Receptor-Mediated Uptake of Boron-Rich Neuropeptide Y Analogues for Boron Neutron Capture Therapy

Peptidic ligands selectively targeting distinct Gprotein-coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor-preferring analogues of neuropeptideY (NPY) bind and activate the human Y-1 receptor subtype (hY(1) receptor), which is found in 90% of breast cancer tissue and in all breast-cancer-derived metastases. Herein, novel highly boron-loaded Y-1-receptor-preferring peptide analogues are described as smart shuttle systems for carbaboranes as B-10-containing moieties. Various positions in the peptide were screened for their susceptibility to carbaborane modification, and the most promising positions were chosen to create a multi-carbaborane peptide containing 30 boron atoms per peptide with excellent activation and internalization patterns at the hY(1) receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi-carbaborane peptide into hY(1)-receptor-expressing cells, exceeding the required amount of 10(9) boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron-containing moieties.