Abstract
5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell 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 effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine.
Highlights
Nucleoside analogs in a process termed “squalenoylaones, were and termed tion”. This method was reproduced withof other fatty acids, mainly poly-unsaturated we report on the synthesis conjugating azacitidine to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),ones, their and termed nanoprecipitation of the obtained prodrugs and the characteristics of these self-assemHerein, we report on the synthesis of conjugating azacitidine to EPA and DHA, their blies
Eicosapentaenoic acid and docosahexaenoic acid were obtained from Combiblocks
This study highlights the importance of this method in protecting the vulnerable azacitidine drug, while increasing its bioavailability and offering improved drug-loading capabilities compared to traditional nanovectors
Summary
Pharmaceuticals 2021, 14, 1317 presence of nucleoside deaminase in the blood further decreases the half-life of this molecule and allows its rapid degradation and elimination [18,19,20,21,22]. First, through the synthesis of an azacytidine-based prodrug via its conjugation to a fatty. 2 of 15 toacid at the amine group of azacitidine, and second, by pushing the obtained prodrug wards self-assemblies. The obtained amphiphilic prodrug would have an enhanced entry into the cells owing to the similar nature of the cell lipid bilayer membrane [23,24], with a specificity to the [2,3].
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