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Enhanced in vitro antitumor activity of gnRH-III-daunorubicin bioconjugates influenced by sequence modification

Schuster, S. and Biri-Kovács, B. and Szeder, Bálint and Buday, László and Gardi, J. (2018) Enhanced in vitro antitumor activity of gnRH-III-daunorubicin bioconjugates influenced by sequence modification. Pharmaceutics, 10 (4). ISSN 1999-4923

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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-[4 Lys(Bu),8 Lys(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-[2 ∆His,3 D-Tic,4 Lys(Bu),8 Lys(Dau=Aoa)] is a highly potent and promising anticancer drug delivery system for targeted tumor therapy. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Item Type: Article
Additional Information: Faculty of Science, Institute of Chemistry, Eötvös Loránd University, Budapest, 1117, Hungary MTA-ELTE Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, 1117, Hungary Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, 1117, Hungary First Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, 6720, Hungary Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, Debrecen, 4032, Hungary Export Date: 5 December 2018 Correspondence Address: Mező, G.; Faculty of Science, Institute of Chemistry, Eötvös Loránd UniversityHungary; email: gmezo@elte.hu
Uncontrolled Keywords: DAUNORUBICIN; drug delivery system; CELLULAR UPTAKE; Antitumor activity; Targeted cancer therapy; oxime linkage; Gonadotropin releasing hormone III; Peptide drug conjugates;
Subjects: Q Science / természettudomány > QD Chemistry / kémia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 05 Dec 2018 12:56
Last Modified: 05 Dec 2018 12:56
URI: http://real.mtak.hu/id/eprint/88226

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