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

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dc.contributor.advisorCui, Zhengrong
dc.contributor.committeeMemberGhosh, Debadyuti
dc.contributor.committeeMemberWilliams III, Robert O
dc.contributor.committeeMemberStavchansky, Salomon
dc.contributor.committeeMemberFinch, Rick A
dc.creatorValdes Curiquen, Solange Alondra
dc.creator.orcid0000-0003-0685-4886
dc.date.accessioned2021-03-19T22:53:10Z
dc.date.available2021-03-19T22:53:10Z
dc.date.created2018-08
dc.date.issued2018-09-13
dc.date.submittedAugust 2018
dc.date.updated2021-03-19T22:53:11Z
dc.description.abstractThe 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
dc.description.departmentPharmaceutical Sciences
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/2152/85047
dc.identifier.urihttp://dx.doi.org/10.26153/tsw/12017
dc.language.isoen
dc.subjectDHA
dc.subjectGemcitabine
dc.subjectRepeat dose-maximum tolerated dose
dc.subjectLethal-repeated dose
dc.subjectEfficacy
dc.subjectSolid lipid nanoparticles
dc.subjectTPGS
dc.subjectDHA-dFdC
dc.subjectAntitumor activity
dc.subjectPlasma pharmacokinetics
dc.titleA solid nanoparticle formulation of 4-(N)-docosahexaenoyl 2′, 2′- difluorodeoxycytidine, a compound with potent, broad spectrum antitumor activity
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentPharmaceutical Sciences
thesis.degree.disciplinePharmaceutical Sciences
thesis.degree.grantorThe University of Texas at Austin
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy

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