Modification of Daunorubicin-GnRH-III Bioconjugates With Oligoethylene Glycol Derivatives to Improve Solubility and Bioavailability for Targeted Cancer Chemotherapy
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Tartalom: http://real.mtak.hu/32077/
Archívum: MTA Könyvtár
Gyűjtemény: Status = Published


Type = Article
Cím:
Modification of Daunorubicin-GnRH-III Bioconjugates With Oligoethylene Glycol Derivatives to Improve Solubility and Bioavailability for Targeted Cancer Chemotherapy
Létrehozó:
HegedĂĽs, RĂłzsa
Pauschert, Aline
Orbán, Erika
SzabĂł, IldikĂł
Andreu, David
Marquardt, Andreas
Mező, Gábor
Manea, Marilena
Kiadó:
Wiley-Blackwell
Dátum:
2015-07
Téma:
QD04 Organic chemistry / szerves kémia
RM Therapeutics. Pharmacology / terápia, gyógyszertan
Tartalmi leírás:
Daunorubicin-GnRH-III bioconjugates have recently been developed as drug delivery systems
with potential applications in targeted cancer chemotherapy. In order to improve their
biochemical properties, several strategies have been pursued: (1) incorporation of an
enzymatic cleavable spacer between the anticancer drug and the peptide-based targeting
moiety, (2) peptide modification by short chain fatty acids or (3) attachment of two anticancer
drugs to the same GnRH-III derivative. Although these modifications led to more potent
bioconjugates, a decrease in their solubility was observed. Here we report on the design,
synthesis and biochemical characterization of daunorubicin-GnRH-III bioconjugates with
increased solubility, which could be achieved by incorporating oligoethylene glycol-based
spacers in their structure. First, we have evaluated the effect of an oligoethylene glycol-based
spacer on the solubility, enzymatic stability/degradation, cellular uptake and in vitro cytostatic
effect of a bioconjugate containing only one daunorubicin attached through a GFLG
tetrapeptide spacer to the GnRH-III targeting moiety. Thereafter, more complex compounds
containing two copies of daunorubicin, GFLG spacers as well as Lys(nBu) in position 4 of
GnRH-III were synthesized and biochemically characterized. Our results indicated that all
synthesized oligoethylene glycol-containing bioconjugates had higher solubility in cell culture
medium than the unmodified analogs. They were degraded in the presence of rat liver
lysosomal homogenate leading to the formation of small drug containing metabolites. In the
case of bioconjugates containing two copies of daunorubicin, the incorporation of
oligoethylene glycol-based spacers led to increased in vitro cytostatic effect on MCF-7 human
breast cancer cells.
Nyelv:
magyar
Típus:
Article
PeerReviewed
info:eu-repo/semantics/article
Formátum:
text
Azonosító:
Hegedüs, Rózsa and Pauschert, Aline and Orbán, Erika and Szabó, Ildikó and Andreu, David and Marquardt, Andreas and Mező, Gábor and Manea, Marilena (2015) Modification of Daunorubicin-GnRH-III Bioconjugates With Oligoethylene Glycol Derivatives to Improve Solubility and Bioavailability for Targeted Cancer Chemotherapy. Peptide Science, 104 (3). pp. 167-177. ISSN 1097-0282
Kapcsolat:
10.1002/bip.22629