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Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety

Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety

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LEURS, Ulrike, Gábor MEZŐ, Erika ORBÁN, Peter ÖHLSCHLÄGER, Andreas MARQUARDT, Marilena MANEA, 2012. Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety. In: Biopolymers. 98(1), pp. 1-10. ISSN 0006-3525

@article{Leurs2012Desig-17237, title={Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety}, year={2012}, doi={10.1002/bip.21640}, number={1}, volume={98}, issn={0006-3525}, journal={Biopolymers}, pages={1--10}, author={Leurs, Ulrike and Mező, Gábor and Orbán, Erika and Öhlschläger, Peter and Marquardt, Andreas and Manea, Marilena} }

Leurs, Ulrike Manea, Marilena 2011-11-30T15:14:53Z Peptide Science ; 98 (2012), 1. - S. 1-10 Design, synthesis, in vitro stability and cytostatic effect of multifunctional anticancer drug-bioconjugates containing GnRH-III as a targeting moiety deposit-license Leurs, Ulrike Öhlschläger, Peter Bioconjugates containing the GnRH-III hormone decapeptide as a targeting moiety are able to deliver chemotherapeutic agents specifically to cancer cells expressing GnRH receptors, thereby increasing their local efficacy while limiting the peripheral toxicity. However, the number of GnRH receptors on cancer cells is limited and they desensitize under continuous hormone treatment. A possible approach to increase the receptor mediated tumor targeting and consequently the cytostatic effect of the bioconjugates would be the attachment of more than one chemotherapeutic agent to one GnRH-III molecule.<br /><br />Here we report on the design, synthesis and biochemical characterization of multifunctional bioconjugates containing GnRH-III as a targeting moiety and daunorubicin as a chemotherapeutic agent. Two different drug design approaches were pursued. The first one was based on the bifunctional [4Lys]-GnRH-III (Glp-His-Trp-Lys-His-Asp-Trp-Lys-Pro-Gly-NH2) containing two lysine residues in positions 4 and 8, whose ε-amino groups were used for the coupling of daunorubicin. In the second drug design, the native GnRH-III (Glp-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH2) was used as a scaffold; an additional lysine residue was coupled to the ε-amino group of 8Lys in order to generate two free amino groups available for conjugation of daunorubicin. The in vitro stability/degradation of all synthesized compounds was investigated in human serum, as well as in the presence of rat liver lysosomal homogenate. Their cellular uptake was determined on human breast cancer cells and the cytostatic effect was evaluated on human breast, colon and prostate cancer cell lines.<br /><br />Compared to a monofunctional compound, both drug design approaches resulted in multifunctional bioconjugates with increased cytostatic effect. Marquardt, Andreas Mező, Gábor eng 2011-11-30T15:14:53Z Öhlschläger, Peter Manea, Marilena Orbán, Erika Marquardt, Andreas Orbán, Erika Mező, Gábor 2012

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