Self-assemblies of azacitidine prodrugs: a promising strategy of treatment for myelodysplastic syndromes
Résumé
5-Azacitidine, a cytidine analogue and a hypomethylating agent, is a staple drug being in the treatment of myelodysplastic syndromes [1]. However, after administration, it exhibits several limitations including restricted diffusion and cellular internalization due to its hydrophilicity, and rapid enzymatic degradation by deaminases. The aim of this research is to improve the drug diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was 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 200 nm, a polydispersity index below 0.2 and a positive zeta potential. Both self-assemblies had an IC50 close to azacitidine. AzaEPA showed a slow and gradual internalization. This strategy would allow protection while increasing azacitidine's specificity and bioavailability. This prodrug should be cleaved by cathepsin B [2], an enzyme overexpressed in cancerous cells [3], thus increasing the specificity of the drug.
Domaines
Chimie thérapeutique
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