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Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection
Yvonne H W Derks1, Mark Rijpkema1, Helene I V Amatdjais-Groenen2
1Department of Medical Imaging, Nuclear Medicine, Radboud university medical center, Radboud Institute for Molecular Life Sciences, 6525GA Nijmegen, The Netherlands.
Bioconjugate Chemistry
|December 27, 2021
Summary
Strain-promoted azide-alkyne cycloaddition (SPAAC) enables modular prostate-specific membrane antigen (PSMA) ligand development for cancer imaging and therapy. SPAAC-conjugated ligands demonstrated effective PSMA-specific tumor targeting in vivo.
Area of Science:
- Medicinal Chemistry
- Molecular Imaging
- Oncology
Background:
- Prostate-specific membrane antigen (PSMA) is a key target for prostate cancer (PCa) diagnostics and therapeutics.
- Modular conjugation strategies are needed to develop versatile PSMA-targeted agents.
- Strain-promoted azide-alkyne cycloaddition (SPAAC) offers efficient and biocompatible click chemistry for bioconjugation.
Purpose of the Study:
- To develop and evaluate novel PSMA ligands using SPAAC chemistry for enhanced PCa imaging and therapy.
- To create a modular platform for conjugating various functional moieties to PSMA ligands.
- To compare SPAAC-based PSMA ligands with those prepared via conventional NHS-ester coupling.
Main Methods:
- Synthesis and characterization of four dual-labeled PSMA ligands incorporating chelators for 111In or 99mTc.
- Conjugation of the fluorophore IRDye800CW to PSMA ligands using SPAAC chemistry and NHS-ester coupling.
- Evaluation of ligand lipophilicity (Log D), PSMA specificity in vitro, and in vivo tumor targeting in mouse models using SPECT/CT and fluorescence imaging.
Main Results:
- SPAAC chemistry modulated ligand lipophilicity (Log D range: -2.4 to -4.4).
- SPAAC-based PSMA ligands exhibited high and specific accumulation in PSMA-expressing tumors in vivo.
- Clear visualization of tumors was achieved using SPECT/CT and fluorescence imaging up to 24 hours post-injection.
- No significant differences were observed between SPAAC and NHS-ester ligands at 2 hours post-injection (p > 0.05).
- 111In-labeled ligands showed superior performance compared to 99mTc-labeled counterparts.
Conclusions:
- The developed SPAAC-based PSMA ligands demonstrate effective and specific tumor targeting for PCa.
- SPAAC chemistry provides a versatile and efficient method for developing modular PSMA-targeted imaging and therapeutic agents.
- This platform facilitates the rapid conjugation of diverse imaging probes and therapeutic payloads for personalized PCa management.
