DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles

Abstract

Cytarabine (1-β-d-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is used for the treatment of both acute and chronic myeloblastic leukemias and non-Hodgkin lymphoma. It has a very short plasma half-life and a very low oral bioavailability. To overcome these disadvantages, much effort has been focused on the design of cytarabine prodrugs. In this study, we have synthesized four different cytarabine prodrugs in order to increase the drug lipophilicity and the affinity of the prodrugs toward the biological membranes, as well as the lipophilic carriers. Differential scanning calorimetry was used to study the interaction of cytarabine and its prodrugs with multilamellar vesicles (MLVs) made of dimyristoylphosphatidylcholine (DMPC) and used as a model of biomembranes as well as a lipophilic carrier. The results showed that the 4-N-acetyl-2′,3′-5′-acetyl derivative and the prodrug with short chain fatty acids do not have a significant affinity with MLVs, whereas the prodrugs with long chain fatty acids have a stronger affinity with the MLVs with respect to cytarabine. The entity of the affinity depends on the fatty acids length. The increased affinity could be due to the fatty acid moieties which allow the molecule to insert among the phospholipid molecules. These results provide information on the interaction of these prodrugs with biomembranes and could be useful to design liposomes as carriers for the prodrugs.

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Funding

Authors thank financing to the University of Antioquia (Project CODI CIQF-155 2012-2014, Strategy of Sustainability 2014-2015).

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Correspondence to Maria Grazia Sarpietro.

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Berrio Escobar, J.F., Marquez Fernandez, D.M., Giordani, C. et al. DSC studies on the interaction of lipophilic cytarabine prodrugs with DMPC multilamellar vesicles. J Therm Anal Calorim 138, 2759–2767 (2019). https://doi.org/10.1007/s10973-019-08780-x

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Keywords

  • Cytarabine
  • Prodrugs
  • DSC
  • Biological membranes
  • DMPC