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Peptide-Drug conjugate gnrh-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth

Peptide-Drug conjugate gnrh-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth
Peptide-Drug conjugate gnrh-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth

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-Lys6]-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 phosphor-ylation 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.

0008-5472
1181-1192
Argyros, Orestis
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Karampelas, Theodoros
abcbe8aa-0421-4422-b178-cf34dd7c9fcd
Asvos, Xenophon
ebc93e29-1327-4e8e-ab34-9996ddace703
Varela, Aimilia
2731683e-7c24-4dc5-84dd-c946cf3e497a
Sayyad, Nisar
b6023006-1de8-43a7-8da1-f4be56b35538
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Davos, Constantinos H.
403ef29c-fd01-464b-87bd-29d206f5941d
Tzakos, Andreas G.
1af1bc7c-e2a9-4002-8a61-4fbe17becd80
Fokas, Demosthenes
9d8c8613-fd56-46ff-bb01-2447cf672af6
Tamvakopoulos, Constantin
8ade63d2-9331-4f09-ab1d-484af1023e03
Argyros, Orestis
738479e2-c42d-4a79-a67f-bf72001ab622
Karampelas, Theodoros
abcbe8aa-0421-4422-b178-cf34dd7c9fcd
Asvos, Xenophon
ebc93e29-1327-4e8e-ab34-9996ddace703
Varela, Aimilia
2731683e-7c24-4dc5-84dd-c946cf3e497a
Sayyad, Nisar
b6023006-1de8-43a7-8da1-f4be56b35538
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Davos, Constantinos H.
403ef29c-fd01-464b-87bd-29d206f5941d
Tzakos, Andreas G.
1af1bc7c-e2a9-4002-8a61-4fbe17becd80
Fokas, Demosthenes
9d8c8613-fd56-46ff-bb01-2447cf672af6
Tamvakopoulos, Constantin
8ade63d2-9331-4f09-ab1d-484af1023e03

Argyros, Orestis, Karampelas, Theodoros, Asvos, Xenophon, Varela, Aimilia, Sayyad, Nisar, Papakyriakou, Athanasios, Davos, Constantinos H., Tzakos, Andreas G., Fokas, Demosthenes and Tamvakopoulos, Constantin (2016) Peptide-Drug conjugate gnrh-sunitinib targets angiogenesis selectively at the site of action to inhibit tumor growth. Cancer Research, 76 (5), 1181-1192. (doi:10.1158/0008-5472.CAN-15-2138).

Record type: Article

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-Lys6]-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 phosphor-ylation 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.

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More information

e-pub ahead of print date: 8 December 2015
Published date: 1 March 2016

Identifiers

Local EPrints ID: 413407
URI: http://eprints.soton.ac.uk/id/eprint/413407
ISSN: 0008-5472
PURE UUID: 22a56bd9-1a4b-4bac-8026-779666a66e6c
ORCID for Athanasios Papakyriakou: ORCID iD orcid.org/0000-0003-3931-6232

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Date deposited: 23 Aug 2017 16:32
Last modified: 17 Dec 2019 01:28

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