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

Peptidic ligands selectively targeting distinct G protein‐coupled receptors that are highly expressed in tumor tissue represent a promising approach in drug delivery. Receptor‐preferring analogues of neuropeptide Y (NPY) bind and activate the human Y1 receptor subtype (hY1 receptor), which is found in 90 % of breast cancer tissue and in all breast‐cancer‐derived metastases. Herein, novel highly boron‐loaded Y1‐receptor‐preferring peptide analogues are described as smart shuttle systems for carbaboranes as 10B‐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 hY1 receptor. Boron uptake studies by inductively coupled plasma mass spectrometry revealed successful uptake of the multi‐carbaborane peptide into hY1‐receptor‐expressing cells, exceeding the required amount of 109 boron atoms per cell. This result demonstrates that the NPY/hY receptor system can act as an effective transport system for boron‐containing moieties. NPY for BNCT: Neuropeptide Y (NPY) derivatives selective for only one receptor subtype are internalized into tumor cells that express these specific surface receptors. The cellular uptake of highly boron‐loaded NPY analogues and their application as an efficient shuttle system for successful boron neutron capture therapy (BNCT) are demonstrated.