A solid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′- difluorodeoxycytidine, a compound with potent, broad spectrum antitumor activity




Valdes Curiquen, Solange Alondra

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The strategy to improve the lipophilicity of gemcitabine by conjugation with a lipid (e.g. docosahexaenoic acid (DHA) or stearoyl acid) allows to prevent the deamination of gemcitabine by cytidine deaminase, main cause of gemcitabine degradation in vivo. In addition, this strategy may confer gemcitabine a strong antitumor activity compared to parental drug. 4-(N)-docosahexaenoyl 2´, 2´-difluorodeoxycytidine (DHA-dFdC) is a novel compound with strong in vitro and in vivo antitumor activity in several cancer models (e.g. pancreatic, breast, leukemia, and lung cancer). However, the toxicity of DHA-dFdC has not been tested in an animal model. In this dissertation, a preclinical short-term toxicity study to evaluate the tolerability of DHA-dFdC was performed in healthy DBA/2 mice. DHA-dFdC showed a dose-dependent toxicity, affecting mainly the spleen. The repeat-dose maximum tolerated dose (RD-MTD) of DHA-dFdC was 50 mg/kg. DHA-dFdC exhibits a strong efficacy at or below its RD-MTD in mouse models of pancreatic cancer or leukemia. Unfortunately, DHA-dFdC has two main issues, chemical instability and poor solubility in water. In this dissertation, a solid lipid nanoparticle (SLN) formulation of DHA-dFdC was developed to improve its chemical stability and water solubility. The SLN formulation improves the apparent water solubility of DHA-dFdC by 2.6-fold, as compared to a previously developed DHA-dFdC in Tween 80-ethanol-water solution. The SLN formulation as a lyophilized powder also improves the chemical stability of DHA-dFdC. In addition, DHA-dFdC-SLNs showed stronger antitumor activity than DHA-dFdC in Tween-ethanol-water solution in a mouse model when given intravenously. Finally, this dissertation demonstrates in a mouse model that the absolute oral bioavailability of DHA-dFdC in the DHA-dFdC-SLN formulation is 68%. It is concluded that the SLN formulation of the DHA-dFdC (i.e. DHA-dFdC-SLNs) improves the chemical stability of DHA-dFdC and increases its apparent water solubility, and the DHA-dFdC-SLNs can be administered intravenously or orally


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