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Scandium-44 Radiolabeled Peptide and Peptidomimetic Conjugates Targeting Neuropilin-1 Co-Receptor as Potential Tools
Katarzyna Masłowska1, Patrycja Redkiewicz2, Paweł Krzysztof Halik1
1Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland.
Abstract:
Pathological angiogenesis, resulting from an imbalance between anti- and pro-angiogenic factors, plays a pivotal role in tumor growth, development and metastasis. The inhibition of the angiogenesis process by the VEGF/VEGFR-2/NRP-1 pathway raises interest in the search for such interaction inhibitors for the purpose of the early diagnosis and treatment of angiogenesis-dependent diseases. In this work we designed and tested peptide-based radiocompounds that selectively bind to the neuropilin-1 co-receptor and prevent the formation of the pro-angiogenic VEGF-A165/NRP-1 complex. Three biomolecules, A7R and retro-inverso DR7A peptides, and the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R), conjugated with macrocyclic chelator through two linkers' types, were labeled with theranostic scandium-44 radionuclide, and studied in vitro as potential targeted radiopharmaceuticals. ELISA (enzyme-linked immunosorbent assay) studies showed no negative effect of the introduced biomolecules' changes and high NRP-1 affinity in the case of A7R- and K4R-radiocompounds and a lack affinity for DR7A-radiocompounds. All radiopeptides showed a hydrophilic nature as well as high stability against ligand exchange reactions in cysteine/histidine solutions. Unfortunately, all radiocompounds showed unsatisfactory nano-scale stability in human serum, especially for use as therapeutic radioagents. Further work is ongoing and focused on the search for angiogenesis inhibitors that are more human serum stable.
Insights
Researchers developed peptide-based radiocompounds targeting neuropilin-1 to inhibit pathological angiogenesis. While promising in vitro, their instability in human serum requires further development for therapeutic use in cancer treatment.
Area of Science:
- Biomedical research
- Radiopharmaceutical development
- Oncology
Background:
- Pathological angiogenesis, driven by angiogenic factor imbalance, is crucial for tumor growth and metastasis.
- The VEGF/VEGFR-2/NRP-1 pathway is a key target for inhibiting angiogenesis in cancer.
- Targeting neuropilin-1 (NRP-1) offers potential for early diagnosis and treatment of angiogenesis-dependent diseases.
Purpose of the Study:
- To design and evaluate peptide-based radiocompounds for selective binding to NRP-1.
- To inhibit the pro-angiogenic VEGF-A165/NRP-1 complex formation.
- To assess the potential of these radiocompounds as targeted radiopharmaceuticals.
Main Methods:
- Design and synthesis of three peptide-based biomolecules (A7R, D R7A, K4R) conjugated to a chelator.
- Labeling of biomolecules with scandium-44 radionuclide.
- In vitro evaluation using ELISA for NRP-1 affinity and stability assays.
Main Results:
- A7R and K4R radiocompounds demonstrated high affinity for NRP-1, while D R7A showed none.
- All radiopeptides were hydrophilic and stable against ligand exchange in cysteine/histidine solutions.
- All radiocompounds exhibited poor nano-scale stability in human serum, limiting therapeutic application.
Conclusions:
- Peptide-based radiocompounds targeting NRP-1 show potential for angiogenesis inhibition.
- The observed instability in human serum necessitates further optimization for clinical translation.
- Future research will focus on developing more human serum-stable angiogenesis inhibitors.
