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Covalent versus Dimeric Optimization of Nectin-4-Targeted Peptide Radiotracers: A Head-to-Head Comparison in
Abstract:
Nectin-4 is highly expressed in several malignancies, including triple-negative breast cancer, and it represents an attractive target for molecular imaging and therapy. In this study, we report the first head-to-head comparison of two structural optimization strategies for Nectin-4-targeted peptide radiotracers: peptide dimerization (for the development of 68Ga-DOTA-HTA-DM) and sulfonyl fluoride modification (for the development of 68Ga-DOTA-HTA-SF). The dimeric peptide DOTA-HTA-DM achieved a pronounced affinity gain (SPR apparent KD ≈ 0.37 nM), consistent with the bivalent binding mode predicted by docking and molecular dynamics simulations. In contrast to the lead compound N188, the sulfonyl fluoride-modified peptide DOTA-HTA-SF retained low-nanomolar affinity, and the 68Ga radiolabeled probe exhibited markedly higher tumor uptake at early time postinjection (∼5% ID/g at 30 min) and sustained tumor retention (>4% ID/g at 2 h), resulting in superior tumor-to-background contrast. Both radiotracers were predominantly cleared through the renal system, and blocking studies confirmed their Nectin-4-mediated tumor accumulation. Taken together, these findings demonstrate that dimerization enhances molecular recognition through multivalency, while sulfonyl fluoride modification prolongs tumor residence and improves imaging contrast. The complementary advantages of these two strategies establish a rational framework for the design of next-generation Nectin-4-targeted radiotracers.
Insights
Researchers compared two methods for creating Nectin-4-targeted peptide radiotracers for cancer imaging. Peptide dimerization improved binding affinity, while sulfonyl fluoride modification enhanced tumor uptake and imaging contrast for better cancer detection.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Nectin-4 is a protein highly expressed in various cancers, including triple-negative breast cancer.
- It serves as a promising target for molecular imaging and therapeutic interventions.
Purpose of the Study:
- To conduct a head-to-head comparison of two structural optimization strategies for Nectin-4-targeted peptide radiotracers.
- To evaluate peptide dimerization versus sulfonyl fluoride modification for developing novel imaging agents.
Main Methods:
- Development of two radiotracers: 68Ga-DOTA-HTA-DM (peptide dimerization) and 68Ga-DOTA-HTA-SF (sulfonyl fluoride modification).
- Assessment of binding affinity using surface plasmon resonance (SPR).
- In vivo evaluation of tumor uptake, retention, and clearance in preclinical models.
- Confirmation of Nectin-4-mediated accumulation through blocking studies.
Main Results:
- Peptide dimerization (68Ga-DOTA-HTA-DM) resulted in significantly enhanced binding affinity (SPR apparent KD ≈ 0.37 nM).
- Sulfonyl fluoride modification (68Ga-DOTA-HTA-SF) led to higher early tumor uptake (∼5% ID/g at 30 min) and sustained retention (>4% ID/g at 2 h).
- 68Ga-DOTA-HTA-SF demonstrated superior tumor-to-background contrast compared to the lead compound.
Conclusions:
- Peptide dimerization effectively enhances molecular recognition via multivalency.
- Sulfonyl fluoride modification improves tumor residence time and imaging contrast.
- These complementary strategies provide a framework for designing advanced Nectin-4-targeted radiotracers for improved cancer diagnostics.
