Stability, permeability and growth-inhibitory properties of gonadotropin-releasing hormone liposaccharides.

PURPOSE: In this study we aimed to address the poor drug-like properties of Gonadotropin-Releasing Hormone (GnRH) peptide through modification with lipids and carbohydrates.

METHODS: GnRH peptide was conjugated to 2-amino-D,L-octanoic acid (C8) and 2-amino-D,L-dodecanoic acid (C12) in monomer and dimer, along with (6-9) or without (2-5 and 11) a glucose moiety. Peptides were tested for their biological activity using different tumour cell lines. The toxicity of the constructs was evaluated in peripheral blood mononuclear cells (PBMC).

RESULTS: All (glyco)lipopeptides showed improved metabolic stability in Caco-2 cell homogenates. Those with single lipid moiety (2, 4 and 8) exhibited prodrug-like properties. Permeability across Caco-2 cell monolayers was enhanced in the dimer C8-modified (glyco)lipopeptide (3) and the lipopeptide with C12 inserted mid-sequence (11). Most of the constructs showed moderate-to-high antiproliferative activity against GnRH-receptor positive DU145 and OVCAR-3 cells (up to 60%). Compound 11 was the most effective with IC50 = 26.4 ± 1.07 μg.ml(-1), which was comparable to triptorelin (25.1 ± 1.14 μg.mL(-1)). The sensitivity of OVCAR-3 cells to the effect of all analogues except for 11 decreased significantly in estrogen-reconstituted media. Only compounds 2, 4, 5 and 8 showed a steroid-dependent effect in DU145 cells. No compounds exhibited significant toxicity on PBMCs.

CONCLUSION: These results indicated lipidation and glycosylation improves the druggability of GnRH and could lead to an increased direct antitumour activity in some hormone dependent and independent reproductive cancers.