Hybrid peptide dendrimers for imaging of chemokine receptor 4 (CXCR4) expression
Joeri Kuil1, Tessa Buckle, Joppe Oldenburg
1Division of Diagnostic Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, The Netherlands.
Abstract:
The chemokine receptor 4 (CXCR4), which is overexpressed in many types of cancer, is an emerging target in the field of molecular imaging and therapeutics. The CXCR4 binding of several peptides, including the cyclic Ac-TZ14011, has already been validated. In this study mono-, di- and tetrameric Ac-TZ14011-containing dendrimers were prepared and functionalized with a multimodal (hybrid) label, consisting of a Cy5.5-like fluorophore and a DTPA chelate. Confocal microscopy revealed that all three dendrimers were membrane bound at 4 °C, consistent with CXCR4 binding in vitro. The unlabeled dimer and tetramer had a somewhat lower affinity for CXCR4 than the unlabeled monomer. However, when labeled with the multimodal label the CXCR4 affinity of the dimer and tetramer was considerably higher compared to that of the labeled monomer. On top of that, biodistribution studies revealed that the additional peptides in the dimer and tetramer reduced nonspecific muscle uptake. Thus, multimerization of the cyclic Ac-TZ14011 peptide reduces the negative influence of the multimodal label on the receptor affinity and the biodistribution.
Insights
Multimerizing peptides targeting chemokine receptor 4 (CXCR4) improves molecular imaging and therapeutic potential. This strategy enhances receptor binding affinity and reduces off-target uptake, optimizing diagnostic and therapeutic applications.
Area of Science:
- Biomedical imaging
- Molecular imaging
- Cancer therapeutics
Background:
- Chemokine receptor 4 (CXCR4) is overexpressed in various cancers.
- CXCR4 is a promising target for molecular imaging and therapeutics.
- The cyclic peptide Ac-TZ14011 binds to CXCR4.
Purpose of the Study:
- To investigate the impact of multimerization on the performance of Ac-TZ14011-based CXCR4-targeting agents.
- To evaluate the influence of a multimodal label on peptide affinity and biodistribution.
- To develop improved imaging and therapeutic agents for CXCR4-positive cancers.
Main Methods:
- Synthesis of mono-, di-, and tetrameric Ac-TZ14011-containing dendrimers.
- Functionalization with a multimodal label (fluorophore and DTPA chelate).
- In vitro validation using confocal microscopy for membrane binding and CXCR4 affinity assessment.
- In vivo evaluation through biodistribution studies.
Main Results:
- All synthesized dendrimers showed membrane binding, indicating CXCR4 interaction.
- Unlabeled dimers and tetramers had slightly lower CXCR4 affinity than monomers.
- Labeled dimers and tetramers exhibited significantly higher CXCR4 affinity than labeled monomers.
- Multimerization reduced nonspecific muscle uptake in biodistribution studies.
Conclusions:
- Multimerization of Ac-TZ14011 peptides mitigates the negative effects of multimodal labeling on CXCR4 affinity.
- Dimeric and tetrameric constructs demonstrate improved receptor binding and biodistribution profiles.
- These findings support the potential of multimerized peptides for enhanced molecular imaging and therapeutics targeting CXCR4.
