Soutenance de Thèse de Mr Milad BAROUD

The December 9, 2021

Self-assemblies of azacitidine prodrugs: a promising strategy of treatment for myelodysplastic syndromes and acute myeloid leukemia

Directeur de Thèse: Pr Olivier DUVAL

Co-directrice de thèse: Dr Elise LEPELTIER

Abstract :

5-Azacitidine, a cytidine analogue and a hypomethylating agent, is one of the main drugs being used for the treatment of myelodysplastic syndromes and of acute myeloid leukemia. However, after administration, it exhibits several limitations including restricted cancer cell internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this project was to improve the cancer cell internalization and protect it from metabolic degradation via the synthesis of an amphiphilic prodrug and their potential self-assembly. The azacitidine was conjugated to two different omega-3 fatty acids, the eicosapentaenoic acid (EPA) and the docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was covalently conjugated to the amine group of azacitidine, yielding an amphiphilic prodrug.  Next, the nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs with a diameter of around 200 nm, a polydispersity index below 0.2 and a positive zeta potential. Both self-assemblies had an IC50 close to azacitidine on a human leukemia cell line HL-60. Moreover, AzaEPA self-assemblies showed a slow and gradual cell internalization. This strategy would allow protection while increasing azacitidine specificity and bioavailability.

Keywords : azacitidine, prodrug, self-assembly, cathepsin B, myelodysplastic syndromes, PUFAylation