Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer
| Autor: | Yvonne H.W. Derks, Peter Laverman, Sandra Heskamp, Annemarie Kip, Kim E. de Roode, Dennis W. P. M. Löwik, Mark Rijpkema, Susanne Lütje, Cato Loeff, Helene I. V. Amatdjais-Groenen |
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| Rok vydání: | 2022 |
| Předmět: |
Azides
Systems Chemistry Biomedical Engineering Pharmaceutical Science Alkyne Bioengineering Synthetic Organic Chemistry Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] urologic and male genital diseases Article chemistry.chemical_compound Prostate cancer Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14] All institutes and research themes of the Radboud University Medical Center medicine Targeting ligands Pharmacology chemistry.chemical_classification Strain (chemistry) Organic Chemistry medicine.disease Cycloaddition Tumor detection chemistry Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] Cancer research Azide Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] Biotechnology |
| Zdroj: | Bioconjugate Chemistry, 33, 1, pp. 194-205 Bioconjugate Chemistry, 33, 194-205 Bioconjugate Chemistry |
| ISSN: | 1043-1802 |
| Popis: | Purpose: Strain-promoted azide-alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. 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. Methods: Ligands were synthesized using solid phase chemistry and contained a chelator for 111In or 99mTc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)-ester coupling. LogD 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 wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies. Results: SPAAC chemistry increased lipophilicity of the ligands (range LogD: -2.4 to -4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 hours 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 111In-labeled ligands outperformed the 99mTc ligands. Conclusion: Here we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. 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. |
| Databáze: | OpenAIRE |
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