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Selective Neuropeptide Y Conjugates with Maximized Carborane Loading as Promising Boron Delivery Agents for Boron
Dennis J Worm1, Paul Hoppenz1, Sylvia Els-Heindl1
1Institute of Biochemistry, Leipzig University, Brüderstrasse 34, 04103 Leipzig, Germany.
Abstract:
G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.
Insights
Researchers developed novel boron-rich peptides targeting human Y1 receptors (hY1R) for cancer therapy. These conjugates effectively deliver boron atoms into cancer cells, enhancing boron neutron capture therapy (BNCT) efficacy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Biology
Background:
- G-protein-coupled receptors, such as the human Y1 receptor (hY1R), are overexpressed on cancer cells and internalize upon ligand binding.
- This internalization mechanism presents an opportunity for targeted drug delivery and therapeutic strategies like boron neutron capture therapy (BNCT).
Purpose of the Study:
- To develop novel boron-containing conjugates for targeted delivery to hY1R-expressing cancer cells.
- To evaluate the efficacy of these conjugates in delivering boron atoms for potential application in BNCT.
Main Methods:
- Solid phase peptide synthesis was employed to create hY1R-preferring ligands ([F7,P34]-NPY) functionalized with multiple carboranes.
- Branched conjugates were synthesized, incorporating up to 80 boron atoms per peptide molecule.
- Internalization studies were conducted to assess selective uptake into hY1R-expressing cells.
- The necessity of eight hydroxyl groups per carborane for aqueous solubility was investigated.
Main Results:
- Synthesized branched conjugates maintained receptor activation profiles while carrying a high payload of boron atoms (up to 80 per molecule).
- Selective uptake into hY1R-expressing cells was confirmed through internalization studies.
- The importance of specific hydroxyl group modifications for ensuring adequate solubility in aqueous solutions was established.
Conclusions:
- Novel boron-rich peptide conjugates targeting hY1R were successfully synthesized.
- These conjugates demonstrate selective uptake into cancer cells, making them promising agents for BNCT.
- The use of bis-deoxygalactosyl-carborane building blocks is proposed for enhanced solubility and targeted boron delivery in BNCT.
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