tc(CO)3-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney. Results Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Administration of sodium maleate before the injection of [99mTc]Tc(CO)3-G3 reduced the kidney-associated activity by 60.4 ± 10.3%, while administration of fructose reduced it by 46.9 ± 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [99mTc]Tc(CO)3-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [99mTc]Tc(CO)3-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups. Conclusion Common clinical strategies were not effective for the reduction of kidney uptake of [99mTc]Tc(CO)3-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.https://doi.org/10.1186/s13550-020-0599-1DARPinRadiolabelKidneyReabsorptionRenal uptake |
| spellingShingle | Mohamed Altai Javad Garousi Sara S. Rinne Alexey Schulga Sergey Deyev Anzhelika Vorobyeva On the prevention of kidney uptake of radiolabeled DARPins EJNMMI Research DARPin Radiolabel Kidney Reabsorption Renal uptake |
| title | On the prevention of kidney uptake of radiolabeled DARPins |
| title_full | On the prevention of kidney uptake of radiolabeled DARPins |
| title_fullStr | On the prevention of kidney uptake of radiolabeled DARPins |
| title_full_unstemmed | On the prevention of kidney uptake of radiolabeled DARPins |
| title_short | On the prevention of kidney uptake of radiolabeled DARPins |
| title_sort | on the prevention of kidney uptake of radiolabeled darpins |
| topic | DARPin Radiolabel Kidney Reabsorption Renal uptake |
| url | https://doi.org/10.1186/s13550-020-0599-1 |
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