Fiche publication
Date publication
septembre 2019
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LEBEAU Luc
,
Dr REMY Jean-Serge
,
Pr PONS Françoise
Tous les auteurs :
Gaillard B, Seguin C, Remy JS, Pons F, Lebeau L
Lien Pubmed
Résumé
Sixteen cationic prodrugs of the antitumor alkylphospholipid (APL) erufosine were rationally synthesized to provide original gene delivery reagents with improved cytotoxicity profile. The DNA complexation properties of these cationic lipids were determined and associated transfection rates were measured. Besides, the self-assembly properties of the pro-erufosine compounds were investigated and their critical aggregation concentration was determined. Their hydrolytic stability under pH conditions mimicking the extracellular environment and the late endosome milieu was measured. Hemolytic activity and cytotoxicity of the compounds were investigated. The results obtained in various cell lines demonstrate that the prodrugs of erufosine display antineoplastic activity similar to that of the parent antitumor drug but are not associated with hemolytic toxicity, a dose-limiting side effect of APLs and a major obstacle to their use in anticancer therapeutic regimen. Furthermore, using lipoplexes prepared from a prodrug of erufosine and a plasmid DNA encoding a pro-apoptotic protein (TRAIL), evidence was provided for selective cytotoxicity towards tumor cells while non-tumor cells were resistant. This study demonstrates that the combination approach involving well tolerated erufosine cationic prodrugs and cancer gene therapy holds significant promise in tumor therapy.
Mots clés
chemotherapy, erufosine, gene therapy, hemolytic toxicity, prodrug
Référence
Chemistry. 2019 Sep 24;:
