Synthesis and Characterization of Luteinizing Hormone-Releasing Hormone (LHRH)-Functionalized Mini-Dendrimers

Abstract

Luteinizing hormone-releasing hormone (LHRH) is the key regulator of the hypothalamic-pituitary-gonadal (HPG) axis, which is responsible for the development and functioning of the reproductive system. Delivery of a continuous supply of LHRH agonists causes down-regulation of the LHRH receptors, resulting in a marked decrease in androgens in males and estrogens in females. LHRH analogues are widely used in the treatment of various diseases, including prostate and breast cancer, and reproductive disorders, such as infertility and precocious puberty. However, they require parenteral administration, and no oral formulations are currently available. We synthesized two types of LHRH mini-dendrimers using thioether ligation, aiming to enhance the stability and bioavailability of the peptide drug while maintaining its biologically active conformation. These two compounds include a poly-lysine core conjugated to either the C-terminus of LHRH or a D-amino acid in position 6 of the LHRH sequence. The synthesized dendrimers were analysed using dynamic light scattering, and showed particle sizes of 155 and 115 nm, respectively. The nanometer size, well-defined structure and water solubility of these dendritic analogues make them excellent candidates for further exploration in oral peptide drug delivery.

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

“…This is critical for the process of receptor or postreceptor desensitization for endocrine activity and would promote the activation of GnRH-receptor mediated cell-signaling pathways to induce cell death. 26 Five different GnRH dendrimers (1−5; Figure 1) were synthesized using convergent (1, 2, 4, and 5) 27 or divergent (3) approaches. Dendrimers were comprised of a polylysine core and GnRH in 1, 2, and 5 or lipid-modified GnRH in 3 and 4.…”

Decapeptide Modified Doxorubicin Loaded Solid Lipid Nanoparticles as Targeted Drug Delivery System against Prostate Cancer

“…Cellular uptake of DSLN and M-DSLN into the LHRH positive cell lines were investigated by confocal microscopy . DOX, itself being fluorescent, could successfully be used as the probe to ascertain cellular uptake of DOX, DSLN, and M-DSLN in LHRH receptors overexpressed PC3 and SKBR3 cell lines were investigated by combined flow cytometry and confocal laser microscopy without any additional fluorescent marker.…”

“…Binding of luteinizing hormone releasing hormone (LHRH), a short-lived (∼3 to 4 min in human blood) decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ) to its receptors (LHRH-R) results in receptor microaggregation and its internalization into the cells . Substitution of amino acid residue in positions 1, 6, and 8 of LHRH sequence with d -amino acid is expected to enhance its metabolic stability and lipophilicity without altering its binding affinity . The LHRH receptors are expected to exert stimulatory effects on leutenizing hormone secretion, resulting in the overexpression on different cancer cells bypassing the healthy human organs. , LHRH receptors are overexpressed up to 86% in prostate cancer cells.…”

“…13 Substitution of amino acid residue in positions 1, 6, and 8 of LHRH sequence with D-amino acid is expected to enhance its metabolic stability and lipophilicity 26 without altering its binding affinity. 27 The LHRH receptors are expected to exert stimulatory effects on leutenizing hormone secretion, resulting in the overexpression on different cancer cells bypassing the healthy human organs. 28,29 LHRH receptors are overexpressed up to 86% in prostate cancer cells.…”

Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope

“…To investigate the immunogenic potential of the GnRH epitope, four copies of a tandem GnRH dimer were synthesised on a poly-lysine lipopeptide to yield 8 copies of the epitope in total (5). The presentation of GnRH was enhanced by replacing the Gly residue at position 6 in the parent peptide sequence with a D-Cys (pEHWSYcLRPG 30 and conjugated to a linear T helper lipopeptide (6') using Michael addition ( Figure 2). 31 The site-specific conjugation allowed for both terminal regions of GnRH to display the free amino groups important for immune system recognition (6).…”