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

• Published in: Journal of peptide science Vol. 24; no. 10; pp. e3119 - n/a
• Main Authors: Worm, Dennis J., Els‐Heindl, Sylvia, Kellert, Martin, Kuhnert, Robert, Saretz, Stefan, Koebberling, Johannes, Riedl, Bernd, Hey‐Hawkins, Evamarie, Beck‐Sickinger, Annette G.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.10.2018
• Subjects: Activation; Boron; Boron - chemistry; Boron - pharmacology; boron delivery agent; Boron Neutron Capture Therapy; Cancer; Cancer therapies; Carborane; carborane‐peptide conjugates; Conjugates; Drug Carriers; Ghrelin; ghrelin receptor activation and internalization; Growth hormones; HEK293 Cells; Humans; Ligands; Localization; Nuclear capture; Oligopeptides - chemistry; Organic chemistry; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Proteins; Receptor mechanisms; Receptors; Receptors, Ghrelin - agonists; Therapy; Tumor cells; Tumors; boron delivery agent; boron neutron capture therapy; carborane-peptide conjugates; ghrelin receptor activation and internalization
• ISSN: 1075-2617; 1099-1387
• DOI: 10.1002/psc.3119

Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron‐containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein‐coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor‐directed boron uptake. In this study, we present the generation of short, boron‐rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super‐agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta‐carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron‐loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin. A stable meta‐carborane building block was used to generate potent, boron‐rich peptide agonists that target the ghrelin receptor. Owing to the overexpression of the ghrelin receptor in various tumors, the carborane‐peptide conjugates can be considered as potential boron delivery agents for boron neutron capture therapy.