Abstract
Gonadotropin-releasing hormone (GnRH) agonists such as triptorelin, are used for androgen suppression therapy in hormone-sensitive prostate cancers. GnRH agonists possess improved stability compared to the native GnRH, yet, they suffer from poor pharmacokinetic profile. We used a GnRH peptide-modified dendrimer platform with/without lipidation strategy in order to enhance the pharmacokinetic properties of GnRH peptide and improve the direct antitumor potential in order to make it more suitable for application in hormone-resistant tumors.
Dendrimers were designed and synthesized on a polylysine core bearing either native GnRH in compounds 1, 2 and 5 or lipid-modified GnRH in compounds 3 and 4. The attachment of a lipidic moiety to the C-terminus of GnRH in a branched tetramer structure, 3, not only resulted in approximately 10-fold higher permeability and metabolic stability but also 39 times higher antitumor activity (in a hormone-resistant prostate cancer cell line: DU145) relative to triptorelin. Through a triptorelin competitive assay it was suggested that this direct antitumor activity is mediated through GnRH receptors. In gonadotropin-release efficacy studies, dendrimer 3 was the most potent construct with comparable potency with triptorelin in stimulating the release of follicle stimulating and luteinizing hormone (LH). Dendrimer 3 showed similar LH-release activity to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analogue with higher potency in the treatment of hormone-resistant prostate cancer compared to the currently available GnRH agonists.
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