Development of New Gonadotropin-Releasing Hormone-Modified Dendrimer Platforms with Direct Antiproliferative and Gonadotropin Releasing Activity

Gonadotropin-releasing hormone (GnRH)
agonists (e.g., triptorelin)
are used for androgen suppression therapy. They possess improved stability
as compared to the natural GnRH, yet they suffer from a poor pharmacokinetic
profile. To address this, we used a GnRH peptide-modified dendrimer
platform with and without lipidation strategy. Dendrimers were synthesized
on a polylysine core and bore either native GnRH (1, 2, and 5) or lipid-modified GnRH (3 and 4). Compound 3, which bore a lipidic
moiety in a branched tetramer structure, showed approximately 10-fold
higher permeability and metabolic stability and 39 times higher antitumor
activity against hormone-resistant prostate cancer cells (DU145) relative
to triptorelin. In gonadotropin-release experiments, dendrimer 3 was shown to be the most potent construct. Dendrimer 3 showed similar luteinizing hormone (LH)-release activity
to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analog with higher potency for the treatment
of hormone-resistant prostate cancer than the currently available
GnRH agonists.