Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates
| Autor: | Ildikó Szabó, Marilena Manea, Rózsa Hegedüs, Éva Sipos, Éva Kiss, Gabor Halmos, Erika Orbán, Gábor Mező |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Daunorubicin
Acylation Antineoplastic Agents Gonadotropin-Releasing Hormone Structure-Activity Relationship Drug Discovery medicine Humans Cell Proliferation Pharmacology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure Circular Dichroism Gyógyszerészeti tudományok Organic Chemistry Short-chain fatty acid Fatty Acids Fatty acid General Medicine Orvostudományok In vitro Pyrrolidonecarboxylic Acid Enzyme chemistry Biochemistry Drug delivery Cancer cell MCF-7 Cells Drug Screening Assays Antitumor HT29 Cells Receptors LHRH medicine.drug |
| Popis: | Here we report on the synthesis and biochemical characterization (enzymatic stability, cellular uptake, in vitro antitumor activity, membrane interaction and GnRH-receptor binding affinity) of novel short-chain fatty acid (SCFA) acylated daunorubicin–GnRH-III bioconjugates, which may serve as drug delivery systems for targeted cancer chemotherapy. Ser in position 4 of GnRH-III was replaced by Lys, followed by the acylation of its e-amino group with various fatty acids. SCFAs are potentially chemoprotective agents by suppressing the growth of cancer cells and therefore may enhance the antitumor activity of the bioconjugates. We found that all synthesized bioconjugates had high cytostatic effect in vitro , were stable in cell culture medium for 6 h and degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked daunorubicin-Lys as the smallest active metabolite. In the presence of α-chymotrypsin, all compounds were digested, the degradation rate strongly depending on the type of fatty acid. The bioconjugate containing Lys(nBu) in position 4 was taken up most efficiently by the cancer cells and exerted higher in vitro cytostatic effect than the previously developed GnRH-III( 4 Lys(Ac), 8 Lys(Dau = Aoa)) or the parent GnRH-III(Dau = Aoa) bioconjugate. Our results could be explained by the increased binding affinity of the newly developed compound containing Lys(nBu) to the GnRH receptors. |
| Databáze: | OpenAIRE |
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