Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756268
Title: Cyclodextrin-based formulations for pulmonary delivery of chemotherapeutic molecules
Author: Binti Mohtar, Noratiqah
ISNI:       0000 0004 7429 2210
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Abstract:
This study investigated cyclodextrin-based formulations for the delivery of fisetin (a flavonoid) and erlotinib (a tyrosine kinase inhibitor) to the lung. In the first part of the study, complexation of fisetin with β-cyclodextrin (β-CD) and its derivatives, namely hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was conducted. Complexation efficiency between fisetin and the cyclodextrins was in the order: SBE-β-CD > HP-β-CD > β-CD. Utilisation of 20%v/v ethanol during complexation with SBE-β-CD improved the solubilisation of fisetin 5.9-fold compared to using water alone. Spray-drying of the fisetin-SBE-β-CD complex from 20%v/v ethanol feed solution, produced a powder with a 2-fold increase in the fine particle fraction (FPF) compared to the spray-dried powder produced from a feed solution containing water alone, when characterised using the Next Generation Impactor (NGI). Addition of 20%w/w leucine into the powder produced from the ethanolic feed solution further improved the FPF by 2.3-fold compared to the powder without leucine. The preparation showed an unchanged cytotoxic activity of fisetin against the human lung adenocarcinoma (A549) cell line, when compared to fisetin solution. In the second part of the study, combinations of fisetin with three tyrosine kinase inhibitors (i.e. erlotinib, gefitinib, crizotinib) were evaluated for their cytotoxic activity against the A549 cell line. Combination of erlotinib and fisetin at 1: 2 molar ratio, showed the highest synergism in cell killing, when analysed using the median effect principle method. This combination was then used to form a complex with SBE-β-CD. Further improvement in the solubility of erlotinib and fisetin, was achieved with the addition of 50%v/v ethanol during complexation, compared to using water alone. The complex solution was lyophilised and reconstituted into a 3-times more concentrated preparation, prior to nebulisation into the NGI. The preparation showed a suitable aerosol size for inhalation of both drugs. In conclusion, cyclodextrin-based formulations in the form of a dry powder inhalation and nebuliser solution, showed promise for pulmonary delivery of fisetin and its combination with erlotinib, respectively, in the treatment of non-small cell lung cancer (NSCLC).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.756268  DOI: Not available
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