Remote substituents on cucurbit[7]uril-bound guests are used to decipher the fierce competition between water and the carbonylated portal of the macrocycle for guest stabilization.
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.
G-protein-coupled receptors like the human Y 1 receptor (hY 1 R) 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 hY 1 R-preferring ligand [F 7 ,P 34 ]-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 hY 1 R-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.
Boron neutron capture therapy (BNCT) allows the selective
elimination
of malignant tumor cells without affecting healthy tissue. Although
this binary radiotherapy approach has been known for decades, BNCT
failed to reach the daily clinics to date. One of the reasons is the
lack of selective boron delivery agents. Using boron loaded peptide
conjugates, which address G protein-coupled receptors overexpressed
on tumor cells allow the intracellular accumulation of boron. The
gastrin-releasing peptide receptor (GRPR) is a well-known target in
cancer diagnosis and can potentially be used for BNCT. Here, we present
the successful introduction of multiple bis-deoxygalactosyl-carborane
building blocks to the GRPR-selective ligand [d-Phe6, β-Ala11, Ala13, Nle14]Bn(6–14)
(sBB2L) generating peptide conjugates with up to 80 boron atoms per
molecule. Receptor activation was retained, metabolic stability was
increased, and uptake into PC3 cells was proven without showing any
intrinsic cytotoxicity. Furthermore, undesired uptake into liver cells
was suppressed by using l-deoxygalactosyl modified carborane
building blocks. Due to its high boron loading and excellent GRPR
selectivity, this conjugate can be considered as a promising boron
delivery agent for BNCT.
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