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

Abstract

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 (10) B-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 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.

A stable meta‐carborane enables the generation of boron‐rich peptide agonists targeting the ghrelin receptor

“…For carboranes 2 and 3 , synthesis was achieved by a thiol‐functionalized intermediate (Supporting information, Figure S1). Carborane building block 5 is a meta ‐substituted version of ortho ‐carborane 4, which was described in a previous publication . Synthesis of meta ‐carborane 5 was also accomplished by a thiol‐functionalized intermediate (Supporting information, Figure S1).…”

“…Carborane building block 5 is a meta-substituted version of orthocarborane 4, which was described in a previous publication. 24 Synthesis of meta-carborane 5 was also accomplished by a thiol-functionalized intermediate (Supporting information, Figure S1). 44 All carborane building blocks contain a carboxyl group (Figure 1), which allows conjugation to peptides on the solid phase by peptide coupling.…”

“…Carboranes in particular are optimal boron compounds for conjugation owing to a high boron content and biological stability . Modification of [F 7 ,P 34 ]‐neuropeptide Y with 1,2‐dicarba‐ closo ‐dodecaborane ( ortho ‐carborane) for targeting the Y 1 receptor in breast tumors was previously described . By this approach, a sufficient amount of boron for BNCT was internalized into receptor‐expressing cells.…”

Drug delivery and release systems for targeted tumor therapy

“…This concept was impressively demonstrated by the successful imaging of breast cancer cells in tumor-bearing patients with an N-terminally 99m Tc-labeled [F 7 ,P 34 ]-NPY analogue [30]. Furthermore, [F 7 ,P 34 ]-NPY was modified at three different positions with carbaborane clusters as a potential application in boron neutron capture therapy (BNCT) [31]. The peptide retained its selective receptor activation and internalization properties and therefore is a well-suited carrier for boron-containing moieties.…”

“…Cell viability assays with hY 1 R-expressing neuroblastoma cells revealed a comparable toxicity of the hydrazone-linked conjugate to free DOX, whereas the amidelinked DOX-NPY conjugate exerted no toxic effect. The development of the hY 1 R-preferring peptide [F 7 ,P 34 ]-NPY [29] allows an even more specific delivery to these types of cancer [30,31]. Furthermore, hY 2 R are overexpressed in neuroblastoma cells, and for colon cancer, hY 4 R are suspected to be promising targets [132].…”