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Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes
[Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular des...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350918/ https://www.ncbi.nlm.nih.gov/pubmed/37322876 http://dx.doi.org/10.1021/acs.jmedchem.3c00258 |
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author | Suzuki, Hiroyuki Araki, Mari Tatsugi, Kouki Ichinohe, Kento Uehara, Tomoya Arano, Yasushi |
author_facet | Suzuki, Hiroyuki Araki, Mari Tatsugi, Kouki Ichinohe, Kento Uehara, Tomoya Arano, Yasushi |
author_sort | Suzuki, Hiroyuki |
collection | PubMed |
description | [Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([(111)In]In-DO3AiBu-Bn-FGK-Fab or [(111)In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [(111)In]In-DO3AiBu-Bn-F and [(111)In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a (111)In-labeled Fab prepared by the conventional procedure ([(111)In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [(111)In]In-DO3AiBu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes. |
format | Online Article Text |
id | pubmed-10350918 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-103509182023-07-18 Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes Suzuki, Hiroyuki Araki, Mari Tatsugi, Kouki Ichinohe, Kento Uehara, Tomoya Arano, Yasushi J Med Chem [Image: see text] The interposition of a cleavable linkage by enzymes on the renal brush border membrane constitutes a promising approach for reducing the renal radioactivity levels of radiolabeled low-molecular-weight antibody fragments and constructs (LMW Abs). Herein, we applied the molecular design to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-based reagents for radiotheranostic applications with trivalent radiometals. DOTA or a derivative thereof was conjugated to a Fab through an FGK linkage ([(111)In]In-DO3AiBu-Bn-FGK-Fab or [(111)In]In-DOTA-Bn-FGK-Fab). When injected into mice, both generated radiometabolites, [(111)In]In-DO3AiBu-Bn-F and [(111)In]In-DOTA-Bn-F, by the angiotensin-converting enzyme at similar rates. Both exhibited significantly lower renal radioactivity levels than a (111)In-labeled Fab prepared by the conventional procedure ([(111)In]In-DOTA-Bn-SCN-Fab). The different elimination rates of each radiometabolite from the kidney significantly affected the renal radioactivity levels. [(111)In]In-DO3AiBu-Bn-FGK-Fab preferentially reduced the renal localization without impairing tumor accumulation. These findings would pave the way for developing a DOTA-based radiotheranostic platform for LMW Abs bearing cleavable linkers for renal brush border enzymes. American Chemical Society 2023-06-16 /pmc/articles/PMC10350918/ /pubmed/37322876 http://dx.doi.org/10.1021/acs.jmedchem.3c00258 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Suzuki, Hiroyuki Araki, Mari Tatsugi, Kouki Ichinohe, Kento Uehara, Tomoya Arano, Yasushi Reduction of the Renal Radioactivity of (111)In-DOTA-Labeled Antibody Fragments with a Linkage Cleaved by the Renal Brush Border Membrane Enzymes |
title | Reduction of
the Renal Radioactivity of (111)In-DOTA-Labeled Antibody
Fragments with a Linkage Cleaved by the
Renal Brush Border Membrane Enzymes |
title_full | Reduction of
the Renal Radioactivity of (111)In-DOTA-Labeled Antibody
Fragments with a Linkage Cleaved by the
Renal Brush Border Membrane Enzymes |
title_fullStr | Reduction of
the Renal Radioactivity of (111)In-DOTA-Labeled Antibody
Fragments with a Linkage Cleaved by the
Renal Brush Border Membrane Enzymes |
title_full_unstemmed | Reduction of
the Renal Radioactivity of (111)In-DOTA-Labeled Antibody
Fragments with a Linkage Cleaved by the
Renal Brush Border Membrane Enzymes |
title_short | Reduction of
the Renal Radioactivity of (111)In-DOTA-Labeled Antibody
Fragments with a Linkage Cleaved by the
Renal Brush Border Membrane Enzymes |
title_sort | reduction of
the renal radioactivity of (111)in-dota-labeled antibody
fragments with a linkage cleaved by the
renal brush border membrane enzymes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350918/ https://www.ncbi.nlm.nih.gov/pubmed/37322876 http://dx.doi.org/10.1021/acs.jmedchem.3c00258 |
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