title: Peptide-Drug Conjugate GnRH-Sunitinib Targets Angiogenesis Selectively at the Site of Action to Inhibit Tumor Growth.
abstract: The potential to heighten the efficacy of antiangiogenic agents was explored in this study based on active targeting of tumor cells overexpressing the gonadotropin-releasing hormone receptor (GnRH-R). The rational design pursued focused on five analogues of a clinically established antiangiogenic compound (sunitinib), from which a lead candidate (SAN1) was conjugated to the targeting peptide [d-Lys(6)]-GnRH, generating SAN1GSC. Conjugation of SAN1 did not disrupt any of its antiangiogenic or cytotoxic properties in GnRH-R-expressing prostate and breast tumor cells. Daily SAN1GSC treatments in mouse xenograft models of castration-resistant prostate cancer resulted in significant tumor growth delay compared with equimolar SAN1 or sunitinib alone. This efficacy correlated with inhibited phosphorylation of AKT and S6, together with reduced Ki-67 and CD31 expression. The superior efficacy of the peptide-drug conjugate was also attributed to the finding that higher amounts of SAN1 were delivered to the tumor site (∼4-fold) following dosing of SAN1GSC compared with equimolar amounts of nonconjugated SAN1. Importantly, treatment with SAN1GSC was associated with minimal hematotoxicity and cardiotoxicity based on measurements of the left ventricular systolic function in treated mice. Our results offer preclinical proof-of-concept for SAN1GSC as a novel molecule that selectively reaches the tumor site and downregulates angiogenesis with negligible cardiotoxicity, thus encouraging its further clinical development and evaluation.
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery & Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece.
authors.forename: Orestis
authors.initials: O
authors.lastname: Argyros
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery & Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karampelas
authors.affiliation: Department of Chemistry, Organic Chemistry and Biochemistry, University of Ioannina, Ioannina, Greece.
authors.forename: Xenophon
authors.initials: X
authors.lastname: Asvos
authors.affiliation: Cardiovascular Research Laboratory, BRFAA, Athens, Greece.
authors.forename: Aimilia
authors.initials: A
authors.lastname: Varela
authors.affiliation: Department of Chemistry, Organic Chemistry and Biochemistry, University of Ioannina, Ioannina, Greece.
authors.forename: Nisar
authors.initials: N
authors.lastname: Sayyad
authors.affiliation: Laboratory of Chemical Biology of Natural Products and Designed Molecules, Institute of Physical Chemistry, NCSR "Demokritos," Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.affiliation: Cardiovascular Research Laboratory, BRFAA, Athens, Greece.
authors.forename: Constantinos H
authors.initials: CH
authors.lastname: Davos
authors.affiliation: Department of Chemistry, Organic Chemistry and Biochemistry, University of Ioannina, Ioannina, Greece.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Tzakos
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Materials Science and Engineering, University of Ioannina, Ioannina, Greece.
authors.forename: Demosthenes
authors.initials: D
authors.lastname: Fokas
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Clinical, Experimental Surgery & Translational Research Center, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece. ctamvakop@bioacademy.gr.
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D011966:Receptors, LHRH / Q000032:analysis; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D000077210:Sunitinib