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Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer

INTRODUCTION: The first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled...

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Autores principales: Derks, Yvonne H. W., van Lith, Sanne A. M., Amatdjais-Groenen, Helene I. V., Wouters, Lieke W. M., Kip, Annemarie, Franssen, Gerben M., Laverman, Peter, Löwik, Dennis W. P. M., Heskamp, Sandra, Rijpkema, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165289/
https://www.ncbi.nlm.nih.gov/pubmed/35029739
http://dx.doi.org/10.1007/s00259-022-05685-0
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author Derks, Yvonne H. W.
van Lith, Sanne A. M.
Amatdjais-Groenen, Helene I. V.
Wouters, Lieke W. M.
Kip, Annemarie
Franssen, Gerben M.
Laverman, Peter
Löwik, Dennis W. P. M.
Heskamp, Sandra
Rijpkema, Mark
author_facet Derks, Yvonne H. W.
van Lith, Sanne A. M.
Amatdjais-Groenen, Helene I. V.
Wouters, Lieke W. M.
Kip, Annemarie
Franssen, Gerben M.
Laverman, Peter
Löwik, Dennis W. P. M.
Heskamp, Sandra
Rijpkema, Mark
author_sort Derks, Yvonne H. W.
collection PubMed
description INTRODUCTION: The first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa. METHODS: Various new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for (111)In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection. RESULTS: In order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC(50) < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (≥ 20 ± 3%ID/g vs 14 ± 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice. CONCLUSION: The new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-05685-0.
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spelling pubmed-91652892022-06-05 Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer Derks, Yvonne H. W. van Lith, Sanne A. M. Amatdjais-Groenen, Helene I. V. Wouters, Lieke W. M. Kip, Annemarie Franssen, Gerben M. Laverman, Peter Löwik, Dennis W. P. M. Heskamp, Sandra Rijpkema, Mark Eur J Nucl Med Mol Imaging Original Article INTRODUCTION: The first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa. METHODS: Various new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for (111)In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection. RESULTS: In order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC(50) < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (≥ 20 ± 3%ID/g vs 14 ± 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice. CONCLUSION: The new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-022-05685-0. Springer Berlin Heidelberg 2022-01-14 2022 /pmc/articles/PMC9165289/ /pubmed/35029739 http://dx.doi.org/10.1007/s00259-022-05685-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Derks, Yvonne H. W.
van Lith, Sanne A. M.
Amatdjais-Groenen, Helene I. V.
Wouters, Lieke W. M.
Kip, Annemarie
Franssen, Gerben M.
Laverman, Peter
Löwik, Dennis W. P. M.
Heskamp, Sandra
Rijpkema, Mark
Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title_full Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title_fullStr Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title_full_unstemmed Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title_short Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
title_sort theranostic psma ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9165289/
https://www.ncbi.nlm.nih.gov/pubmed/35029739
http://dx.doi.org/10.1007/s00259-022-05685-0
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