Anthracycline-GnRH derivative bioconjugates with different linkages: Synthesis, in vitro drug release and cytostatic effect

Pascal Schlage, Gábor Mezo, Erika Orbán, Szilvia Bosze, Marilena Manea

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To increase the selectivity and consequently to minimize the side effects of chemotherapeutic agents, receptor mediated tumor targeting approaches have been developed. In the present work, various anthracycline-GnRH derivative bioconjugates were synthesized with the aim of investigating the influence of (i) different anthracycline anticancer drugs, (ii) different linkages between the targeting moiety and the anticancer drug, and (iii) different targeting moieties (e.g., GnRH-III and [D-Lys 6]-GnRH-I) on their in vitro drug release and cytostatic effect. The anthracyclines, daunorubicin or doxorubicin, were attached to the ε-amino group of Lys of GnRH-III or [D-Lys 6]-GnRH-I through oxime, hydrazone or ester bonds. In another bioconjugate, a self-immolative p-aminobenzyloxycarbonyl spacer was used to link daunorubicin to GnRH-III. The in vitro degradation of the bioconjugates was investigated in the presence of rat liver lysosomal homogenate and cathepsin B. The cellular uptake of the compounds was evaluated by flow cytometry and their in vitro cytostatic effect was determined by 3-(4,5-dimethylthiazolyl-2)-2,5- diphenyltetrazolium bromide assay. The results indicate that on the tested cancer cell lines there is no significant difference in the cellular uptake and in vitro cytostatic effect of bioconjugates containing GnRH-III or [D-Lys 6]-GnRH-I as a targeting moiety. The bioconjugates containing ester bond, hydrazone bond and the self-immolative spacer exert the highest cytostatic effect, followed by oxime bond-linked compounds.

Original languageEnglish
Pages (from-to)170-178
Number of pages9
JournalJournal of Controlled Release
Issue number2
Publication statusPublished - Dec 10 2011



  • Anthracyclines
  • Anticancer drug-peptide bioconjugates
  • Gonadotropin-releasing hormone
  • In vitro cytostatic effect
  • In vitro degradation

ASJC Scopus subject areas

  • Pharmaceutical Science

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