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


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.

Share and Cite:

A. Rafiee, F. Mansfeld, P. Moyle and I. Toth, "Synthesis and Characterization of Luteinizing Hormone-Releasing Hormone (LHRH)-Functionalized Mini-Dendrimers," International Journal of Organic Chemistry, Vol. 3 No. 1, 2013, pp. 51-57. doi: 10.4236/ijoc.2013.31006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] S. V. Meethal and C. S. Atwood, “The Role of Hypothalamic-Pituitary-Gonadal Hormones in the Normal Structure and Functioning of the Brain,” Cellular and Molecular Life Sciences: CMLS, Vol. 62, No. 3, 2005, pp. 257-270. doi:10.1007/s00018-004-4381-3
[2] R. P. Millar, Z. L. Lu, A. J. Pawson, C. A. Flanagan, K. Morgan and S. R. Maudsley, “Gonadotropin-Releasing Hormone Receptors,” Endocrine Reviews, Vol. 25, No. 2, 2004, pp. 235-275. doi:10.1210/er.2003-0002
[3] D. A. Beyer, F. Amari, M, Thill, A. Schultze-Mosgau, S. Al-Hasani, K. Diedrich and G. Griesinger, “Emerging Gonadotropin-Releasing Hormone Agonists,” Expert Opinion on Emerging Drugs, Vol. 16, No. 2, 2011, pp. 323-340. doi:10.1517/14728214.2010.547472
[4] J. Sandow, “Clinical Applications of LHRH and Its Analogues,” Clinical Endocrinology, Vol. 18, No. 6, 1983, pp. 571-592.
[5] J. B. Engel and A. V. Schally, “Drug Insight: Clinical Use of Agonists and Antagonists of Luteinizing-Hormone-Releasing Hormone,” Nature Clinical Practice Endocrinology & Metabolism, Vol. 3, No. 2, 2007, pp. 157-167. doi:10.1038/ncpendmet0399
[6] M. J. Karten and J. E. Rivier, “Gonadotropin-Releasing Hormone Analog Design. Structure-Function Studies toward the Development of Agonists and Antagonists: Rationale and Perspective,” Endocrine Reviews, Vol. 7, No. 1, 1986, pp. 44-66. doi:10.1210/edrv-7-1-44
[7] J. P. Moreau, P. Delavault and J. Blumberg, “Luteinizing Hormone-Releasing Hormone Agonists in the Treatment of Prostate Cancer: A Review of Their Discovery, Development, and Place in Therapy,” Clinical Therapeutics, Vol. 28, No. 10, 2006, pp. 1485-1508. doi:10.1016/j.clinthera.2006.10.018
[8] H. Matsuo, Y. Baba, R. M. G. Nair, A. Arimura and A. V. Schally, “Structure of the Porcine LH- and FSH-Releasing Hormone. I. The Proposed Amino Acid Sequence,” Biochemical and Biophysical Research Communications, Vol. 43, No. 6, 1971, pp. 1334-1339. doi:10.1016/S0006-291X(71)80019-0
[9] C. A. Flanagan, R. P. Millar and N. Illing, “Advances in Understanding Gonadotrophin-Releasing Hormone Receptor Structure and Ligand Interactions,” Reviews of Reproduction, Vol. 2, No 2, 1997, pp. 113-120. doi:10.1530/ror.0.0020113
[10] G. V. Nikiforovich and G. R. Marshall, “Conformation-Function Relationships in LHRH Analogs,” International Journal of Peptide and Protein Research, Vol. 42, No. 2, 1993, pp. 181-193. doi:10.1111/j.1399-3011.1993.tb00495.x
[11] J. H. Hamman, G. M. Enslin and A. F. Kotzé, “Oral Delivery of Peptide Drugs: Barriers and Developments,” Biodrugs, Vol. 19, No. 3, 2005, pp. 165-177.
[12] M. Morishita and N. A. Peppas, “Is the Oral Route Possible for Peptide and Protein Drug Delivery?” Drug Discovery Today, Vol. 11, No. 19, 2006, pp. 905-910. doi:10.1016/j.drudis.2006.08.005
[13] H. Chen and R. Langer, “Oral Particulate Delivery: Status and Future Trends,” Advanced Drug Delivery Reviews, Vol. 34, No. 2, 1998, pp. 339-350. doi:10.1016/S0169-409X(98)00047-7
[14] B. K. Nanjwade, V. K. Nanjwade, H. M. Bechra, G. K. Derkar and F. V. Manvi, “Dendrimers: Emerging Polymers for Drug-Delivery Systems,” European Journal of Pharmaceutical Sciences, Vol. 38, No. 3, 2009, pp. 185- 196. doi:10.1016/j.ejps.2009.07.008
[15] V. V. Ranade, “Drug Delivery Systems,” CRC Press, Hoboken, 2011.
[16] A. T. Florence, T. Sakthivel and I. Toth, “Oral Uptake and Translocation of a Polylysine Dendrimer with a Lipid Surface,” Journal of Controlled Release, Vol. 65, No. 1, 2000, pp. 253-259. doi:10.1016/S0168-3659(99)00237-0
[17] Y. Cheng, Z. Xu, M. Ma and T. Xu, “Dendrimers as Drug Carriers: Applications in Different Routes of Drug Administration,” Journal of Pharmaceutical Sciences, Vol. 97, No. 1, 2007, pp. 123-143. doi:10.1002/jps.21079
[18] R. Esfand and D. A. Tomalia, “Poly (Amidoamine) (PAMAM) Dendrimers: From Biomimicry to Drug Delivery and Biomedical Applications,” Drug Discovery Today, Vol. 6, No. 8, 2001, pp. 427-436. doi:10.1016/S1359-6446(01)01757-3
[19] L. M. Kaminskas, V. M. McLeod, M. Victoria, B. D. Kelly. P. Karellas and C. J. H. Porter, “PEGylation of Polylysine Dendrimers Improves Absorption and Lymphatic Targeting Following SC Administration in Rats,” Journal of Controlled Release, Vol. 140, No. 2, 2009, pp. 108-116. doi:10.1016/j.jconrel.2009.08.005
[20] L. M. Kaminskas, B. J. Boyd, P. Karellas, S. A. Henderson, M. P. Giannis, G. Y. Krippner and C. H. J Porter, “Impact of Surface Derivatization of Poly-L-Lysine Dendrimers with Anionic Arylsulfonate or Succinate Groups on Intravenous Pharmacokinetics and Disposition,” Molecular Pharmaceutics, Vol. 4, No. 6, 2007, pp. 949-961. doi:10.1021/mp070047s
[21] B. J. Boyd, L. M. Kaminskas, P. Karellas, G. Y. Krippner, R. Lessene and C. H. J Porter, “Cationic Poly-L-Lysine Dendrimers: Pharmacokinetics, Biodistribution, and Evidence for Metabolism and Bioresorption after Intravenous Administration to Rats,” Molecular Pharmaceutics, Vol. 3, No. 5, 2006, pp. 614-627. doi:10.1021/mp060032e
[22] D. A Tomalia, H. Baker, J. Dewald, M. Hall, G. Kallos, S. Martin, J. Roeck, J. Ryder and P. Smith, “A New Class of Polymers: Starburst-Dendritic Macromolecules,” Polymer Journal, Vol. 17, No. 1, 1985, pp. 117-132. doi:10.1295/polymj.17.117
[23] K. Sadler and J. P. Tam, “Peptide Dendrimers: Applications and Synthesis,” Reviews in Molecular Biotechnology, Vol. 90, No. 3, 2002, pp. 195-229. doi:10.1016/S1389-0352(01)00061-7
[24] M. Monso, W. Kowalczyk, D. Andreu and B. G. de la Torre, “Reverse Thioether Ligation Route to Multimeric Peptide Antigens,” Organic & Biomolecular Chemistry, Vol. 10, No. 15, 2012, pp. 3116-3121. doi:10.1039/c2ob06819b
[25] F. A. Robey, R. L. Fields and W. Lindner, “Synthesis of Chloroacetyl and Bromoacetyl Modified Peptides for the Preparation of Synthetic Peptide Polymers, Conjugated Peptides, and Cyclic Peptides,” US Patents No. 5066716, 1991.
[26] A. Isidro-Llobet, M. Alvarez and F. Albericio, “Amino Acid-Protecting Groups,” Chemical Reviews, Vol. 109, No. 6, 2009, pp. 2455-2504. doi:10.1021/cr800323s
[27] K. Y. Win and S. S. Feng, “Effects of Particle Size and Surface Coating on Cellular Uptake of Polymeric Nanoparticles for Oral Delivery of Anticancer Drugs,” Biomaterials, Vol. 26, No. 15, 2005, pp. 2713-2722. doi:10.1016/j.biomaterials.2004.07.050

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.