Thesis

Development of a non-ionic surfactant vesicles formulation of gemcitabine for pulmonary delivery

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Awarding institution
  • University of Strathclyde
Date of award
  • 2013
Thesis identifier
  • T13595
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Abstract
  • Lung cancer is a major cause of death in the world. Cancer chemotherapy is limited by adverse toxicities to normal tissues. Targeted delivery of anticancer drugs to lung cancer by inhalation would help to reduce these toxicities. Lipid based delivery systems have been shown to be effective in improving the delivery of a number of drugs and the potential of using non-ionic surfactant vesicles (NIV) to improve the delivery of Gemcitabine (Gem) was studied in this project. NIV were used to encapsulate Gem (Gem-NIV) for delivery by the pulmonary route. NIV were prepared using different concentrations of lipid (30, 60 and 150 mM) and characterised on the basis of size, drug entrapment efficiency and zeta potential. In vitro pulmonary delivery of Gem-NIV was compared with Gem solution using a multistage liquid impinger (MSLI). In vivo pulmonary delivery of Gem-NIV was also compared with Gem solution using two rodent models (Sprague-Dawley rats and BALB/c mice). The cytotoxicity of Gem formulations was assessed in in vitro studies using the B16-F0 luciferase melanoma cell line and in in vivo studies using lung cancer bearing BALB/c mice. Gem-NIV composed of 60 mM lipid exhibited the highest entrapment efficacy (80 ± 4%), nebulization efficiency (87 ± 6%) and physicochemical stability over a three-month period. Gem-NIV (60mM) were more effective at reaching the lower stages of the MSLI compared to Gem solution with significantly (P < 0.01) greater amounts of the drug being present in stage 1 and 2 of the MSLI, whereas Gem solution had a higher deposition in the mouth piece (P <0.01). In vivo drug delivery studies showed that there was a greater accumulation of Gem in the lungs of rats when administered as a NIV formulation prepared with 30 or 60 mM lipid at a dose of Gem of 15 or 6 mg/kg in comparison with free drug treatment. In lung cancer bearing mice, the Gem lung level was higher for Gem-NIV (60 mM) treated mice at dose 14 mg/ml (0.5ml) compared with the same dose of Gem solution. Gem-NIV prepared with 60 mM lipid were significantly (P < 0.01) more cytotoxic (IC50 0.87 ± 0.01 mg/ml) than Gem solution (IC50 4.45 ± 0.03 mg/ml) against the B16 F0 cell line. In this study, male mice had a significantly (P<0.05) higher severity of lung cancer than female mice according to lung weight data. On treatment with Gem-NIV (60 mM), a dose of 7 mg/ml was more effective in reducing the tumour burden in lungs than Gem solution in male BALB/c mice. The results of these studies indicate that Gem-NIV show significant potential to improve delivery of Gem for the treatment of lung cancer using pulmonary administration compared with Gem solution alone.
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DOI
Date Created
  • 2013
Former identifier
  • 1001989

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