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Pharmaceutics 2018, 10(4), 223; https://doi.org/10.3390/pharmaceutics10040223

Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification

1
Faculty of Science, Institute of Chemistry, Eötvös Loránd University, 1117 Budapest, Hungary
2
MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, 1117 Budapest, Hungary
3
Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, 1117 Budapest, Hungary
4
First Department of Internal Medicine, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary
5
Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary
*
Author to whom correspondence should be addressed.
Received: 20 September 2018 / Revised: 1 November 2018 / Accepted: 6 November 2018 / Published: 9 November 2018
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Abstract

Receptors for gonadotropin releasing hormone (GnRH) are highly expressed in various human cancers including breast, ovarian, endometrial, prostate and colorectal cancer. Ligands like human GnRH-I or the sea lamprey analogue GnRH-III represent a promising approach for the development of efficient drug delivery systems for targeted tumor therapy. Here, we report on the synthesis and cytostatic effect of 14 oxime bond-linked daunorubicin GnRH-III conjugates containing a variety of unnatural amino acids within the peptide sequence. All compounds demonstrated a reduced cell viability in vitro on estrogen receptor α (ERα) positive and ERα negative cancer cells. The best candidate revealed an increased cancer cell growth inhibitory effect compared to our lead-compound GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)]. Flow cytometry and fluorescence microscopy studies showed that the cellular uptake of the novel conjugate is substantially improved leading to an accelerated delivery of the drug to its site of action. However, the release of the active drug-metabolite by lysosomal enzymes was not negatively affected by amino acid substitution, while the compound provided a high stability in human blood plasma. Receptor binding studies were carried out to ensure a high binding affinity of the new compound for the GnRH-receptor. It was demonstrated that GnRH-III-[2ΔHis,3d-Tic,4Lys(Bu),8Lys(Dau=Aoa)] is a highly potent and promising anticancer drug delivery system for targeted tumor therapy. View Full-Text
Keywords: targeted cancer therapy; drug delivery system; daunorubicin; gonadotropin releasing hormone III; peptide drug conjugates; oxime linkage; antitumor activity; cellular uptake targeted cancer therapy; drug delivery system; daunorubicin; gonadotropin releasing hormone III; peptide drug conjugates; oxime linkage; antitumor activity; cellular uptake
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Schuster, S.; Biri-Kovács, B.; Szeder, B.; Buday, L.; Gardi, J.; Szabó, Z.; Halmos, G.; Mező, G. Enhanced In Vitro Antitumor Activity of GnRH-III-Daunorubicin Bioconjugates Influenced by Sequence Modification. Pharmaceutics 2018, 10, 223.

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