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Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer
[Image: see text] Strain-promoted azide–alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. The use of SPAAC to link different functional elements to prostate-specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778659/ https://www.ncbi.nlm.nih.gov/pubmed/34957825 http://dx.doi.org/10.1021/acs.bioconjchem.1c00537 |
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author | Derks, Yvonne H. W. Rijpkema, Mark Amatdjais-Groenen, Helene I. V. Loeff, Cato C. de Roode, Kim E. Kip, Annemarie Laverman, Peter Lütje, Susanne Heskamp, Sandra Löwik, Dennis W. P. M. |
author_facet | Derks, Yvonne H. W. Rijpkema, Mark Amatdjais-Groenen, Helene I. V. Loeff, Cato C. de Roode, Kim E. Kip, Annemarie Laverman, Peter Lütje, Susanne Heskamp, Sandra Löwik, Dennis W. P. M. |
author_sort | Derks, Yvonne H. W. |
collection | PubMed |
description | [Image: see text] Strain-promoted azide–alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. The use of SPAAC to link different functional elements to prostate-specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof of concept for the SPAAC chemistry platform, we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Ligands were synthesized using solid-phase chemistry and contained a chelator for (111)In or (99m)Tc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)–ester coupling. Log D values were measured and PSMA specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wild-type tumors using μSPECT/CT imaging, fluorescence imaging, and biodistribution studies. SPAAC chemistry increased the lipophilicity of the ligands (log D range: −2.4 to −4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 h after injection, enabling clear visualization using μSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while (111)In-labeled ligands outperformed the (99m)Tc ligands. Here, we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. The use of click chemistry in PSMA ligand development opens up the opportunity for fast, efficient, and versatile conjugations of multiple imaging moieties and/or drugs. |
format | Online Article Text |
id | pubmed-8778659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-87786592022-01-24 Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer Derks, Yvonne H. W. Rijpkema, Mark Amatdjais-Groenen, Helene I. V. Loeff, Cato C. de Roode, Kim E. Kip, Annemarie Laverman, Peter Lütje, Susanne Heskamp, Sandra Löwik, Dennis W. P. M. Bioconjug Chem [Image: see text] Strain-promoted azide–alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. The use of SPAAC to link different functional elements to prostate-specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof of concept for the SPAAC chemistry platform, we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Ligands were synthesized using solid-phase chemistry and contained a chelator for (111)In or (99m)Tc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)–ester coupling. Log D values were measured and PSMA specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wild-type tumors using μSPECT/CT imaging, fluorescence imaging, and biodistribution studies. SPAAC chemistry increased the lipophilicity of the ligands (log D range: −2.4 to −4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 h after injection, enabling clear visualization using μSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while (111)In-labeled ligands outperformed the (99m)Tc ligands. Here, we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. The use of click chemistry in PSMA ligand development opens up the opportunity for fast, efficient, and versatile conjugations of multiple imaging moieties and/or drugs. American Chemical Society 2021-12-25 2022-01-19 /pmc/articles/PMC8778659/ /pubmed/34957825 http://dx.doi.org/10.1021/acs.bioconjchem.1c00537 Text en © 2021 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 | Derks, Yvonne H. W. Rijpkema, Mark Amatdjais-Groenen, Helene I. V. Loeff, Cato C. de Roode, Kim E. Kip, Annemarie Laverman, Peter Lütje, Susanne Heskamp, Sandra Löwik, Dennis W. P. M. Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer |
title | Strain-Promoted Azide–Alkyne Cycloaddition-Based
PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
of Prostate Cancer |
title_full | Strain-Promoted Azide–Alkyne Cycloaddition-Based
PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
of Prostate Cancer |
title_fullStr | Strain-Promoted Azide–Alkyne Cycloaddition-Based
PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
of Prostate Cancer |
title_full_unstemmed | Strain-Promoted Azide–Alkyne Cycloaddition-Based
PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
of Prostate Cancer |
title_short | Strain-Promoted Azide–Alkyne Cycloaddition-Based
PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
of Prostate Cancer |
title_sort | strain-promoted azide–alkyne cycloaddition-based
psma-targeting ligands for multimodal intraoperative tumor detection
of prostate cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8778659/ https://www.ncbi.nlm.nih.gov/pubmed/34957825 http://dx.doi.org/10.1021/acs.bioconjchem.1c00537 |
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